In the diagnosis of lung cancer, pulmonologists have several tools at their disposal. From the tried and true convex probe endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration to robotic bronchoscopy for peripheral lesions and new technology to unblind the biopsy tools, this article elucidates and expounds on the tools currently available and being developed for lung cancer diagnosis.
Key points
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Linear, convex probe endobronchial ultrasonography is highly sensitive and specific for diagnosis and staging of lymph node metastasis in lung cancer.
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Radial probe ultrasonography can provide proof of nodule localization but requires extensive knowledge of distal airway anatomy and computed tomography (CT)–anatomic correlation.
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Virtual bronchoscopic navigation, electromagnetic navigation bronchoscopy, and transthoracic needle aspiration improve correct airway selection and ability to find nodules, respectively, but do not provide real-time tools-to-target colocalization.
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Robotic bronchoscopy seeks to increase tool control and precision in the lung periphery but requires additional study of its effect on lung cancer diagnosis.
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Cone-beam CT and augmented fluoroscopy may provide improved imaging-based confirmation of location of bronchoscopy tools in relationship to the target nodule.
Introduction
Lung cancer (LC) remains the most lethal form of cancer in the United States, leading to a projected 155,870 deaths in 2017/2018, more than the next 3 most common causes of cancer death combined. In addition to high mortality, the incidence of new LC cases remains high and is increasingly borne by women and nonsmokers. Despite improvements in thoracic imaging, the rate of false-positive and false-negative findings precludes their use as sole diagnostic modalities and instead aids in the risk stratification of those abnormal findings potentially in need of tissue confirmation. Coupled with an aging population, this increase in significant comorbidities among patients at risk for LC and screen eligible patients and the need for advanced molecular/biomarker testing have led to advances in bronchoscopic technology geared toward the care of patients with known or suspected LC. ,
As the tools evolve to include intrathoracic/extrathoracic perioperative imaging and virtual and/or visual endoluminal navigation, it is apparent that the data available to support the use of these technologies range from robust to absent. This article presents a brief overview of historical diagnostic bronchoscopy tools and focuses discussion on maturing and emerging technologies as well as the available data for their use.
Flexible bronchoscopy
The conventional flexible bronchoscope (FB) and its uses in LC diagnosis have been well described since its introduction in 1965 by Dr Shigeto Ikeda. Although the introduction of the FB constituted a major advancement in the care of patients with known or suspected LC, new challenges were quickly uncovered. These challenges included newly found biopsy targets outside the reach of FBs and inadequate evaluation of regional sites of metastasis. Attempts to overcome these challenges have included the introduction of transbronchial tools for biopsy and the use of monoplane fluoroscopy. Despite early reports of success, FBs have found limited use outside the central airways and in biopsy of large or diffuse peripheral lung lesions, with poor results when attempting diagnosis of lesions with the following characteristics: subsolid, less than 20 mm, lack of an air-bronchus sign on CT, and a lack of transbronchial needle aspiration (TBNA) use.
Convex (linear) probe endobronchial ultrasound–guided transbronchial needle aspiration
Introduced in 2004, the endobronchial ultrasound (EBUS) transbronchial needle aspiration (TBNA) bronchoscope ( Fig. 1 ) allows real-time, ultrasound-guided needle aspiration of mediastinal, hilar, and central lung lesions under either moderate conscious sedation or general anesthesia. Among the tools available to pulmonologists, the data associated with EBUS-TBNA are the most robust in terms of safety and efficacy when applied to the diagnosis and staging of LC. These data show EBUS having equivalent sensitivity, specificity, and access to a wider array of lymph node stations to mediastinoscopy for LC diagnosis, and subsequently led to its recommendation as the first-line approach in the diagnosis and staging of suspected LC. ,
Advances in Endobronchial Ultrasound Bronchoscope Technology
Until recently there had been little change in EBUS bronchoscope technology aside from an increase in the working channel size from 2.0 to 2.2 mm. This situation seems to be changing with the introduction of a hybrid EBUS scope that offers a higher degree of flexion, narrower external diameter, larger ultrasound scanning angle (50°), and a 120° field of view at a 10° forward oblique viewing field compared with conventional EBUS (C-EBUS) bronchoscopes. These advances were shown in a randomized controlled trial comparing the H-EBUS scope with a C-EBUS scope, which found use of H-EBUS to be associated with improved visualization of airway segments and a significantly decreased need to convert to an FB during airway inspection. Further advances seem on the horizon with the recent reports of a thin EBUS scope featuring a narrower outer diameter and improved flexion angle (170°) compared with C-EBUS. Publications in porcine and ex vivo human lung models reported an improved ability to insert the thin EBUS scope into deeper bronchi and upper lobe segments compared with C-EBUS. , Although these advances have not resulted in an improvement in TBNA diagnostic yield or specimen adequacy, studies evaluating how their reach may affect the sampling of targets unreachable by C-EBUS are needed.
Advances in Endobronchial Ultrasonography Sampling Tools
As EBUS-TBNA use has grown, a variety of needle sizes have been introduced (19–25 gauge). Multiple publications evaluating the effect of needle gauge on diagnostic yield and specimen adequacy have reported conflicting results, with most data suggesting little or no clinical difference. In addition to diagnostic success, EBUS-TBNA has reproducibly shown a high degree of adequacy for LC subtyping and molecular/biomarker testing. , , Despite this, a recommendation for a minimum number of passes needed for advanced molecular testing has not been established, nor have best methods/practices been determined for ensuring adequacy of EBUS-TBNA samples for performance of the entire compendium of testing now required from a single procedure (diagnosis, subtyping, staging, programmed death-ligand 1 (PDL-1) biomarker status, molecular markers, and/or next-generation sequencing [NGS]).
The perceived need for increasing quantities of tissue for advanced testing has led to exploration into new device concepts and designs. Biopsy needles adapted from the gastrointestinal (GI) endoscopy space with additional cutting edges are being introduced to the EBUS-TBNA market in hopes that they will allow improved specimen acquisition ( Fig. 2 ). Current GI literature suggests that these fine-needle biopsy needles may provide higher diagnostic yields; better-quality samples for histology; and qualitative data not obtainable by fine-needle aspiration, such as tissue architecture, degree of differentiation, metastatic origin, and rate of proliferation. In addition to new needle design, GI miniaturized forceps have been adapted for use in the lung ( Fig. 3 ). Intranodal forceps biopsies (IFBs) are performed via passage of miniforceps into a target lymph node through a previously performed TBNA puncture site. Herth and colleagues reported significant improvement in diagnostic yield in 75 patients compared with 19-gauge and 22-gauge TBNA needles (88% vs 49% vs 36%, respectively) in patients without high suspicion of LC; yield was highest in sarcoidosis (88% vs 35% for TBNA) and lymphoma (81% vs 35%). Chrissian and colleagues prospectively evaluated IFB in 50 patients and reported a significant improvement in diagnostic yield when combining techniques (IFB and TBNA). Further study is needed to fully evaluate the benefit of these new needle designs and IFB with regard to the diagnosis and treatment of patients with known or suspected LCA.
Approaches to sampling peripheral pulmonary lesions
The management of peripheral pulmonary nodules (PPNs) remains a challenging clinical situation. Publication of the National Lung Screening Trial reporting an associated reduction in LC mortality with application of chest low-dose CT (LDCT) screening in a high-risk population, the increasing rates of nodules (>4 mm and <30 mm) detected on chest CT scanning (up to 30.6% in 2012), and the subsequent US Preventive Services Task Force recommendation endorsing LDCT in at-risk populations has driven increased interest in this issue. , ,
Radial Probe Endobronchial Ultrasonography
Historically, fluoroscopy (monoplanar and/or biplanar) alone as a method of bronchoscope/tool guidance in the evaluation of PPNs has been largely abandoned because of poor localization and diagnostic rates, particularly with decreasing target size and/or location in the outer one-third of the lung. Introduced in the 1990s, radial probe EBUS (R-EBUS) was first used to assess tracheobronchial wall integrity and mediastinal adenopathy. Since then, R-EBUS has been adapted for the evaluation of PPN because its radial side-scanning properties are able to produce a high-resolution 360° ultrasonography image of the surrounding lung parenchyma. Since 2002, use of R-EBUS (plus or minus guide sheath [GS] and/or ultrathin bronchoscope [UTB]) to evaluate and diagnose PPN has reported diagnostic yield ranging from 58% to 85%. Comparative trials of R-EBUS (plus or minus GS) and electromagnetic navigation bronchoscopy (ENB) reported comparable diagnostic yields of 69% and 63% respectively. , A later study by Eberhardt and colleagues evaluated R-EBUS, ENB, and a combination of the two. Alone, R-EBUS and ENB had diagnostic yields of 69% and 59% respectively; however, the combined approach significantly improved the diagnostic yield (88%). Subsequent meta-analyses of R-EBUS have reported diagnostic yields ranging from 56.3% to 60.9% for lesions smaller than 20 mm versus 77.7% to 82.5% for lesions larger than 20 mm. , The American College of Chest Physicians’ (ACCP) AQuIRE (ACCP Quality Improvement Registry, Evaluation, and Education) registry, a retrospective multi-center evaluation of peripheral bronchoscopy, confirmed incremental improvement of diagnostic yield when combining R-EBUS with ENB (38.5% for ENB alone vs 47.1% with ENB plus R-EBUS). However, these results revealed diagnostic yields significantly lower than previously reported, which may be explained by the elimination of biases previously associated with earlier single-center retrospective studies. Most recently, a multicenter, prospective, randomized trial comparing PPN biopsy using FB plus fluoroscopy or R-EBUS plus UTB found R-EBUS to be associated with a significantly higher diagnostic yield of 49% compared with 37% with FB. Of note, this study did not include the use of peripheral TBNA, which may have contributed to the lower than previously reported yields.
When considering use of R-EBUS for PPN sampling, factors that have been shown to significantly affect PPN visualization and diagnostic yield include lesion size, presence of bronchus sign, distance from the hilum, lobar distribution, the presence of malignancy, and positioning of the probe in relation to the lesion (eccentric vs within /concentric) ( Fig. 4 ). Of these, the characteristics most reproducibly reported have been size of the lesion and probe positioning within the lesion (a concentric view). With regard to safety, R-EBUS–guided biopsy of PPN has been reported to be favorable. In the 2 previously mentioned meta-analyses, pneumothorax rates of 1% and 1.5% and no episodes of significant bleeding were reported. ,
The primary limitation to the applicability of R-EBUS has been its reliance on the bronchoscopist’s ability and comfort in using CT-anatomic correlation to pilot a bronchoscope and R-EBUS probe to the intended PPN while navigating increasingly small airways and numerous branch points, often without direct visualization. The other most prominent limitation of R-EBUS involves the ultrasound image and the reflective properties of the lung. Although solid PPNs create a well-demarcated interface between themselves and normally aerated lung parenchyma, ground-glass nodules return poor or no ultrasound signals, which leads to poor representations of these lesions during localization. Despite these limitations, the reported pooled diagnostic yields comparable with other forms of peripheral lung navigation make R-EBUS–guided bronchoscopy, alone or in combination with an additional guidance modality, an attractive option to PPN biopsy.
Virtual Navigation Bronchoscopy
Virtual airway reconstruction software/platforms for navigation bronchoscopy provide pre- and peri-procedural guidance for the bronchoscopist by assisting in plotting an appropriate course through the bronchial tree to the target lesion. Pre-procedural CT scanning is required, with specific requirements for scan resolution and image thickness per manufacturer guidelines. After uploading CT data to the virtual navigation bronchoscopy (VNB) platform, a three-dimensional (3D) bronchial tree and roadmap is created. During procedural planning, the target, or region of interest (ROI), is identified and software provides a virtual roadmap of the bronchial tree, providing a potential bronchus-by-bronchus route access to the ROI. Multiple different views are often available, including views of the vascular tree, virtual fluoroscopy, and the ability to rotate an ROI in almost any plane or direction. These software platforms are available as stand-alone platforms or in conjunction with tracked navigation systems. The term VNB is used here to refer to those stand-alone systems. Intraprocedural VNB requires an additional operator to advance through the planned virtual route (akin to a navigator providing map-based directions to a driver), but has shown improvement in appropriate pathway selection in a simulated patient setting.
The Bf-NAVI system (not available in the United States; Olympus, Tokyo, Japan) and the LungPoint system (Broncus, Mountain View, CA) are the two VNB systems available that have been studied in humans, with varied data regarding their efficacy. Of the 2 systems, the Bf-NAVI has a more extensive dataset in human patients, including 2 randomized trials in patients undergoing bronchoscopy for PPNs. The initial feasibility study of the Bf-NAVI VNB system suggested good success. Subsequent trials, including a prospective Bf-NAVI trial, identified no improvement in diagnostic yield when comparing R-EBUS alone with R-EBUS with VNB in PPNs. This trial was followed by a large randomized trial using the same comparison, which reported a significant increase in diagnostic yield for both malignant and nonmalignant diseases in the combined technique arm. In contrast, another large, randomized controlled trial (n = 334) compared VNB with fluoroscopy versus standard bronchoscopy with fluoroscopy. No overall difference in diagnostic yield was identified; however, in subgroup analysis, there seemed to be some improvement in patients with lesions in the right upper lobe, fluoroscopically invisible lesions, and lesions located in the peripheral one-third of the lung field.
LungPoint VNB has several preclinical animal studies suggesting improved ability to properly select bronchial pathways and locate phantom lesions. , Limitations of these studies include the use of a 24-mm ROI lesions and that half of the participating bronchoscopists were pulmonary fellow trainees. , The system’s single human study (n = 25) was a pilot feasibility study of VNB use in a patient cohort with 18F-fluorodeoxyglucose–avid peripheral pulmonary lesions less than 42 mm (mean size, 28 mm) assessing sensitivity, specificity, and overall accuracy of the system. Using VNB and an ultrathin bronchoscope, more than 50% of the lesions were directly visualized and the reported overall diagnostic yield was 80% (all patients with a directly visualized lesion obtained a diagnosis). In addition, a recent meta-analysis of peripheral lung biopsy has suggested an overall diagnostic yield of 72% when using VNB.
In addition, the use of VNB seems to offer no advantage compared with standard fluoroscopy for bronchoscopists with advanced training. However, VNB may offer improvements with regard to bronchoscopy training or bronchoscopists with less experience. Anecdotally, the primary drawback to using VNB technology is its lack of instrument tracking in space and time. This lack of real-time guidance was shown in a porcine model of VNB. The wedging of the bronchoscope near an ROI was associated with significant anatomic displacement, and “the wedging maneuver could pose a substantive problem as one could risk that no part of the tumor is within the preoperative CT image location.”
These limitations have resulted in the limited adoption of VNB for peripheral bronchoscopy, whereas ENB has grown in use. Further study of VNB is required alone or in combination of other advanced diagnostic procedures, although it seems that bronchoscopy has moved on in other directions.
Electromagnetic Navigation Bronchoscopy
ENB uses the creation of a magnetic field around the patient to detect spatially tracked devices to display device position within the magnetic field superimposed over the 3D virtual bronchoscopic route; that is, an integrated electromagnetic tracking system within VNB. The final product is a dynamic, spatially and temporally tracked virtual representation of the device within the preplanned, patient-specific anatomic map.
In the United States, there are 2 commercially available ENB systems: SuperDimension (SD; Medtronic, United States) ( Fig. 5 ) and Veran SPiNDrive (VSPN; Veran Medical Technologies, United States) ( Fig. 6 ). Both systems require thin-cut protocol-specific CT imaging to plan biopsy targets and overlay/match the magnetic field to CT scan anatomy. The primary differences between the systems are the VSPN system’s use of inspiratory and expiratory CT images to add respiratory gating versus a static inspiratory breath hold (SD) and which devices are tracked during ENB (SD, locatable guide [LG] via an extended working channel [EWC]; VSPN, tip-tracked biopsy instruments). The SD LG is similar to a probe that passes through the EWC, which requires a minimum FB working channel size of 2.6 mm. The EWC comes in various angles (45°, 90°, 180°), offers steerability during navigation, and remains in place after the LG is removed. Standard PPN biopsy instruments are then used to sample the lesion in question and/or R-EBUS is used for real-time confirmation of the target lesion. Although the VSPN system has recently introduced its own version of an LG/EWC combination, the platform is primarily predicated on the use of always-on tipped track biopsy instruments (forceps, brush, and needle) allowing continuous direct navigation of the biopsy instrument. Both platforms use similar planning systems and computer software to generate four-dimensional (4D) reconstructions of the patient’s chest CT and allowing PPN targeting and pathway building.
