computed tomography bronchus sign and the diagnostic yield of different guided ­bronchoscopy modalities. In this meta-analysis the results of 23 studies were evaluated, including 2199 lesions with bronchus sign and 971 lesions without bronchus sign. The overall weighted diagnostic yield was respectively 74.1% and 49.6% when the bronchus sign was present or not.

Table 20.1 shows the results of different studies using fuoroscopic guidance for the diagnostic approach to PPLs (only trials with more than 50 patients are considered).

The complications of the transbronchial approach to PPLs using fuoroscopy as a guidance system are not frequent. The risk of major bleeding is reported with an incidence of 1–4% and its rate may further increase in immunocompromised patients, subjects with uremia, ventilated patients, pulmonary hypertension, and in coagulation disorders [20]. The incidence of pneumothorax in transbronchial biopsy under fuoroscopic guidance of PPLs is low and reported as less than 1% on large series of cases [28].

In conclusion, advantages of fuoroscopic guidance are the possibility to perform the sampling under real-time vision and the low-cost of the procedure, if a biplane or rotating C-arm fuoroscope is available, such as in most hospitals. Disadvantages are radiation exposure, both for the patients and the operators, and the dif culties to visualize small lesions, radiologically faint opacity or fuoroscopically hardly visible PPLs due their position superimposed on the mediastinal structures.

Radial EBUS Mini Probe (rEBUS)

Endobronchial ultrasound technology, applied to the diagnostic workup of PPLs, utilizes a rotating ultrasound transducer located at the end of a mini probe that can be introduced through the working channel of a fexible bronchoscope and pushed in the peripheral airways, until a characteristic ultrasound signal of a solid lesion is visualized, different from “snowstorm-like” whitish image of air-containing lung tissue. Thinner mini probes

(1.4 mm) are also available, and they can be used through ultrathin bronchoscopes with a 1.7 working channel.

The main advantages of rEBUS are real time visualization of the lesion and the possibility to identify small PPLs not detectable by fuoroscopy. However, there is no direct control when the sampling instrument is inserted into the target and for this reason rEBUS was employed together with fuoroscopy or other guidance systems in most of the studies.

Various meta-analyses and systematic reviews were published on rEBUS sensitivity [32–35], the rst in 2011 and the latest in 2020. The results of these meta-analyses are reported in Table 20.2 and the diagnostic yield is quite similar (from 69% to 73%). However, all the meta-analyses highlight the great heterogeneity of the results, with a sensitivity ranging from 36% to 96%. The reasons for this heterogeneity may be consequent to several factors. In the meta-analyses by Steinfort et al. [32] and by Ali et al. [33], lesion size and prevalence of malignancy were identi-ed as possible cause of different results, while Sainz Zuniga et al. [35] failed to demonstrate an association between sensitivity and average nodule size or cancer prevalence. Other factors that may infuence sensitivity are the different additional guidance systems that in many studies are utilized with rEBUS (fuoroscopy, virtual bronchoscopy, EMN), making it dif cult to assess the single value of this technique [36].

However, in the majority of the studies on rEBUS, the presence of concentric lesions (rEBUS probe within the lesion), rather than eccentric (rEBUS probe adjacent to the lesion), and PPLs with a prevalent ground glass component are associated with a lower diagnostic yield.

Overall complication rate reported with rEBUS is very low, with an incidence of pneumothorax of 0.7% [35].

Only a few studies directly compared rEBUS and fuoroscopy.

In a prospective study on 50 patients with PPLs (mean diameter = 3.31 cm, range 2–6 cm), fuoroscopy-guided and rEBUS-guided transbronchial biopsies were performed in a random order [9]. Diagnostic material was obtained in 80% of patients with EBUS and in 76% with fuoroscopy. Even if there was a trend for EBUS to have a higher yield than fuoroscopy for lesions <3 cm in diameter, the authors did notnd a signi cant difference between the two techniques. Tanner et al., in a multicenter randomized study [37], compared the diagnostic yield of a thin bronchoscope and rEBUS with standard bronchoscopy and fuoroscopy in 197 patients affected by PPL (lesion size = 31.2 mm). Although the diagnostic yield was higher in rEBUS arm (49% vs. 37%), this difference was not statistically signi cant. The largest trial comparing rEBUS-­guided and fuoroscopicguided transbronchial lung biopsy for PPLs was performed by Triller et al. [38] on 304 consecutive patients. 116 patients underwent rEBUS (mean diameter of the lesions = 31.5 mm) and 188 fuoroscopic guidance with conventional bronchoscopes (mean diameter of the lesions = 34.5 mm). Diagnostic biopsy samples were obtained in 77% using rEBUS and in 74% using fuoroscopy, without any statistically signi cant difference. Even if the diagnostic yield was not different, the authors conclude that rEBUS procedure is safer because it does not involve exposure to radiation for the patients and the medical staff.

Transbronchial needle aspiration under echo endoscopic guidance, with the use of a ­bronchoscope with a linear ultrasound probe at its tip, is widely reported for the transbronchial (EBUS-­TBNA) or transesophageal approach (EUS-B-­FNA) to hilar-mediastinal lymph nodes for diagnosis and staging of lung cancer. This instrument is generally not mentioned among the techniques for the diagnosis of PPL. However, in selected cases, where the lung lesion is adjacent to the trachea or the major bronchi or to the esophagus, this technique can also be used to sampling pulmonary nodules or masses that originate peripherally and that are not visible on bronchoscopy, due to their location outside the bronchial tree. The sensitivity of EBUS-TBNA in the diagnosis of pulmonary lesions is very high and reported with a value greater than 90% [39]. Furthermore, it is possible to wedge the tip of the echo bronchoscope in smaller bronchi up to 5 mm in size, making possible the ultrasound visualization even of small PPLs if they are adjacent or in close proximity with the airway. Even if the lesion is not closely adjacent to the airway and there is a distance of few millimeters between the tracheobronchial wall and the PPL, it is possible to bend the tip of the echoscope in this way pushing the bronchus toward the target and making possible the visualization and the sampling of the lesion.

Figure 20.5 shows two cases of PPLs diagnosed using EBUS-TBNA.

A major limit of this technique is the impossibility to insert the eco-bronchoscope in the upper lobes segmental bronchi and this approach is mainly feasible in PPLs located in the lower lobes.

Pulmonologists should be aware of the possibility that, in selected cases of PPLs, EBUSTBNA may be an alternative for a safe and effective technique of sampling.

Virtual bronchoscopy (VB) is a software which allows, based on CT scan, the development of 3D high-resolution images of the tracheobronchial tree and endobronchial view that simulate thendings of a conventional bronchoscopy. In case of PPL, VB shows the bronchial pathway that must be followed for reaching the target. Several VB systems are currently available.

Generally, virtual bronchoscopy is utilized together with other navigation systems, such as fuoroscopy and rEBUS.

Ishida et al. published the results of a multicenter randomized trial on 199 PPLs ≤30 mm in which VB was associated with rEBUS [40]. The sensitivity of VB-assisted procedure was 80.8% compared to 67.0% when VB was not employed. In this study the difference between two groups was even greater for PPLs <20 mm, in which the diagnostic yield for the VB group was 75.9% vs. 59.3% in the non-VB group. In another randomized trial on 334 patients, where fuoroscopy and ultrathin bronchoscope were used with or without VB to approach PPLs less than 30 mm, the overall diagnostic yield of two groups was similar (67.1% with VB and 59.9% without VB), but it was signi cantly higher when VB was utilized in PPLs located in the right upper lobe (81.3% vs. 53.2%), in the peripheral third of the lung eld (64.7% vs. 52.1%) and for lesions not visible on fuoroscopy (63.2% vs. 40.5%) [41].

In a meta-analysis evaluating 12 studies performed with VB [42], the overall diagnostic yield was 73.8% and 67.4% for lesions ≤2 cm. The diagnostic yield ranged from 65.4% to 81.6% in the studies where VB was associated to computed tomography and ultrathin bronchoscope, 63.3– 84.4% using rEBUS with a guide sheath, and from 62.5% to 78.7% using fuoroscopy.

The major limit of VB is that it just provides a bronchial route for approaching the lesion, but it requires other systems for con rming the arrival to the target.

Fig. 20.5  Examples of PPLs approached using EBUS-­ TBNA. Upper: nodule located in the right lower lobe, adjacent to a subsegmental bronchus. The echo bronchoscope wedged in the bronchus allows to visualize the nodule (a) and to perform EBUS-TBNA (b) (diagnosis:

carcinoid). Lower: 8 mm nodule located in the right lower lobe, close to a small bronchus (5 mm) (arrows) (c); the echo bronchoscope wedged in this bronchus allows to visualize the nodule (d) (diagnosis: metastasis from urothelial cancer)

Electromagnetic Navigation

Bronchoscopy (EMN)

EMN is a method that uses a pre-procedure CT scan-derived virtual 3D reconstruction of the lung and of the tracheobronchial tree and superimposes the real-time position of the bronchoscope instruments using an electromagnetic sensor, inserted into the working channel of the bronchoscope. An electromagnetic eld generator, located outside the patient’s body, tracks the position of the sensor. To overcome the limit of PPLs located tangentially to the bronchus, catheters with the possibility to bend the tip were developed. At the current time the two

ENB systems available on the market in Europe and the United States are: superDimension (Medtronic, Minneapolis, MN) and SPiN Thoracic Navigation System (Veran Medical Technologies, Inc, St. Louis, MO, now acquired and distributed by Olympus Corporation, Tokyo, Japan). There are no clinical trials that compare the two systems.

The overall diagnostic yield of EMN is ranging from 64% to 82%, as reported by four meta-­ analyses (Table 20.3). As we have seen for fuoroscopic guidance and for rEBUS, also for EMN a signi cant heterogeneity of results is observed. The reasons for this heterogeneity are the size and location of the lesions, the use of dif-