Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a well-established first-line minimally invasive modality for mediastinal lymph node staging in lung cancer patients,1–7 and in the diagnostic workup of patients with mediastinal adenopathy.8–13 This procedure can sometimes be limited by the degree of flexibility in the needles when a greater degree of angulation by a loaded EBUS scope is required. In addition, a larger needle may allow improved sample acquisition for the ever increasing requirements for ancillary testing in lung cancer14–18 or histologic assessment in conditions where the diagnostic yield of current needles is suboptimal such as in sarcoidosis13,19–21 or lymphoma.22–24
A new EBUS-TBNA device which is more flexible and larger (19 G vs. 21 to 22 G) than prior devices is now commercially available. To date only 2 small studies, including one which used a since modified prototype device, have been published.25,26 We describe the result of our experience with the commercially available device in 3 centers with prior EBUS experience to assess the feasibility and safety of its use.
MATERIALS AND METHODS
This study aims to describe a series of clinical cases performed with a commercially available 19-G EBUS-TBNA device in 3 centers [Calgary (Canada), London (UK), and Ancona (Italy)]. The collection and analysis of the data were approved by the Calgary Conjoint Health Research Ethics Board (protocol REB16-0184).
19-G Needle Device
A 19-G EBUS-TBNA needle (Flex 19G; Olympus Respiratory America, Redmond, WA) was used during selected cases at the discretion of the bronchoscopist caring for the patient. In the first phase of the study, the devices were provided free of charge to each center as part of a product performance evaluation phase by the manufacturer (n=80) and the subsequent cases performed with purchased devices. All devices were approved by the respective regulatory authorities in each country before use. No other industry involvement occurred in the design, performance, or analysis of the study. All procedures were performed with a convex probe-EBUS bronchoscope (BF-UC180F; Olympus, Tokyo, Japan) under sedation and without endotracheal intubation.
We completed a retrospective chart review of all cases performed to the time of data analysis at each site. All cases where at least 1 attempt was made to sample a target lesion with the device were included. Information extracted from the charts included demographics (age, sex), indication for procedure, presence of trainee during procedure, location and size of the mediastinal node stations/lesion sampled, overall and per-lesion diagnosis, final clinical diagnosis, procedure complications. Cytopathologic data were obtained from clinical reports. A specimen was deemed “diagnostic” if a specific finding was seen on the sample. Cases where only benign lymphocytes were noted were not considered diagnostic, but are included with diagnostic samples as “adequate samples.” Specimens where no diagnosis was offered, and the presence of lymphocytes not specifically commented on were coded as inadequate. In cases where >1 type of needle was used, the following approach was applied. If a given target was sampled only with the 19-G device, while other targets were sampled with another needle, the 19 G target was included. If a target was sampled with >1 needle, but the specimens were collected separately or the pooled specimen was nondiagnostic, the target was included. Cases/targets where the specimens from >1 needle type were pooled together and were diagnostic were excluded from the analysis, although any complications related to these procedures were included.
Diagnostic yield was calculated on a per-procedure basis for the 19 G samples alone, as well as on a per-node basis, and according to procedure indication. Binary logistic regression analysis was performed to identify variables associated with specimen adequacy on a per-lymph node basis.
Anonymized information was collected and combined into a REDCap (Research Electronic Data Capture) electronic data capture tool hosted at the Clinical Research Unit at the University of Calgary. Further analysis was performed with IBM SPSS Statistics (version 24, Armonk, NY).
A total of 165 procedures were performed between July 2015 and January 2017 (18 mo) with a total of 297 individual lymph nodes or lesions sampled with the 19-G device (mean 1.8/median 2 per case). Ten different operators performed procedures (median 10 cases; range, 1 to 43). All operators were experienced EBUS operators (>500 cases performed). Eleven cases/17 node targets were excluded due to diagnostic aspirates obtained with both a 21 and a 19 G in a pooled sample, leaving 154 cases and 280 lesions included on the analysis. Baseline characteristics and indication for the procedure are outlined in Table 1. A single 19-G needle was used for all targets during a given procedure, and in 20 (12.1%) procedures a smaller (22 or 21 G) needle was also used but these results are not included in the analysis. Rapid on-site cytological evaluation of specimens was performed in 32 cases, all in 1 center.
Overall, a specific diagnosis was obtained with the 19-G device in 119/154 (77.3%) of cases with an additional 21/154 (13.6%) of cases with benign lymphocytes, for a procedural adequacy rate of 140/154 (90.9%). Procedure sample adequacy was 39/44 (88.6%) in suspected malignant cases, 61/67 (91.0%) in suspected sarcoidosis/lymphadenopathy not-yet-diagnosed cases, and 12/14 (85.7%) of cases with suspected lymphoma. A total of 7 cases of lymphoma were diagnosed, including 2 cases of the Hodgkin lymphoma and 1 posttransplant lymphoproliferative disorder. Specific diagnoses obtained for these subgroups are outlined in Table 2. Molecular testing was performed in 43 cases. Epidermal growth factor receptor mutations were detected in 3/24 (12.5%) of lung adenocarcinoma cases, and none of the 24 samples tested were reported as inadequate.
Overall, mean lymph node size was 20.4 mm (SD±9.9) while lung lesions were 33.5 mm (SD±19.9). On a per-target basis, a specific diagnosis was noted in 191/280 (68.2%) of samples, with an additional 61/280 (21.8%) showing benign lymphocytes for a per-node sample adequacy rate of 252/280 (90.0%). The most common sites sampled with the 19-G device were lymph node stations 7, 4R, 11R, 11L, 4L, and lung lesions (Table 1). The frequency of inadequate samples did not differ between these sites (χ2 P=0.157, Fig. 1). Multivariable logistic regression revealed only that lymph node size (odds ratio, 1.068; 95% confidence interval, 1.009-1.132; P=0.017), and age (odds ratio, 1.043; 95% confidence interval, 1.012-1.075; P=0.006), but not sex, presence of trainee, nodal station, hospital center nor preprocedure indication were related to specimen adequacy.
In 1 case, significant hemoptysis (<50 mL) was noted immediately after withdrawal of the EBUS bronchoscope. This was managed by reinsertion of the standard bronchoscope to suction retained blood in the airway, after which no active bleeding was noted. In one other case, the operator could not penetrate the target with the device, which was then sampled with a 21-G needle.
This multicenter, retrospective study demonstrates the feasibility and safety of EBUS-TBNA with a new 19-G needle device with only 1 case of bleeding and another case of failure to access a target in 165 patients of 297 targets sampled. A high specimen adequacy rate (90.9%) as well as high diagnostic rates across all indication subgroups in the largest cohort to date assessed was also noted with this device. These findings add to the results obtained with a prototype 19-G device in a smaller series of 47 patients which demonstrated an 89% diagnostic yield25 and another small series of 22 cases demonstrating 100% specimen adequacy by smear.26
Although the overall diagnostic yield achieved in this study was high, it remains to be proven if results are substantially better than with standard (defined as 21 or 22 G) devices, where excellent results have been well demonstrated in various clinical conditions.21,27,28 The impact of needle size on diagnostic yield remains controversial and neither randomized trials nor meta-analysis have demonstrated any significant differences for EBUS performed with 21 versus 22-G devices.29,30 One retrospective study did suggest that a 21-G device performed better with regard to sarcoidosis diagnosis as well as lung cancer subtyping over the 22-G device.31 Another suggested that while diagnostic yield was similar, the 21-G device required fewer passes to make a diagnosis with rapid on-site evaluation.32 In contrast, it has been observed that larger needle size may be associated with increased blood contamination of specimens, an issue of concern in particular during rapid on-site evaluation.33 To date, no comparative studies have been performed with the 19-G EBUS-TBNA device versus any other needle. Some information could be extrapolated from the endoscopic ultrasound-guided needle aspiration literature as well, where a variety of needles from 25 to 19 G are in clinical use. Interestingly, a smaller 25-G device was found to offer similar diagnostic performance to a 22-G device for pancreatic lesions,34 and a meta-analysis actually suggested better yield with the 25-G device.35 Preclinical data does suggest that the 19-G EBUS device collects larger specimens than a 22-G needle.36 As such, the utility of the 19-G device may be more specific to situations where a larger core of tissue is important for diagnostics or ancillary (molecular) testing rather than to improve overall diagnostic yield. This may be analogous to the EUS sampling of gastric tumors, where histologic assessment is critical and where 19 G devices have proved superior.37
Sarcoidosis and lymphoma may be 2 scenarios where larger specimens may facilitate diagnosis and subtyping. Our series achieved a high diagnostic yield in patients suspected of having sarcoidosis, but within the range of what has been described in a meta-analysis with standard needles with a mean diagnostic yield of 79% and a range between studies from 54% to 93%.21 Unfortunately, only a fairly large trial would have the power to detect a 10% improvement (n=800 patients) or 5% improvement (n=1800 patients) in yield between approaches. Our diagnostic yield in patients suspected of harboring a lymphoma was lower than all other subgroups, as expected, due to the difficulty of differentiating between the different subtypes of lymphoma on nonsurgical specimens.23 Nevertheless, 7 cases of lymphoma, including 2 with the Hodgkin disease, were successfully diagnosed, the latter felt to be most difficult to identify with such techniques.38,39 Unfortunately our study design did not allow us to calculate a sensitivity estimate for lymphoma given the lack of final diagnosis in all patients with adenopathy. Previous reports have highlighted the lower yield of EBUS in this condition, in particular in the setting of de novo disease (vs. at disease recurrence) when subtyping is most important.38 Nevertheless, more recent reports appear to demonstrate improved results in this setting, perhaps related to increased experience by cytopathologists with such specimens and availability of ancillary testing such as flow cytometry, as demonstrated by a 67% subtyping success rate in de novo disease by the group at MD Anderson Cancer Center.39 Further studies will be required to test the hypothesis that the 19-G device may further increase the diagnostic yield and ability to subtype lymphomas via EBUS.
EBUS-TBNA has consistently demonstrated high diagnostic yield and accuracy for both diagnosis and staging of lung malignancies.27 Given these high diagnostic rates, and the technical challenges of using a larger needle in the staging of subcentimeter lymph nodes, it seems unlikely that the 19-G device will have an important role in this setting. Nevertheless, with the increasing importance of subtyping non–small cell lung cancers and the ever increasing need for ancillary testing to guide treatment, the larger samples afforded by the 19-G device could be of value especially in patients with large mediastinal nodes and advanced stage disease. When appropriate, our specimens were successfully used for molecular testing, although this is also feasible with standard needles as has been extensively demonstrated and reviewed.40
The main structural advantage the 19-G needle has over prior devices is improved flexibility due to its nitinol design. Anecdotally, this allowed facilitated access to node stations 4 L and 10 L in situations where we were unable to access the target with a standard needle. One group measured the difference of angulation feasible with the 19-G needle while in the bronchoscope to be 78 versus 57 degrees with a 22-G device.26 The increased size and flexibility of the device does require some adjustment in technique and is likely best limited to operators with significant EBUS experience, and to sampling of larger lesions.
Strengths of this study include the multicenter/multiple operator setting with a relatively large and varied patient cohort (n=165) performed outside of a strict clinical trial setting and as such representing a real-world setting. All operators were highly experienced with EBUS techniques, and the success rates may not be reproduced by more novice EBUS bronchoscopists. As well, targets were relatively large, and results as well as technical aspects may be more challenging for smaller lesions <1 cm or in a staging setting. We do not recommend this device’s use in those settings and our reported diagnostic yield and safety profile should not be extrapolated to smaller target lesions (<1 cm). The absence of long-term follow-up also limits our analysis as some cases remained undiagnosed at the time of chart review. Finally, the lack of a control group sampled with a different needle does not allow us to make any conclusions about comparative performance of this new device.
In conclusion, a new flexible 19-G EBUS needle was successfully and safely applied in a large patient cohort for sampling of lung and mediastinal lesions with high diagnostic rates across clinical indications and in our experience occasional technical advantages over the smaller and stiffer devices. Future studies should aim to compare the performance of this device versus standard needles in specific patient scenarios/indications for EBUS-TBNA to determine if it can improve procedure results.
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