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Current Respiratory Medicine Reviews, 2012, 8, 396-408

An Interventional Pulmonologist’s Tool: Endobronchial UltrasoundGuided Transbronchial Needle Aspiration (EBUS-TBNA) in Thoracic Disease – An Update Andrew R.L. Medford* North Bristol Lung Centre, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, Avon, UK Abstract: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive mediastinal staging tool for lung cancer but also a diagnostic tool for mediastinal lesions near the airway. This review focuses on the technique of linear probe EBUS-TBNA, clinical indications and utility, comparative factors with respect to other mediastinal sampling techniques; and training and financial issues. This review will be relevant to centres considering establishing an EBUS-TBNA service especially in healthcare systems which are resource-limited and rationed. EBUS-TBNA is commonly used for lung cancer staging and diagnosis, specifically non-small cell lung cancer (NSCLC). It is often used for both diagnosis and staging in the setting of bulky mediastinal lymphadenopathy with enlarged N2 or N3 disease on cross-sectional imaging, but is also used for diagnosis of unexplained mediastinal lymphadenopathy and lesions near the airway due to other (often non-malignant) causes. When there is radical treatment intent, many centres still perform cervical mediastinoscopy (CM) first line as the staging procedure and this should certainly be done to corroborate negative EBUS-TBNA results in this scenario or when the clinical probability of lung cancer is high. EBUSTBNA may be increasingly used in the future for staging when the “normal” (according to cross-sectional imaging) mediastinum and also in re-staging. It has a long learning curve requiring appropriate training and mentorship; it offers numerous advantages over CM including being less invasive and reducing operational costs. Long may it continue as one of the interventional pulmonologist’s main tools.

Keywords: Endobronchial ultrasound, interventional pulmonology, lung cancer, mediastinoscopy, mediastinum, thoracic oncology, transbronchial needle aspiration. INTRODUCTION

THE TECHNIQUE OF EBUS-TBNA

When lung cancer is suspected, patients require rapid staging and diagnosis. Currently, radiological cross-sectional anatomical and functional imaging (contrast-enhanced CT of the chest and upper abdomen with/without positron emission tomography (PET)) are used for radiological staging to determine whether treatment intent will be radical or palliative. CT and PET also guide further diagnostic workup specifically whether to sample the mediastinal lymph nodes or most distal (possibly metastatic) sites. Mediastinal lymph node metastases determine outcome and this has influenced staging algorithms and treatment practices from learned societies [1]. Surgical staging of the mediastinal nodes via cervical mediastinoscopy (CM) has been standard practice but this can access only lymph node stations 1-4 and 7 (see Fig. 1). CM does not access stations 5-6 (requiring anterior mediastinotomy or oesophageal endoscopic ultrasound-guided fine needle aspiration (EUSFNA)), stations 8-9 (requiring thoracoscopy or EUS-FNA) and stations 10-11 (requiring EBUS-TBNA). As such, lung cancer staging algorithms have evolved as EUS-FNA and EBUSTBNA have developed with updating of guidelines, for example in the UK [2].

EBUS-TBNA can be performed at the same time as conventional flexible bronchoscopy allowing sampling of mediastinal lymph nodes at stations 2-4, 7, 10-11 (see Fig. 1). The aorto-pulmonary window, para-aortic, paraoesophageal and pulmonary ligament lymph nodes (stations 5-6, 8 and 9, see Fig. 1) can be accessed by EUS-FNA. EBUS-TBNA uses ultrasound to image structures that are within and juxtaposed to the tracheobronchial wall in contrast to conventional transbronchial needle aspiration (TBNA). EBUS-TBNA (when using a linear probe) allows real-time visualisation of the needle in the target lesion throughout the sampling procedure.

*Address correspondence to this author at the North Bristol Lung Centre, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, Avon, UK; Tel: 44-1173235284; Fax: 44-1173232947; E-mail: [email protected] 1875-6387/12 $58.00+.00

Ultrasound Bronchoscope and Sedation The EBUS-TBNA bronchoscope uses chimeric technology of fibreoptics with ultrasound [3]. It has a larger external diameter (6.9 mm compared to 5-6 mm in most standard flexible bronchoscopes, see Fig. 2A) with a stiffer, more fragile and bulkier tip so that oral intubation is mandatory [4]. Intubation of the supine patient with the operator standing behind the patient is conventionally adopted and aids cross-correlation with cross-sectional imaging. Conscious sedation (midazolam and fentanyl being commonly used in the UK) is typically used as for conventional flexible bronchoscopy with the same monitoring but other EBUS-TBNA centres may use propofol © 2012 Bentham Science Publishers

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Fig. (1). Regional lymph node map. Reproduced with permission from: Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997; 111: 1718-23.

infusions with a laryngeal mask in situ. Additionally, the degree and extent of lymph node sampling and the patient population influence sedation mode [5-8].

image at an angled forward view of 90 degrees parallel to the EBUS-TBNA bronchoscope shaft. Colour flow (or Power Doppler) allows localisation of vascular structures and reduces the risk of vascular puncture (see Fig. 2C).

Ultrasound Probe

The frequency of the linear probe is relatively low at typically 7.5 megahertz (MHz) allowing good depth penetration of 9 cm but with less resolution (as compared to the higher 20 MHz frequency radial probe allowing better resolution but limited depth penetration of less than 5cm, see Fig. 3). The inflatable balloon around the ultrasound tip can be inflated if the image quality is poor (contact is improved

Linear (convex, see Fig. 2A, B) and radial (not discussed further) probes are available. Linear probes are the most commonly used and allow real-time sampling. The probe system provides an endoscopic image at an obliquely angled view of 30 degrees forward (see Fig. 2B) and an ultrasound

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by having a liquid interface between the ultrasound probe and airway wall) but this is seldom needed in the author’s experience.

Andrew R.L. Medford

Transbronchial Node Aspiration Real-time lymph node sampling is performed to optimise yield and safety (see Fig. 2C). Typically, a two person approach is used, although some centres use one person only. One experienced operator (the ultrasound bronchoscopist) is required to locate the node, align and maintain the optimal ultrasound view, and an assistant (typically a trained bronchoscopy nurse) to load/unload the needle apparatus and assist with the needle aspiration. The most distal lymph nodes are sampled first to prevent upstaging (ie, N3 nodes first). A 22-gauge or (more recently available) 21-gauge [9] EBUS-TBNA needle is used. This is sheathed (as with conventional flexible bronchoscopy biopsy forceps and cytology brushes, see Fig. 2A, B). After intubation, the needle sheath is positioned with the tip just visible (and secured) prior to manipulation of the needle to avoid working channel and optical fibre damage [3]. Before puncturing the airway wall, the stylet should be slightly withdrawn to allow “jiggling” (see later). The needle puncture depth is then adjusted and locked accordingly with the needle inside (up to 4 cm) having viewed the sonographic image, see Fig. 2C). As for conventional TBNA, a jabbing technique allows entry of the needle into the node. The internal stylet should be “jiggled” (advanced and withdrawn a small distance a few times) to remove occluding debris. Provided blood is not aspirated, the EBUSTBNA is performed using a 3-way vacuum syringe in place of the stylet. Additional material in the syringe should be sent for concurrent cytological analysis as well as the aspirate as this can be a diagnostic adjunct in the author’s experience. This is particularly helpful when aspirating mediastinal cyst fluid [10, 11]. To expel the sample from the needle, the needle is advanced and then the stylet is reintroduced (unless the lesion is a cyst). The stylet pushes the core of tissue out of the needle: a long serpentine cast signifies a good sample. Typically, 2 passes should be performed as standard (and are adequate if visible tissue cores are obtained [12]) at each lymph node station, although many centres perform 4 passes per node during their initial setup phase. In suspected benign disease or lymphoma in particular, more than 4 passes per node may be performed and a 21-gauge needle [9] may be used, although more recent data suggests cancer subtyping may also be superior too with the larger needle [13]. Specimen Handling

Fig. (2). (A, B) EBUS-TBNA has the (linear) ultrasound transducer at the distal end of the bronchoscope. The direct view is 30° to the horizontal. The biopsy needle is placed through the working channel, extending from the end of the bronchoscope at 20° to the direct view. (C) The linear ultrasound image (needle in a node) is a 50° slice, in parallel to the long axis of the bronchoscope (Doppler colour flow image shown in bottom half). Reproduced with permission from: Sheski FD, Mathur PN. Endobronchial ultrasound. Chest 2008; 133(1): 264-70. AO: aorta, LN: lymph node.

Specimen preparation will vary depending on the availability of a rapid on-site evaluation for cytology (ROSE) service. If ROSE is available, part of the sample is smeared onto glass slides and air dried for confirmation of adequacy (if technician-delivered [14]) or a diagnosis (if cytologist-delivered [15]). Due to rationing and cost, ROSE is not available in many centres but the slide method and fixing in alcohol is less cytodisruptive for granulomatous conditions than liquid cytology bottles [16-18]. Tissue cores are also put into formalin pots for histological analysis, immunostaining and mutation testing or saline depending on whether mycobacterial culture is required. A recent multicentre study has confirmed EBUS-TBNA samples with

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Fig. (3). Left: Radial probe placed in the working channel of bronchoscope but must be removed prior to sampling. Right: radial probe ultrasound image is 360 degrees to long axis of bronchoscope. Reproduced with permission from: Sheski FD, Mathur PN. Endobronchial ultrasound. Chest 2008; 133(1): 264-70. LN#3: lymph node.

immunostaining can provide adequate information for subtyping (77%) and genotyping (90%) [19]. CLINICAL INDICATIONS AND UTILITY The indications for EBUS-TBNA are staging and diagnosis (where not accessible otherwise) of NSCLC, diagnosis of other malignant or benign mediastinal lesions adjacent to the airway and for tissue banking for research purposes. It should be noted there is no literature on yield of EBUS-TBNA with respect to age or gender of patient in any of the conditions described. Staging Mediastinal node metastases in NSCLC influence resectability, prognosis and correlate with extra-thoracic metastases [20]. Node sampling is generally indicated for mediastinal lymph nodes greater than 1 cm diameter on CT short axis and/or metabolically “active” on PET (standard uptake value greater than 2.5 [21]) as radiological staging has its limitations [22] (although if radical treatment is planned, sampling of all accessible mediastinal nodes is standard practice as micrometastatic disease is detectable even in the radiologically “normal” mediastinum [23]). EBUS-TBNA can access lymph node stations 2-4, 7, 10-11 (see Fig. 1). Stations 5-6, 8-9 are not accessible but can be sampled by EUS-FNA. Some centres with relevant expertise offer a combined EBUS-TBNA/EUS-FNA service with a higher diagnostic yield compared to either procedure alone [23-27].

a subcarinal location (where there was no difference) were higher with radial EBUS (68.2% versus 33.3%). There are only two studies using the linear probe. A retrospective cytological single centre study of 262 samples comparing EBUS-TBNA with conventional TBNA favoured EBUS-TBNA with a lower non-diagnostic rate (8.7% versus 28.3%) and higher sensitivity (85.2% versus 54.5%) in lymph node samples although ROSE may have increased the yield in both arms [30]. A further study by Wallace et al. [24] compared the sensitivity of conventional TBNA, EBUS-TBNA and EUSFNA. All 3 procedures were performed as one combined, sequential procedure in 138 patients and all visible lymph nodes were sampled with the largest node being sampled at any given station. Malignancy was detected in 42 patients (30%), with a combination of surgical biopsy and clinical follow up at 6 to 12 months in patients that were combined procedure negative. EBUS-TBNA had a higher sensitivity than conventional TBNA, detecting 29 (69%) compared to 15 (36%) malignant lymph nodes (p =0.003). The negative predictive value of EBUS-TBNA was superior at 88% versus 78% for conventional TBNA. Subgroup analysis of patients with lymphadenopathy in areas thought better suited to sampling by conventional TBNA (subcarinal) still suggested superiority of EBUS-TBNA with a sensitivity of 68% (13/19) compared to 47% (9/19). The superiority of EBUS-TBNA over conventional TBNA is also reflected in a systematic review of mediastinal staging procedures, (90% sensitivity versus 78%) [1].

EBUS-TBNA Versus Conventional TBNA

EBUS-TBNA Versus CT and PET

The performance of EBUS-TBNA is superior to conventional TBNA although there are few comparative studies. In a comparative trial, EBUS-TBNA was superior to conventional TBNA at stations other than station 7 (84% versus 58% positivity in these stations) but this was with radial probe EBUS-TBNA [28]. A further randomised trial using radial probe EBUS versus conventional TBNA confirmed a superior yield for radial EBUS (66.7%) versus conventional TBNA (33.3%) [29]. Yields at nodes other than

EBUS-TBNA is superior to radiological staging (CT and PET scanning) in patients with an apparently “normal” radiological mediastinum, as micrometastases can occur even in clinical stage 1 disease [5, 31, 32]. For example, lesions under 10mm lower PET sensitivity and adenocarcinomas have lower PET activity but a higher rate of lymph node metastases so tissue is needed [33]. In the previously mentioned study by Wallace et al. [24], the sensitivity (69% versus 24% for PET and 67% for CT) and

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specificity (100% versus 53% for CT and 90% for PET) of EBUS-TBNA were superior to radiological staging. In a prospective trial of 102 patients, EBUS-TBNA achieved a superior sensitivity (92.3% versus 76.9% and 80.0% respectively for CT and PET), specificity (100% versus 55.3% and 70.1% respectively for CT and PET) and accuracy (98.0% versus 60.8% and 72.5% respectively for CT and PET) [31]. It should be noted the PET sensitivity may have been lowered further by the small nodal diameter (27% of the nodes had a short axis of only 5mm). Herth et al. [34] performed EBUS-TBNA in 100 patients with CT scans with no lymph nodes greater than 1cm in size (mean diameter 8.1 mm). All patients underwent surgical staging and results were compared. Malignancy was detected in 17 patients by EBUS-TBNA but not detected in 2 patients who were diagnosed surgically, yielding a sensitivity of 92.3%, negative predictive value of 96.3% and accuracy of 98.3%. Nineteen nodes were “normal” on radiological staging but positive on EBUS-TBNA leading to an upstaging of 19 patients. It should be noted some of the EBUS-TBNA procedures were done under general anaesthesia. Herth et al. [5] performed EBUS-TBNA followed by surgical staging (blinded to the EBUS-TBNA result) in patients with a normal mediastinum based on CT and PET in patients with suspected lung cancer. Malignancy was detected in 9 patients, 8 by EBUS-TBNA alone. The overall prevalence of mediastinal lymph node metastases in this population was 9% and the mean diameter of nodes small (less than 8mm). The determined sensitivity was 89%, negative predictive value 98.9% and accuracy 98.9%. EBUS-TBNA was performed via general anaesthesia, and this study did not evaluate the use of PET combined with CT which is now used in many institutions and reportedly superior to PET alone. Finally, the low mean nodal diameter may have contributed to the false negative PET findings. In another prospective study, Hwangbo et al. [32] performed EBUS-TBNA in 117 patients with potentially operable lung cancer with accessible nodes (5-20 mm diameter). The prevalence of lymph node metastases was 26%, with a superior sensitivity, negative predictive value and accuracy for EBUS-TBNA versus PET/CT, especially in adenocarcinoma (results were equivalent in squamous carcinoma). Szlubowski et al. [23] conducted a prospective trial of combined endosonography (EBUS-TBNA and EUS-FNA) in 120 lung cancer patients with normal size mediastinal nodes on CT. Negative results on endosonography were followed by bilateral transcervical extended mediastinal lymphadenectomy (TEMLA). The prevalence of mediastinal metastases was 22% with a higher sensitivity of combined endosonography than EBUS-TBNA alone. The diagnostic utility of CT/PET was not assessed in this study but even EBUS-TBNA via conscious sedation, without ROSE achieved a total sensitivity of 46%, NPV of 86% and accuracy of 87% with validation of results by TEMLA. EBUS-TBNA (unlike CT and PET) therefore can detect mediastinal micrometastases but the natural history of these are unknown and therefore the clinical relevance of this remains unclear but EBUS-TBNA should be considered in the radiologically normal mediastinum.

Andrew R.L. Medford

EBUS-TBNA Versus CM EBUS-TBNA has the ability to avoid CM. In a prospective cohort of 108 patients with suspected NSCLC, EBUS-TBNA performed with 95% sensitivity, 90% negative predictive value and 96% accuracy allowing 50 more invasive sampling procedures to be avoided [35]. No randomised controlled trials exist comparing EBUS-TBNA in isolation with CM, although one has compared combined endosonography added to CM (discussed later). The majority of studies are prospective case series in which cytology obtained which is positive for malignancy is taken as a definitive diagnosis (and not corroborated with surgical biopsy) assuming 100% specificity and 100% positive predictive value (PPV). Negative results are however assessed further with a variety of surgical staging or clinicoradiological follow up. An early study by Yasufuku et al. reported the results of EBUS-TBNA in 70 patients in whom malignancy was suspected or known with hilar or mediastinal lymphadenopathy on CT scan [36]. Malignancy was proven by this method in 45 patients, with 25 patients shown to be benign or inadequate sampling was obtained. These 25 patients were further investigated with clinical follow up in 4 patients, and an undetailed combination of surgery, thoracoscopy or CM in the remaining 21 patients. A further 2 patients were identified as having malignancy, ie) false negatives. Overall, the sensitivity of EBUS-TBNA was 95.7%, specificity 100% and accuracy 97.1%. This was a non-comparative study and used ROSE which may have increased the sensitivity. A similar small early UK study assessed the performance of EBUS-TBNA in 20 patients with similar inclusion criteria [25]. In 2 patients, TBNA was not performed based on EBUS appearances (benign looking nodes and less than 5mm in diameter). Subsequent surgical resection or clinicoradiological follow up confirmed these as benign. Eleven of the remaining 18 patients were shown to have malignancy. The 7 patients that were EBUS-TBNA negative went straight to thoracotomy, underwent CM with subsequent thoracotomy if negative, or underwent clinical follow up with repeat imaging. Overall 2 false negatives were identified, 1 of which was also negative at CM, and 5 true negatives yielding a sensitivity of 85%, specificity 100% and accuracy 89%. Two prospective controlled trials have attempted to compare cervical CM and EBUS-TBNA as diagnostic tests. Ernst et al. [37] performed EBUS-TBNA in 66 patients for clinically suspected NSCLC with technically resectable pulmonary lesions that were fit enough for surgery. All patients then underwent CM at the time of EBUS-TBNA, or 1 week later under general anaesthetic. Only patients with lymphadenopathy accessible to both modalities were included in the study. Patients that were both EBUS-TBNA and CM negative, or confirmed as having limited stage 3A disease with single station N2 disease proceeded to surgery which allowed further comparison. Diagnostic yield per patient was non-statistically higher for EBUS-TBNA (89% versus 79% for CM, p = 0.1). Sensitivity was superior per node: 87% versus 68%, as well as NPV, 78% versus 59%. There were no complications following EBUS-TBNA, compared to 2 cases of postoperative wound infection and 3

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episodes of prolonged bleeding following CM. It should be noted all EBUS-TBNA were performed under general anaesthesia and the analysis was largely presented relating to per nodal rather than per patient analysis. The second trial suggested equivalence of EBUS-TBNA and CM [38]. EBUS-TBNA and CM were performed concurrently in 153 patients. Surgical resection was then performed if still appropriate. There were 4 patients with metastases that were missed by both modalities, 3 of which had metastases in stations out of reach for either test. Seven patients were incorrectly staged by CM but correctly staged by EBUS-TBNA and 6 patients were incorrectly staged by EBUS-TBNA but correctly staged by CM. There were 8 false negative results generated by EBUS-TBNA compared to 14 for CM. Overall, sensitivity for EBUS was 81% versus 79% for CM, NPV 91% versus 90% and accuracy 93% for both, suggesting non-inferiority. No complications occurred with EBUS-TBNA, though a small proportion of patients that underwent CM experienced minor complications. It should be noted EBUS-TBNA was performed under general anaesthesia in a tertiary EBUS-TBNA centre, sampling nodes down to 5 mm in diameter in some cases (mean < 7mm) using different EBUS-TBNA needles at each different nodal locations, with the addition of ROSE and employing a systematic examination of the mediastinum in all cases; all these factors are not typical of EBUS-TBNA in other studies. The negative predictive value only increased by 5% when CM was combined with EBUS-TBNA compared to EBUSTBNA alone. The only current randomised controlled trial that evaluated CM with EBUS-TBNA combined this with EUSFNA as combined endosonography [27]. 241 patients were randomised to combined endosonography or CM. If patients were negative on combined endosonography for mediastinal metastases, they underwent CM prior to surgery, while patients in the CM alone arm proceeded straight to surgery if appropriate. If needed, left parasternal mediastinoscopy or video-assisted thoracoscopy was performed to sample abnormal lymph nodes (6 of 117 patients). Combined endosonography without surgical staging had an equivalent sensitivity to CM (85% versus 79%), which significantly improved to 94% when both procedures were combined (p = 0.02). Unnecessary thoracotomies occurred in significantly fewer patients in the endosonography group (9 versus 21 in the surgical arm, p=0.02). A further health economic study of the same trial demonstrated cost savings of £746 per patient in favour of EBUS-TBNA [39]. There are a number of caveats: EBUS-TBNA was not assessed alone, this was conducted done in tertiary endosonography centres using different sampling handling techniques in the different Table 1.

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centres. Despite the above, this trial provides the strongest evidence for EBUS-TBNA to replace CM as the “gold standard” for mediastinal staging, and questions the need for CM to be performed following negative endosonography in such expert centres. EBUS-TBNA (and EUS-FNA) has at least equivalent sensitivity to CM for staging NSCLC and superiority to conventional TBNA on the basis of pooled sensitivities from systematic reviews (see Table 1) [1, 40]. It should be noted that the apparent lower sensitivity for CM may be attributable to the lower disease prevalence in these studies. However, the negative predictive value of CM remains better than EBUS-TBNA (and EUS-FNA); i.e. when the pre-test clinical probability of malignancy is high, negative EBUSTBNA results should be corroborated with CM. The American College of Chest Physicians [1] advocate CM for mediastinal staging when radical treatment is proposed including single station N2 disease (since the lung cancer staging revision) [41], reserving EBUS-TBNA as a minimally invasive alternative to CM when there are localised enlarged multi-station N2 or discrete N3 nodes or bulky mediastinal adenopathy. EBUS-TBNA is also the investigation of choice for staging the hilar nodes which are not accessible to CM [42]. The UK guidelines from the National Institute of Clinical Excellence (NICE) recommend a more pragmatic graded approach to the choice of mediastinal staging technique according to the size of the mediastinal nodes [2]. Diagnosis EBUS-TBNA is used to make the diagnosis of lung cancers which have no endobronchially accessible component at flexible bronchoscopy (22% in one real world cohort of patients with suspected lung cancer, unpublished observations), other malignant nodes or masses in the mediastinum adjacent to the airway (including lymphoproliferative conditions), benign granulomatous disease and mediastinal cysts. In a recent multi-centre study, EBUS-TBNA had a high yield in patients with known extrathoracic malignancy and unexplained mediastinal lymphadenopathy [43]. Sensitivity, negative predictive value for malignancy, and overall accuracy for EBUS-TBNA were 87%, 73% and 88%. Many patients (68%) had a final diagnosis of malignant intrathoracic lymphadenopathy. Tuberculosis and Lymphoma Although not its original intention, EBUS-TBNA is increasingly being used in the diagnosis of intrathoracic

Relative Diagnostic Performance of Mediastinal Staging Techniques Based on Systematic Reviews [6, 11] Technique

Sensitivity

Negative Predictive Value

Prevalence (Range)

CM

78-81%

91%

39% (15-71)

Conventional TBNA

76-78%

71-72%

75% (30-100)

EBUS-TBNA

90%

76%

68% (17-98)

EUS-FNA

84-88%

77-81%

61% (33-85)

TBNA denotes transbronchial needle aspiration, EBUS-TBNA denotes endobronchial ultrasound-guided transbronchial needle aspiration, EUS-FNA denotes endoscopic ultrasoundguided fine needle aspiration.

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lymph node tuberculosis and lymphoma. According to a report by the Health Protection Agency, intrathoracic TB lymphadenitis (TBLA) accounts for around 20% of extrapulmonary TB in the UK and 9% of all cases [44]. Historically, CM or empirical anti-tuberculous therapy have been used as diagnostic options with the risk of suboptimal treatment of resistant organisms with the latter. A multicentre case series evaluated EBUS-TBNA in the diagnosis of intrathoracic TBLA in 156 patients [45]. In this cohort of patients, 10 following EBUS-TBNA were smear, culture and histology negative for TBLA. Four patients had CM proven TBLA and another 6 responded to empirical anti-tuberculous therapy yielding a sensitivity, positive predictive value and accuracy of 94%. One patient developed symptomatic bacteraemia. Thirty-eight patients were classified as TBLA with non-caseating granulomas but response to therapy, and a positive tuberculin skin test or interferon gamma release assay. However, it is possible that these patients had sarcoidosis that may have spontaneously improved. Treatment regimens for lymphoma traditionally require tissue cores for accurate subtyping. In the absence of more accessible lymph nodes, CM traditionally has been the usual diagnostic tool in this regard for evaluating mediastinal lymphoma. Steinfort et al. [46] evaluated EBUS-TBNA as the initial test for the evaluation of isolated mediastinal lymphadenopathy, with surgical biopsy or radiological follow up in non-diagnostic cases. Lymphoma was diagnosed in 16 patients. Of these patients 4 required a further surgical biopsy to subtype the lymphoma. In addition, a further 5 patients were identified by surgical biopsy alone where EBUS-TBNA had been non-diagnostic. The sensitivity for EBUS-TBNA for the diagnosis of lymphoma was 76%, adjusted down to 57% including where additional surgical biopsy was needed with a negative predictive value of 79%. It should also be noted that ROSE was used in this study. In a retrospective review of 25 patients, mediastinal lymphoma was diagnosed by EBUS-TBNA with 91% sensitivity and 93% predictive value in a population with lymphoma prevalence of 44% [47]. The importance of the sample size is further illustrated by the superiority of 1.15 mm mini-forceps biopsy over both cytology (22G) and histology (19G) gauge TBNA needles particularly for lymphoma (sensitivity 81% mini-forceps versus 35% combined TBNA) in 75 patients with 2.5 cm subcarinal lesions (not thought to be lung cancer) [48]. A more recent study using transbronchial needle forceps biopsy appears promising for suspected lymphoma [49]. In summary, EBUS-TBNA is useful in lymphoma but cytopathological expertise is required and this should probably not be currently the first line procedure here as a large tissue core is preferable. Sarcoidosis The diagnosis of sarcoidosis currently involves transbronchial lung biopsy (TBLB) for parenchymal and bronchocentric disease with endobronchial biopsy (EBB) in the latter but TBLB is frequently non-diagnostic and carries a risk of pneumothorax and bleeding. Thoracic adenopathy is often present in sarcoidosis which may also be amenable to conventional TBNA, but CM traditionally would be the gold

Andrew R.L. Medford

standard investigation adenopathy.

for

undiagnosed

mediastinal

EBUS-TBNA may improve the diagnostic yield further in sarcoidosis. This has been suggested by two feasibility studies and one prospective study that combined EBUSTBNA with TBLB +/- EBB [50, 51]. Navani et al. [50] evaluated EBUS-TBNA followed by sequential TBLB and EBB in 40 patients with stage 1 and 2 sarcoidosis. The sensitivity was for sarcoidosis for significantly higher in EBUS-TBNA (85%) versus TBLB and EBB combined (35%) although combining all techniques improved sensitivity to 93%. Plit et al. performed EBUS-TBNA followed by sequential TBLB and EBB in a similar number of similar patients [51]. EBUS-TBNA had a significantly higher diagnostic accuracy (83%) than EBB (27%), although not superior to TBLB (78%). Oki et al. [52] performed EBUS-TBNA followed by TBLB in 62 patients with stage 1 and 2 sarcoidosis. The mean diagnostic yield for EBUSTBNA was superior to TBLB (94% versus 37%) for both stages, with 1 pneumothorax and 3 bleeds from TBLB demonstrating the risks of this procedure. A large multicentre prospective study of 136 patients evaluated combined endosonography (EBUS-TBNA +/EUS-FNA) in 80 patients with negative results from flexible bronchoscopy (including conventional TBNA, TBLB and EBB) [53]. Where combined endosonography was nondiagnostic, surgical biopsy was performed: CM, videoassisted thoracoscopic or open lung biopsy. Conventional bronchoscopy led to a diagnosis of sarcoidosis in 45% of patients, with combined endosonography providing a diagnosis in an additional 39% compared to an additional 25% for EBUS-TBNA alone. These data do suggest combined endosonography may be of more value than EBUS-TBNA alone although information on nodal stations sampled was not included and 17% of patients were stage 34 sarcoidosis indicating a slightly different case mix to other similar studies. In the only randomised control trial to date evaluating the use of EBUS-TBNA in the diagnosis of sarcoidosis, 50 patients with clinically suspected sarcoidosis and mediastinal or hilar adenopathy were recruited and randomised to receiving conventional 19 gauge TBNA or EBUS-TBNA [54]. The clinician and pathologist were blinded to the sampling method and sample type. The diagnostic yield for EBUS-TBNA (83.3%) was superior to conventional TBNA (53.8%), an absolute increase of 29.5% (95% CI 8.6-55.4%, p25 mm) central nodal disease, conventional TBNA is a reasonable alternative to EBUS-TBNA (where the latter is unavailable). However, EBUS-TBNA results in a longer more contiguous tissue core, and is superior especially at more distal stations, and for all smaller nodes. The cost saving potential for EBUS-TBNA is far greater than for conventional TBNA as it can avoid a far greater number of mediastinoscopies and this can offset the higher capital and running costs. Where EBUS-TBNA is not available, conventional TBNA can be utilised as first line for those with central bulky mediastinal disease. If EUS-FNA is not available too, EUS-B-FNA is an alternative adjunct to EUSB-FNA which is also cost saving too if the expertise is available locally.

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mediastinoscopies and improving thoracic surgery capacity. In the absence of an EBUS-TBNA service, conventional TBNA should still be performed especially in patients with bulky central mediastinal lymphadenopathy where it has a good yield. In the future, centres may seek to develop a combined EBUS-TBNA/EUS-FNA service giving access to all the nodal stations (or develop concurrent EUS-B-FNA if EUS-FNA is not available) and EBUS-TBNA may have an increasing role in assessing airways and pulmonary vascular disease. CONFLICT OF INTEREST The author confirms that this article content has no conflicts of interest. ACKNOWLEDGEMENTS Declared none. DISCLOSURES Part of the information included in this review article has been previously published in Current Respiratory Medicine Reviews, Volume 6, Number 2, May 2010, pp. 133-141(9). REFERENCES [1]

[2]

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CONCLUDING REMARKS EBUS-TBNA is indicated for NSCLC mediastinal staging and also diagnosis of malignant and benign mediastinal nodes and masses or cysts accessible from the airway, including sarcoidosis, tuberculosis and lymphoma. EBUS-TBNA provides a minimally invasive alternative to CM with equivalent sensitivity although its negative predictive value is inferior at the current time so that a negative EBUS-TBNA result should be confirmed with CM if the clinical suspicion of malignancy is high. In scenarios where radical treatment is contemplated, CM remains the preferred current mediastinal staging tool although practice varies widely. Indeed, recent studies have demonstrated the potential of EBUS-TBNA in the radiologically normal mediastinum. In tertiary EBUS-TBNA centres, this modality is increasingly being used first line ahead of CM. EBUSTBNA may also be used as the primary re-staging technique. There is a learning period for even experienced conventional bronchoscopists. The capital and running costs should be thoroughly considered before setting up a service although EBUS-TBNA is cost-saving by avoiding

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Medford AR, Agrawal S, Free CM, Bennett JA. Retrospective analysis of Healthcare Resource Group coding allocation for local anaesthetic video-assisted 'medical' thoracoscopy in a UK tertiary respiratory centre. QJM 2009; 102(5): 329-33.

Received: August 29, 2012

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Medford AR. Interventional procedures: physician involvement enhances clinical coding. Clin Med 2012; 12(4): 396. Pillai A, Medford AR. Does greater physician involvement with interventional procedure coding improve coding outcome? Thorax 2011; 66(Suppl 4): A143-4.

Revised: October 16, 2012

Accepted: October 17, 2012