28  Lung Cancer Staging Methods: A Practical Approach				493
Table 28.2  Accuracy of staging tests in lung cancer patients: meta-analysis ACCP guidelines
Procedure	Number of studies	N	Sensitivity	Speci city
Mediastinoscopy	33	9267	78	100
EUS	26	2443	88	100
EBUS	31	2756	89	100
EBUS/EUS	7	811	91	100

Endobronchial Ultrasound with Transbronchial Needle Aspiration

Endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) utilizes real-­ time ultrasound to visualize the target lesion within the airway wall/mediastinum and to visualize the biopsy needle itself during biopsy [47]. Not only is EBUS-TBNA used to diagnose and stage advanced lung cancer, but can also provide enough material for molecular analysis for treatable driver mutations [48]. There are two types of EBUS, the radial probe EBUS (RP-EBUS) and the curvilinear probe EBUS (CP-EBUS). RP-EBUS is utilized by passing the probe through the working channel of a bronchoscope and advanced into the airway to obtain a 360-degree grey scale image of the airway and surrounding structures. Unfortunately, the RP-EBUS does not allow for ultrasound guidance biopsy in real time. In comparison, the CP-EBUS has a 35 degrees forward oblique view. The scope is passed directly into the airway and the probe balloon is infated with water to allow contact with the airway wall and conduction of ultrasound waves. This provides a higher resolution image with the ability to perform real-time ultrasound guided biopsies. Color fow and Doppler can also be utilized for identi cation of vascular and cystic structures [49].

The EBUS scope can access a wide range of mediastinal and hilar lymph nodes that include 2R, 2L, 3P, 4R, 4L, 7, 10R, 10L, 11R, 11L (Fig. 28.7). The overall median sensitivity of EBUS-TBNA is reported to be 89% in a systematic review of 2756 patients, with values ranging from 46% to 97%. The median NPV was 91% ( [12], Table 28.2). Most of the studies in the review included patients with bulky lymphadenopathy, mostly radiographic group B and some

A and C. However, two studies evaluated the performance of EBUS-TBNA in patients with a normal mediastinum by CT scan and PET-CT, respectively. The prevalence of mediastinal disease was lower in the negative PET-CT group, likely due to the higher sensitivity of PET-CT to detect disease. Despite this, the negative predictive value was comparable in both groups at around 96% [50, 51].

Navigational and Robotic

Bronchoscopy

Peripheral pulmonary lesions (PPL) frequently pose a dilemma for patients and physicians trying to establish the best strategy for workup. Historically, RP-EBUS and standard bronchoscopy with fuoroscopy have been used to try to biopsy these peripheral lesions. Tanner et al. in a RTC in 2018 compared thin bronchoscopy with radial EBUS (R-EBUS) with standard bronchoscopy and fuoroscopy (SB-F) and found a diagnostic yield of 49% for the R-EBUS arm and 37% for the SB-F arm. This was not statistically signi cant [52].Newer technologies such as virtual bronchoscopic navigation (VBN), electromagnetic navigational bronchoscopy (ENB) and robotic bronchoscopy (RB), facilitates PPL diagnosis by directing a bronchoscope to its intended target via visualized three-dimensional lung models [53].

Virtual bronchoscopy involves two phases, planning phase which uses a CT scan to construct a virtual bronchial tree and the actual bronchoscopy [53]. A prospective, multicenter trial randomized 199 patients to a procedure with or without VBN resulting in a diagnostic yield of 80% for VBN vs. 67% without VBN [54]. Recently, there have been controversies involving utility and yield of VBN. Bo et al. randomized

494	T. L. Ferguson et al.

1R 1L

	6
Ao	5 mPA

3p	T	3a
		vc
E50

Fig. 28.7  Regional lymph node stations

Supraclavicular zone

1Low cervical, supraclavicular, and sternal notch nodes

SUPERIOR MEDIASTINAL NODES

Upper zone

2R Upper Paratracheal (right)

2L Upper Paratracheal (left)

3a Prevascular

3p Retrotracheal

4R Lower Paratracheal (right)

4L Lower Paratracheal (left)

AORTIC NODES

AP zone

5 Subaortic

6 Para-aortic (ascending aorta or phrenic)

INFERIOR MEDIASTINAL NODES

Subcarinal zone

7 Subcarinal

Lower zone

8 Paraesophageal (below carina)

9 Pulmonary ligament

N1 NODES

Hilar/Interlobar zone

10Hilar

11Interlobar

Peripheral zone

12Lobar

13Segmental

14Subsegmental

subjects to a standard bronchoscopy, RP-EBUS-­ guided bronchoscopy, or bronchoscopy combining both RP-EBUS and VBN. While both guided bronchoscopy groups were superior to standard bronchoscopy, there was again no difference in diagnostic yield between groups with and without VBN [55].

Electromagnetic navigational bronchoscopy involves generation of an electromagnetic eld around the patient in which devices equipped with small transponders can be tracked [53]. One

RTC looked at three arms, either RP-EBUS, ENB, or a combination of the two. The diagnostic yields were 88% for the combined procedure, 69% for RP-EBUS alone, and 59% for ENB alone [56]. Similar to VBN, there have been conficting data regarding yield of ENB. The results from the AQuIRE registry showed a much lower diagnostic yield of 38.5% with ENB alone and 47.1% with EBN combined with RP-EBUS [57].

Robotic bronchoscopy shows the ability to hold the endoscope in a locked curved position,

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28  Lung Cancer Staging Methods: A Practical Approach	495

favoring the placement of biopsy tools within the target without straightening during sampling [58]. A recent prospective, multicenter study involving 54 patients from Chen and colleagues showed a diagnostic yield of 74% [59]. Ideally, a prospective, randomized trial or a robust comparison of diagnostic yield will need to be performed before robotic bronchoscopy can become mainstream in diagnosis and staging of lung cancer.

Transthoracic Needle Aspiration

Transthoracic needle aspiration has been utilized by clinicians for decades to biopsy lung lesions and rarely stage the mediastinum. Advances in histopathology and imaging, speci cally the switch between fuoroscopy to CT, have increased the accuracy and ef cacy of TTNA [60]. The procedure involves marking the patient’s skin with radio-opaque markers and then undergoing a short spiral CT for planning of needle trajectory. Once the site and trajectory are selected, the needle passes percutaneously under image guidance to aspirate or biopsy (TTNB) tissue [61]. The pooled sensitivity for TTNA is reported to be 90% in a meta-analysis of 19 studies with a trend toward a lower sensitivity involving lesions <2 cm [62]. Given the proximity of lymph nodes to major thoracic vessels and to heart, TTNA is mostly limited to the superior mediastinal lymph nodes. The most common complication of TTNA is iatrogenic pneumothorax. The incidence of pneumothorax averages approximately 15% and 6.6% requiring chest tube placement for evacuation [63]. These factors limit the use of TTNA in staging the mediastinum and clinicians may have to rely on other biopsy modalities to obtain tissue.

Transbronchial Needle Aspiration

Transbronchial needle aspiration (TBNA) has been utilized for decades to biopsy the mediastinum, but this was initially done through a rigid bronchoscope. The rst use of TBNA through a fexible bronchoscope was introduced in 1983,

but it wasn’t until a year later that Wang and colleagues described the procedure in detail [64]. The procedure involves passing the needle catheter, which comes in different sizes, through the working channel of the bronchoscope and then directed to the target lesion. The needle is then passed through the bronchial wall and material is aspirated for tissue sampling. It can be performed as an unguided procedure during bronchoscopy or under image-guidance using a bronchoscope with endobronchial ultrasound or electromagnetic navigational capability. It is used most commonly to assess subcarinal lymph nodes and less frequently with paratracheal lymph nodes due to dif culty with directing the bronchoscope and the needle toward these lymph nodes. The overall median sensitivity was 78% (range 14%–100%) and the negative predictive value was 77% in a systematic review evaluating 2408 patients [12]. The patients included in the studies mainly had N2/N3 disease. As such, these results can be reliably applied to patients with bulky mediastinal disease; however, the high false negative rates make TBNA less useful for staging the mediastinum in patients with normal sized lymph nodes. A negative TBNA therefore cannot effectively rule out mediastinal nodal involvement and additional staging procedures should be performed. In a comparative study directly evaluating the accuracy of TBNA against the endobronchial ultrasound ne needle aspiration (EBUS-FNA) and endoscopic ultrasound ne needle aspiration (EUS-FNA), TBNA was less sensitive when individually compared to EBUS-FNA and EUS-FNA in identifying mediastinal involvement (36% vs. 69%). Ultrasound guided techniques, such as EBUS-TBNA and EUS-FNA, have largely replaced TBNA and this is due to TBNA having a lower sensitivity than ultrasound guided biopsy techniques [65].

Endoscopic Ultrasound with Needle Aspiration

Endoscopic ultrasound with ne needle aspiration for cytologic diagnosis of pancreatic cancer was rst performed by Peter Vilmann in 1991