Mediastinal staging procedures in lung cancer: EBUS, TBNA and mediastinoscopy Andrew R.L. Medford, Jonathan A. Bennett, Catherine M. Free and Sanjay Agrawal Department of Respiratory Medicine, Allergy and Thoracic Surgery, Institute for Lung Health, Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester LE3 9QP, Leicestershire, UK Correspondence to Dr Andrew R.L. Medford (Interventional Pulmonology Fellow), Department of Respiratory Medicine, Allergy and Thoracic Surgery, Institute for Lung Health, Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester LE3 9QP, Leicestershire, UK Tel: +44 1162502766; fax: +44 1162502787; e-mail: andrew.medford@uhl-tr.nhs.uk Current Opinion in Pulmonary Medicine 2009, 15:334–342
Purpose of review There is increasing awareness of minimally invasive endoscopic techniques for mediastinal staging in lung cancer. Traditionally, cervical mediastinoscopy has been utilized. Endobronchial ultrasound-guided fine needle aspiration (EBUS) has recently emerged as a potential alternative. Recent findings EBUS has sensitivity for lung cancer which is at least equivalent (if not superior) to cervical mediastinoscopy. However, cervical mediastinoscopy remains superior to EBUS and other techniques in its high negative predictive value. More recent data suggest EBUS may have a role in presurgical staging of radiologically normal subcentimetre nodes and its negative predictive value may be equivalent to surgical staging. Ongoing comparative studies between EBUS and cervical mediastinoscopy may well clarify relative performance and cost analyses. Summary Currently, insufficient data are present to recommend replacing cervical mediastinoscopy with EBUS for lung cancer staging; the negative predictive value of EBUS requires validation. However, EBUS can be recommended for initial staging as a minimally invasive option provided negative results are followed by cervical mediastinoscopy. This would also allow cervical mediastinoscopy to be reserved for restaging. Conventional transbronchial needle aspiration has a limited role only as a firstline staging procedure but may aid diagnosis. In the future, EBUS may have a role in presurgical staging of the radiologically normal mediastinum and re-staging if prior staging is done by cervical mediastinoscopy. Keywords endobronchial ultrasound, lung cancer, mediastinal staging, mediastinoscopy, transbronchial needle aspiration Curr Opin Pulm Med 15:334–342 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 1070-5287
Introduction Patients with suspected lung cancer require accurate staging and diagnosis to determine optimal treatment. In the absence of distant metastases, mediastinal lymph node staging is pivotal to determining treatment. Noninvasive radiological staging can provide guidance to assess how best to obtain a tissue diagnosis and assess metastatic spread in one visit. Mediastinal nodal sampling is often necessary and has traditionally been performed by cervical mediastinoscopy or anterior mediastinotomy. However, with the advent of endoscopic needle aspiration techniques such as endobronchial ultrasound (EBUS) to guide transbronchial needle aspiration (TBNA) and endoscopic ultrasound (EUS), the diagnostic algorithm for lung cancer is evolving. This review will consider the utility of EBUS, TBNA and cervical 1070-5287 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
mediastinoscopy in the light of more recent studies with particular reference to lung cancer staging (EUS is not considered here and the reader is directed to other recent reviews on this topic [1]).
Mediastinoscopy Surgical (cervical) mediastinoscopy has traditionally been the gold standard invasive mediastinal staging tool for the management of nonsmall cell lung cancer (NSCLC). Technique
Cervical mediastinoscopy is usually performed in an operating theatre under general anaesthesia and may require overnight admission (mean length of stay 1.5 days in a UK tertiary centre, unpublished data). It is timeconsuming (average 2 h 24 min in one tertiary UK centre). DOI:10.1097/MCP.0b013e32832b8a45
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Mediastinal staging Medford et al. 335
An incision is made just above the suprasternal notch and the mediastinoscope is inserted adjacent to the trachea to view and biopsy the accessible mediastinal nodes. Performance
Cervical mediastinoscopy has been the standard investigation of choice for mediastinal staging and can sample nodal stations 1–4, 7 but not stations 8–12 (see Fig. 1). Stations 5–6 can be accessed via an anterior mediastinotomy and stations 8, 9 by video-assisted thoracoscopic approach (see Fig. 1). Cervical mediastinoscopy is viewed as the gold standard for mediastinal nodal assessment with a pooled diagnostic sensitivity of 78–81% (superior to conventional TBNA but inferior to EBUS and EUS) in two recent systematic reviews (see Table 1). However, the sensitivity and specificity of a procedure is influenced by the disease prevalence and in the analysed studies, lung cancer prevalence was markedly lower in the cervi-
cal mediastinoscopy studies which may have contributed to its lower sensitivity (see Table 1). Importantly, cervical mediastinoscopy has a negative predictive value of 91% which is superior to that of endoscopic techniques thus far (see Table 1) [2,3]. Cervical mediastinoscopy is more invasive than endoscopic techniques and results in a neck scar which may be cosmetically unacceptable to some patients. It does have a 2% risk of morbidity (see Table 1) [4] and 0.08% mortality [3]. Video mediastinoscopy
Video mediastinoscopy allows better visualization and a more complete dissection of nodal tissue than cervical mediastinoscopy [3]. A recent retrospective analysis of the two techniques revealed a lower incidence of recurrent laryngeal nerve palsies (2.1 versus 3.0%) and postoperative bleeding with video mediastinoscopy (0.9 versus 2.3%) [5 ]. The number of nodes sampled
Figure 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– 1723.
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336 Neoplasms of the lung Table 1 Comparative diagnostic performance of mediastinal techniques, based on data from systematic reviews [2,3] Technique Cervical mediastinoscopy
Conventional TBNA EBUS EUS
Nodes 1–4, 7a
Risks
Sensitivity
Negative predictive value
Prevalence (range)
0.08% mortality and 2% morbidity: arrhythmias [4], haemorrhage, thoracic duct injury, recurrent laryngeal nerve injury, pneumonia, bronchial/pleural laceration [3]
78–81%
91%
39% (15–71)
76–78% 90% 84–88%
71–72% 76% 77–81%
75% (30–100) 68% (17–98) 61% (33–85)
2, 4, 7,11 2–4, 7, 10–12 5–9
EBUS, endobronchial ultrasound; TBNA, transbronchial needle aspiration. a Nodes at station 5,6 accessible via anterior mediastinotomy and 8,9 via thoracoscopic approach.
was also higher with video mediastinoscopy (8.1 versus 6.0 nodes). Accuracy compared to lymphadenectomy via thoracotomy was 87.9 versus 83.8%, slightly favouring video mediastinoscopy, with negative predictive values also slightly better for video mediastinoscopy (83 versus 81%, respectively). This supports existing studies which show a higher sensitivity for video mediastinoscopy (86–93%) over the conventional version (81%) [6–8]. A recent retrospective review of video mediastinoscopy showed the diagnostic utility varied according to the disease prevalence for malignancy; a 93.6% diagnostic sensitivity was achieved for undiagnosed mediastinal lesions (malignancy prevalence 45.1%) compared to a sensitivity of 80.9% for N2 metastases in patients all with known lung cancer [8]. Re-staging
Re-mediastinoscopy is technically more difficult after downstaging with induction chemotherapy or chemoradiotherapy because of adhesions and fibrotic change from the initial cervical mediastinoscopy and induction treatment. Its performance is inferior varying from 29% sensitivity in the only prospective study [9] to 70–73% in two retrospective studies [10,11]. The inferior performance in the prospective study may be due to the more extensive initial cervical mediastinoscopy causing more adhesions and fibrosis, a higher presence of multilevel N2 disease and its prospective design. There is some evidence that video mediastinoscopy might be superior to cervical mediastinoscopy in this setting. Lardinois et al. [6] achieved a re-mediastinoscopy sensitivity of 81% in patients after induction treatment which compares favourably to expected sensitivities for Lardinois in patients prior to any treatment [2].
Transbronchial needle aspiration Conventional (blind) TBNA has been long established as a minimally invasive adjunct for sampling patients with bulky subcarinal and paratracheal nodes for diagnostic and staging information at the same time as fibreoptic bronchoscopy.
Technique
Transbronchial needle aspiration is performed under local anaesthesia with sedation as required as a day case procedure in the endoscopy suite. It is a well tolerated procedure with no additional risks to a standard fibreoptic bronchoscopy. In reality, it is most often used to sample nodes at station 7, although stations 2 and 4 can also be sampled but these are technically more challenging due to the angulation of the scope required. Conventional TBNA is operator-dependent and requires thorough appreciation of mediastinal anatomy and accurate correlation with the staging CT scan without the assurance of real-time ultrasound sampling as in EBUS. Typically a 20-gauge to 22-gauge cytology needle is used, although a 19-gauge histology needle can be used. The hub must be locked outside the scope to avoid extrusion of the needle into the scope. A variety of techniques are used to insert the needle into the node including coughing, jabbing and piggyback methods; it is important to keep the angle between the needle and the airway wall at greater than 45 degrees. Typically, four passes are taken per node. Samples can either be smeared onto slides with alcohol or put into liquid cytology medium if rapid on-site cytology is not available. Staging
Two recent systematic reviews have confirmed that conventional (blind) TBNA is inferior to surgical techniques for mediastinal staging (pooled sensitivity 76–78% and negative predictive value 71–72%) (see Table 1) [2,3]. This can be explained by the fact that conventional TBNA is a blind technique, accessing limited nodal stations, and requires larger nodal size for safe sampling. Studies of TBNA in mediastinal staging are hampered by the fact that most have not confirmed positive TBNA results with surgical staging (a mean false-positive rate of 0.7% has been noted in those that have [12–14]) and the patients have generally been those with bulky N2–3 disease. Diagnosis
Transbronchial needle aspiration, however, remains a valuable diagnostic adjunct. A recent retrospective
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Mediastinal staging Medford et al. 337
review of 363 patients with suspected malignancy (191 undergoing TBNA) in real clinical practice has confirmed its added value in improving the combined diagnostic yield at bronchoscopy with endobronchial biopsy over and above either technique alone (even including brush biopsies and lavage) [15]. Moreover, Stratakos et al. [16 ] have recently demonstrated the added diagnostic utility of obtaining histology specimens via TBNA using a 19gauge needle, increasing the yield by over 35% versus cytology alone, giving a sensitivity of 88% with a negative predictive value of 58% in 77 patients with CT evidence of enlarged nodes (lymph node metastases prevalence 86%).
Figure 2 Linear endobronchial ultrasound
Learning
Recent evidence regarding learning curves and conventional TBNA is conflicting. Goldberg et al. [17] have recently illustrated the benefits of training on a lo-fidelity model of porcine tracheobronchial tree attached to a Leardal Airway Model in improving dexterity with TBNA techniques to TBNA bronchoscopists of varying experience. However, experienced bronchoscopists alone showed no evidence of a learning curve for TBNA in another recent study: Hermens et al. [18 ] demonstrated no significant difference in TBNA yield (77–82%) with learning time or lymph node location, although yield was dependent on lymph node size (mean 22 mm).
Endobronchial ultrasound Endobronchial ultrasound has been evaluated as a mediastinal staging and more recently as a re-staging tool but also has a role in diagnosis of malignancy and benign mediastinal and parabronchial masses. Technique
Endobronchial ultrasound is a procedure similar to conventional TBNA: it is a day case procedure using local anaesthesia and sedation with a similar gauge needle, sampling handling technique using four passes per node and similar or superior safety profile. There are, however, a few differences. The patient is intubated orally from behind due to the larger external diameter of the EBUS bronchoscope (6.9 versus 4.9–5.1 mm in a standard bronchoscope; see Fig. 2). In general, the linear-type ultrasound probe (see Fig. 2) is most commonly used for real-time imaging; the radial ultrasound probe is less commonly used for assessing airway wall invasion to consider endoluminal therapies such as photodynamic therapy. Other rarer applications of EBUS include guidance of endobronchial therapy and aiding transbronchial lung biopsy [19 ]. A balloon sheath is around the ultrasound tip; this can be inflated with water if image quality is poor by improving contact between the ultrasound probe and airway wall but
(a and b) Linear EBUS has the ultrasound transducer at the distal end of the bronchoscope. The direct view is 308 to the horizontal. The biopsy needle is placed through the working channel, extending from the end of the bronchoscope at 208 to the direct view. (c) The linear ultrasound image (needle in a node) is a 508 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):264–270. AO, aorta; EBUS, endobronchial ultrasound; LN, lymph node.
typically this is not needed, although it is good practice to have the balloon mounted before starting. The needle apparatus system is more robust and real-time sampling
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338 Neoplasms of the lung
of nodal stations 2–4, 7, 10–12 is possible (see Fig. 1). The highest stage nodes are sampled first (i.e. N3) to prevent upstaging by contamination. Finally, the standard view is 30 degrees forward oblique which requires readjustment (see Fig. 2), and only the proximal tracheobronchial tree can be examined endobronchially due to the larger external diameter. Therefore, a second standard bronchoscopy is required for endobronchial biopsies if clinically indicated. Advantages of endobronchial ultrasound over cervical mediastinoscopy
Potential advantages over surgical staging include access to the hilar nodes, less risk of morbidity, local anaesthesia and a day case procedure, the absence of a neck scar, less healthcare costs and the potential to streamline thoracic surgical capacity. When combined with EUS (not reviewed here), all the key nodal stations can be sampled by minimally invasive techniques. Endobronchial ultrasound versus cervical mediastinoscopy: comparative studies
There have been very few comparative studies on cervical mediastinoscopy and EBUS (see Table 2). Existing data are not consistent. A recent prospective cross-over trial of 66 patients compared the two techniques in patients with suspected NSCLC [20 ]. The disease prevalence was high at 89% and the diagnostic yield was significantly in favour of EBUS over cervical mediastinoscopy (91 versus 78%). Discordance between the two techniques occurred at station 7. The sensitivities and negative predictive values were also in favour of EBUS over cervical mediastinoscopy (see Table 2). There were, however, no significant differences in determining true N status, although suggesting superiority for EBUS (93 versus 82%). There is another ongoing study (due for final publication in 2009) evaluating EBUS versus cervical mediastinoscopy for nodal staging of patients with suspected or confirmed lung cancer [21]. Initial data for 33 patients revealed a lower sensitivity and slightly inferior negative predictive value for EBUS (see Table 2) with similar accuracies (90.9 versus 93.9% for EBUS and cervical
mediastinoscopy, respectively). The prevalence of N2 or N3 disease was lower at 39.4% and EBUS visualized 4.4 nodes per patient and then sampled 3.4 nodes per patient (versus 4.0 nodes per patient for cervical mediastinoscopy). Importantly, three patients were upstaged by cervical mediastinoscopy from N0 (on EBUS) to N2, indicating it may not completely replace cervical mediastinoscopy. The results of a further randomized multicentre controlled trial of EBUS and EUS versus cervical mediastinoscopy (ASTER trial) should be available in 2012 [22]. Available data suggest EBUS may indeed reduce the number of cervical mediastinoscopy procedures but the variability in performance in these two studies may relate to the significant variation in disease prevalence. When disease prevalence is high, existing data favour EBUS but when it is moderate then cervical mediastinoscopy appears superior. Endobronchial ultrasound versus conventional transbronchial needle aspiration: comparative studies
Using real-time guidance ensures safety and theoretically improves diagnostic utility compared to conventional TBNA. Systematic reviews confirm this with a superior sensitivity of EBUS compared to conventional TBNA (90 versus 76–78%) and superior negative predictive value (76 versus 71–72%) [2,3]. Studies assessing EBUS have generally involved patients with discrete nodal enlargement and greater than 2 cm nodal size [23–25]. Endobronchial ultrasound staging
Szlubowski et al. [26 ] evaluated EBUS in a recent prospective cohort study of patients with similar discrete nodal enlargement and revealed a sensitivity of 89% with a negative predictive value of 84% in patients with a prevalence of lymph node metastasis of 53%. This study employed transcervical extended bilateral mediastinal lymphadenectomy as a more rigorous evaluation of negative EBUS results. The negative predictive value, although better than systematic reviews, is inferior to surgical staging and reinforces the need for surgical clarification of negative EBUS results at the present time. It should be noted that this study used a more rigorous surgical technique, making comparison between EBUS and standard surgical staging difficult here.
Table 2 Comparative studies: endobronchial ultrasound versus cervical mediastinoscopy Sensitivity Study Ernst et al. [20 ] Yasufuku et al. [21]
Number 66 33
a
Design; criteria Prospective cross-over trial; suspected NSCLC Prospective controlled trial; suspected or confirmed NSCLC
EBUS 87% 76.9%
Cervical mediastinoscopy 68% 84.6%
Negative predictive value EBUS 78% 85.9%
Cervical mediastinoscopy 59% 90.4%
Prevalence 89% 39.4%
EBUS, endobronchial ultrasound; NSCLC, nonsmall cell lung cancer. a Ongoing recruitment, negative predictive values calculated from original data in abstract publication.
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Mediastinal staging Medford et al. 339
Endobronchial ultrasound staging and positron emission tomography
Bauwens et al. [27 ] recently demonstrated the potential value of EBUS in collaboration with positron emission tomography (PET) and use of EBUS in staging of PET hot spots (prevalence 58%) with a sensitivity of 95% and negative predictive value of 91% even for relatively small nodes (mean diameter 14 mm) and without rapid on-site cytopathology. Indeed, significant differences in standard uptake value (SUV) with PET between EBUS-positive and EBUS-negative nodes were seen (10.0 versus 3.7), leading to the possibility that a threshold PET SUV may help refine the utility of EBUS. Herth et al. [28 ] recently demonstrated an impressive sensitivity (89%) for EBUS in suspected malignancy in lymph nodes (mean diameter 8 mm ranging between 5 and 10 mm) in patients with normal radiological staging by CT and PET. The negative predictive value was impressive at 99% (but may partially be explained by the low prevalence of nodal metastases of 9%) but these data suggest that EBUS could have a role in presurgical staging. Further studies are required both to corroborate the impressive negative predictive value which is superior to that of conventional surgical staging and to verify the potential benefits of diagnosing micrometastases in patients with normal radiological staging. Learning curve
Koh et al. [29 ] recently demonstrated the short learning curve of EBUS with moderate results in staging utility from 38 patients with discrete nodal enlargement in a centre just setting up the service: sensitivity 83%, negative predictive value 67%, lymph node metastasis prevalence 75%; these latter results are similar to those of another series describing their experience in their first 20 cases with sensitivity 85%, negative predictive value 70%, prevalence of nodal metastasis 70% [30]. Technical aspects
Recent data suggest a minimum of three passes is required for EBUS nodal staging unless a reasonable tissue core is obtained, in which case two passes are sufficient [31 ]. The sensitivity (91–95%) and negative predictive values (96–7%) obtained using these two paradigms are impressive considering no rapid on-site cytology was used, although the prevalence of nodal metastases was lower (31%) than in other studies and negative results were not all confirmed surgically. Rapid on-site cytology improves utility of fine needle aspiration (FNA) techniques [32]; in particular the presence of 40 lymphocytes per high power field and tingible macrophages is a good predictor of accuracy to maintain specificity and accuracy of true negative samples, although this is time-consuming and a resource issue [33 ].
Miscellaneous applications
Recent studies highlight the potential value of guidance systems with a guide sheath, although this may be of more value for peripheral pulmonary lesions [34]. The ability of EBUS to stage the mediastinum can also have other potential benefits, including aiding selection for benefit from metastectomy demonstrated in a recent study showing a sensitivity of 92% and negative predictive value of 95% for EBUS (prevalence of nodal metastasis 22%) [35], as well as serendipitous diagnosis of synchronous primary lung cancer after intended nodal staging which may alter treatment [36]. EBUS may offer an alternative to cervical mediastinoscopy in re-staging which is technically difficult because of adhesions and fibrosis partially related to initial surgical staging. Herth et al. [37 ] obtained a sensitivity of 76% with EBUS for re-staging which compares favourably to surgical re-staging results in a retrospective study without CT-PET. Importantly, the negative predictive value was only 20% (prevalent of nodal metastases 94%) possibly due to sampling error due to fibrotic nodal change, reinforcing the need for surgical staging after negative EBUS results. All patients underwent systematic lymph node dissection at thoracotomy. Endobronchial ultrasound also offers a minimally invasive tool with which to provide lymph node tissue for analysing cell-cycle proteins and providing prognostic information as well as staging with p53 overexpression, predicting a poor response to chemotherapy in a recent retrospective study of 36 NSCLC patients using rapid onsite cytopathology [38 ]. Recent data suggest EBUS may have a role in diagnosis of lymphoma and paratracheal tumours. EBUS diagnosed lymphoma in a recent retrospective study of 25 patients with sensitivity 91% and negative predictive value 93% (prevalence of disease 44%) using rapid on-site cytopathology [39]. EBUS also had a sensitivity of 94% for diagnosis of paratracheal and parabronchial tumours (prevalence of disease 91%) with a negative predictive value of 33% in a further retrospective study [40]. Cost analysis of endobronchial ultrasound
The cost-effectiveness of EBUS has not yet been formally evaluated. Data are available for EUS which demonstrated a cost reduction of 40% per patient by decreasing the number of surgical staging procedures (by 62%) in a prospective study of patients with mediastinal or upper retroperitoneal PET positive nodes with known or suspected lung cancer [41]. Wallace et al. avoided 28% of their patients undergoing cervical mediastinoscopy in a recent study using combined EBUS and EUS staging [42 ]. Three more recent EBUS studies have demonstrated avoidance of other procedures from between 30 and 56%. Cervical mediastinoscopy procedures were avoided in 43% of 152 patients in a
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340 Neoplasms of the lung
retrospective study (prevalence of lung cancer 59%) with a primary lung mass or undiagnosed mediastinal adenopathy, using rapid on-site cytopathological examination [43]. Cervical mediastinoscopy procedures were avoided in 30% and CT-guided lung biopsies in 47%, respectively, of 60 patients with suspected central primary lung cancer (prevalence of lung cancer 77%) [44]. Surgical staging was avoided in 56% of patients using EBUS to assess hot spots on PET in 106 patients (prevalence of nodal disease 58%) [26 ]. A recent conventional TBNA study demonstrated avoidance of surgical staging procedures in 79% of patients but this percentage is unlikely to be reproducible as this was a small retrospective study of preselected patients with high prevalence of nodal metastases using rapid on-site cytology and PET–CT [45]. The approximate cost of EBUS equipment ranges from $43 000 (£27 500) for an Olympus ultrasound probe and radial transducer to $100 000 (£63 900) for a linear probe EBUS bronchoscope and linear processor; the EBUS needle aspiration apparatus costs approximately $180 (£115) each. Rapid on-site cytopathology improves the diagnostic performance of needle FNA techniques [32] but is another cost consideration, as well as two skilled operators, and the fact that EBUS is a longer procedure than bronchoscopy. In North America, EBUS is reimbursed by Medicaid and Medicare as an additional procedure to bronchoscopy (ICD9 code 31.620). Charges in US centres for EBUS (and EUS) are both approximately $4000 (£2600) compared to $12 000 (£7700) for cervical mediastinoscopy [19 ].
to develop a combined EBUS/EUS service giving access to all the nodal stations. EBUS cannot be seen as a replacement for cervical mediastinoscopy at the current time. Limited recent data suggest EBUS may indeed match cervical mediastinoscopy for negative predictive value and have superior sensitivity, but more studies are required to confirm these findings. Further comparative studies between EBUS and cervical mediastinoscopy are required to examine relative diagnostic utility and cost effectiveness.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 390). 1
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On the basis of current evidence, TBNA should be regarded as an ancillary mediastinal staging procedure without real-time EBUS in the context of large volume subcarinal and paratracheal adenopathy, as well as providing supplementary diagnostic information. EBUS presents a minimally invasive option as an alternative to cervical mediastinoscopy for first-line staging NSCLC when discrete N2–3 enlargement is present. However, negative EBUS results must be confirmed by cervical mediastinoscopy. If radical treatment is contemplated in the context of single station N2 disease, cervical mediastinoscopy remains the staging investigation of choice.
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In the future, EBUS may have a role (if confirmed in further studies) in staging CT and PET negative subcentimetre nodes, re-staging after induction chemotherapy and initial cervical mediastinoscopy or as a substitute for repeat cervical mediastinoscopy if re-staging is planned after induction treatment. Centres may seek
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14 Ratto GB, Mereu C, Motta G. The prognostic significance of preoperative assessment of mediastinal lymph nodes in patients with lung cancer. Chest 1988; 93:807–813. 15 Roth K, Hardie JA, Andreassen AH, et al. Predictors of diagnostic yield in bronchoscopy: a retrospective cohort study comparing different combinations of sampling techniques. BMC Pulm Med 2008; 8:2.
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Mediastinal staging Medford et al. 341 16 Stratakos G, Porfyridis I, Papas V, et al. Exclusive diagnostic contribution of the histology specimens obtained by 19-gauge transbronchial aspiration needle in suspected malignant intrathoracic lymphadenopathy. Chest 2008; 133:131– 136. A cohort study using 19-gauge needles in TBNA to obtain histology samples demonstrating their safety, a 35% increase in diagnostic yield for TBNA over cytology alone and a higher sensitivity and for TBNA than in systematic reviews.
29 Koh MS, Tee A, Wong P, et al. Advances in lung cancer diagnosis and staging: endobronchial ultrasound. Int Med J 2008; 38:85–89. A recent observational study evaluating the experience of setting up a recent EBUS service and its clinical utility using CT and PET but without rapid on-site cytopathology. The reported sensitivity compares favourably with surgical staging techniques (although the negative predictive value was inferior). These data in a real world setting and nonexperienced centre demonstrate the short learning curve of EBUS and potential to be developed in other centres.
17 Goldberg R, Colt HG, Davoudi M, Cherrison L. Realistic and affordable lo-fidelity model for learning bronchoscopic transbronchial needle aspiration. Surg Endosc 2008 [Epub ahead of print].
30 Rintoul RC, Skwarski KM, Murchison JT, et al. Endobronchial and endoscopic ultrasound-guided real-time fine-needle aspiration for mediastinal staging. Eur Respir J 2005; 25:416–421.
18 Hermens FH, Limonard GJ, Termeer R, et al. Learning curve of conventional transbronchial needle aspiration in pulmonologists experienced in bronchoscopy. Respiration 2008; 75:189–192. A recent retrospective study performed by operators experienced in normal bronchoscopy confirming no significant learning curve for TBNA and that diagnostic yield was related to the size of the lymph node but not location.
31 Lee HS, Lee GK, Lee HS, et al. Real-time endobronchial ultrasound-guided transbronchial needle aspiration in mediastinal staging of nonsmall cell lung cancer: how many aspirations per target lymph node station? Chest 2008; 134:368–374. An important recent cohort study assessing the number of passes necessary at EBUS for clinical utility. A minimum of three passes are needed unless a tissue core is obtained, in which case two passes per node gives acceptable sensitivity and negative predictive value. The drop off in sensitivity below three passes (in the absence of tissue core) is marked.
19 Sheski FD, Mathur PN. Endobronchial ultrasound. Chest 2008; 133:264– 270. A recent review including studies up to 2006 of all aspects pertaining to EBUS including technical aspects, cost analysis, performance, indications, training and service development. 20 Ernst A, Anantham D, Eberhardt R, et al. Diagnosis of mediastinal adenopathy real-time endobronchial ultrasound guided needle aspiration versus mediastinoscopy. J Thorac Oncol 2008; 3:577–582. The only published completed comparative trial for EBUS and cervical mediastinoscopy to date. Prospective cross-over trial in patients with suspected NSCLC and enlarged mediastinal nodes showing superior diagnostic yield, sensitivity and negative predictive value for EBUS but no significant difference in N status in a cohort of high disease prevalence. There was significant disagreement between EBUS and cervical mediastinoscopy at station 7. Two other trials are in progress due for publication in 2009 and 2012. The combined results of all these will be important in assessing how well EBUS can replace cervical mediastinoscopy. 21 Yasufuku K, Quadri M, dePerrot M, et al. A prospective controlled trial of endobronchial ultrasound guided transbronchial needle aspiration compared to mediastinoscopy for mediastinal lymph node staging of lung cancer. Western Thoracic Surgical Association 33rd Annual Meeting (abstract). Canada; 2007. 22 http://www.ncchta.org/project/1603.asp. Assessment of Surgical sTaging versus Endobronchial and endoscopic ultrasound in lung cancer: a Randomised controlled trial (ASTER) 2008–12. 23 Herth FJ, Eberhardt R, Vilmann P, et al. Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes. Thorax 2006; 61:795–798. 24 Yasufuku K, Chiyo M, Koh E, et al. Endobronchial ultrasound guided transbronchial needle aspiration for staging of lung cancer. Lung Cancer 2005; 50:347–354. 25 Yasufuku K, Chiyo M, Sekine Y, et al. Real-time endobronchial ultrasoundguided transbronchial needle aspiration of mediastinal and hilar lymph nodes. Chest 2004; 126:122–128. 26 Szlubowski A, Kuzdzal J, Kolodziej M, et al. Endobronchial ultrasound-guided needle aspiration in the nonsmall cell lung cancer staging. Eur J Cardiothorac Surg 2009; 35:332–335. A recent prospective cohort study using extended surgical lymphadenectomy to rigorously confirm negative EBUS results. The negative predictive value for EBUS here was superior to systematic reviews but still inferior to cervical mediastinoscopy, reinforcing the need for surgical staging if EBUS results are negative for malignancy. 27 Bauwens O, Dusart M, Pierard P, et al. Endobronchial ultrasound and value of PET for prediction of pathological results of mediastinal hot spots in lung cancer patients. Lung Cancer 2008; 61:356–361. A recent prospective study of EBUS assessment of relatively small nodes with high SUV on PET demonstrating a sensitivity and negative predictive value of EBUS far superior to systematic reviews and comparing favourably with cervical mediastinoscopy. This study also suggests the utility of EBUS may be better refined in combination with PET, as the SUV for positive and negative nodes differed significantly. 28 Herth FJ, Eberhardt R, Krasnik M, Ernst A. Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically and positron emission tomography-normal mediastinum in patients with lung cancer. Chest 2008; 133:887–891. A recent landmark study demonstrating the ability of EBUS to sample subcentimetre nodes which are radiologically normal (on CT and PET) with a sensitivity and negative predictive value superior to conventional surgical staging. This suggests that EBUS could have a role in presurgical staging but further studies are needed to corroborate these findings. The low prevalence of nodal metastases may have contributed to the high negative predictive value.
32 Klapman JB, Logrono R, Dye CE, Waxman I. Clinical impact of on-site cytopathology interpretation on endoscopic ultrasound-guided fine needle aspiration. Am J Gastroenterol 2003; 98:1289–1294. 33 Alsharif M, Andrade RS, Groth SS, et al. Endobronchial ultrasound-guided transbronchial fine-needle aspiration: the University of Minnesota experience, with emphasis on usefulness, adequacy assessment, and diagnostic difficulties. Am J Clin Pathol 2008; 130:434–443. An excellent cytopathological review of experience with EBUS cytology samples at a centre between 2006 and 2008 using an on-site cytopathologist. The presence of abundant lymphocytes and tingible macrophages predicts an adequate sample but this service has resource implications. With such a cytological service, EBUS achieved an excellent negative predictive value and comparable sensitivity to surgical staging. 34 Asano F, Matsuno Y, Tsuzuku A, et al. Diagnosis of peripheral pulmonary lesions using a bronchoscope insertion guidance system combined with endobronchial ultrasonography with a guide sheath. Lung Cancer 2008; 60:366–373. 35 Nakajima T, Yasufuku K, Iyoda A, et al. The evaluation of lymph node metastasis by endobronchial ultrasound-guided transbronchial needle aspiration: crucial for selection of surgical candidates with metastatic lung tumours. J Thorac Cardiovasc Surg 2007; 134:1485–1490. 36 Wong MK, Wong MP, Lam DC, et al. Endobronchial ultrasound for diagnosis of synchronous primary lung cancers. Lung Cancer 2009; 63:154–157. 37 Herth FJ, Annema JT, Eberhardt R, et al. Endobronchial ultrasound with transbronchial needle aspiration for restaging the mediastinum in lung cancer. J Clin Oncol 2008; 26:3346–3350. The first study to demonstrate the potential utility of EBUS in re-staging the mediastinum. This retrospective cohort study did not use CT-PET and achieved a sensitivity superior to that of surgical re-staging, although the negative predictive value was poor probably relating to sampling error. This study requires validation but suggests that EBUS might be a feasible re-staging tool in place of surgical restaging. 38 Mohamed S, Yasufuku K, Nakajima T, et al. Analysis of cell cycle-related proteins in mediastinal lymph nodes of patients with N2-NSCLC obtained by EBUS-TBNA: relevance to chemotherapy response. Thorax 2008; 63:642– 647. A recent retrospective study demonstrating for the first time that EBUS can obtain nodal tissue that can be used for prognostic cell cycle protein studies. p53 overexpression predicted poorer response to chemotherapy. This study suggests EBUS may facilitate molecular marking to further refine treatment planning for lung cancer in addition to staging. 39 Kennedy MP, Jimenez CA, Bruzzi JF, et al. Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of lymphoma. Thorax 2008; 63:360–365. 40 Nakajima T, Yasufuku K, Fujiwara T, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for the diagnosis of intrapulmonary lesions. J Thorac Oncol 2008; 3:985–988. 41 Kramer H, van Putten JW, Post WJ, et al. Oesophageal endoscopic ultrasound with fine needle aspiration improves and simplifies the staging of lung cancer. Thorax 2004; 59:596–601. 42 Wallace MB, Pascual JM, Raimondo M, et al. Minimally invasive endoscopic staging of suspected lung cancer. J Am Med Assoc 2008; 299:540–546. This recent study demonstrates the ability of EBUS to avoid surgical staging in a significant proportion of patients despite being done in a centre only recently trained in EBUS and without rapid on-site cytopathology. This study also performed EUS but similar avoidance of surgical staging has been reported in other studies using EBUS alone.
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342 Neoplasms of the lung 43 Vincent BD, El-Bayoumi E, Hoffman B, et al. Real-time endobronchial ultrasound-guided transbronchial lymph node aspiration. Ann Thorac Surg 2008; 85:224–230. 44 Tournoy KG, Rintoul RC, van Meerbeeck JP, et al. EBUS-TBNA for the diagnosis of central parenchymal lung lesions not visible at routine bronchoscopy. Lung Cancer 2009; 63:45–49.
45 Hsu LH, Ko JS, You DL, et al. Transbronchial needle aspiration accurately diagnoses subcentimetre mediastinal and hilar lymph nodes detected by integrated positron emission tomography and computed tomography. Respirology 2007; 12:848–855.
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