Interventional pulmonology is a dynamic and evolving field in respiratory medicine. Advances have improved the ability to diagnose and manage diseases of the airways. A shift toward early detection of malignant disease has generated a focus on innovative diagnostic techniques. With patient populations living longer with malignant and benign diseases, the role for interventional bronchoscopy has grown. In cancer groups, novel immunotherapies have improved the prospects of clinical outcomes and reignited a focus on optimizing patient performance status to enable access to anticancer therapy. This review discusses current and emerging diagnostic modalities and therapeutic approaches available to manage airway diseases.
Key points
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Interventional pulmonology has evolved into a major field with a crucial role in patient care pathways.
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Implementation of lung cancer screening has meant that more patients with peripheral lung nodules are detected and has increased the need for advanced and innovative bronchoscopic approaches.
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Bronchoscopic intervention commonly is used to treat benign and malignant airway obstruction in order to improve symptoms and performance status, which may allow access to further therapies previously considered not appropriate.
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There are several newer diagnostic and therapeutic bronchoscopic approaches now available in clinical practice and this review aims to provide a more detailed insight in to their utility.
Introduction
The past decade has seen somewhat of a shift away from diagnostic thoracic surgery due largely to a rapid development in technologies in interventional pulmonology (IP). Multidisciplinary thoracic cancer diagnosis and treatment involving IP, thoracic surgery, and oncology are increasingly adopted approaches. Increased focus on lung cancer screening and early detection, in particular, to aid diagnosis of peripheral pulmonary lesions (PPLs) has meant that the incidence of detection is likely to rise. Determining etiology is essential, because lesions between 0.8 cm and 2 cm have an 18% prevalence of malignancy, whereas those above 2 cm have a risk that climbs to 50%. , Therefore, timely and accurate location, sampling, and diagnosis of PPL through a minimally invasive, less morbid approach increasingly are vital.
Computed tomography (CT)-guided biopsy often is performed to investigate PPLs but suffers somewhat from certain limitations. Anatomic accessibility, size of lesion (<10 mm associated with lower diagnostic yield), and patient comorbidities all play a role in candidacy. This technique also carries a risk of pneumothorax, reported overall at approximately 15% to 20% but with a heterogeneous risk profile as high as 60% in biopsies of lesions under 20 mm. ,
Surgical biopsy still has a role to play, although this has diminished over the past decade. The main advantage remains conferring high diagnostic yield but with higher perioperative risk stratification than IP techniques. Mediastinoscopy anatomically is disadvantaged due to reduced ability to access posteriorly located subcarinal nodes and lower hilar stations (11R & 11L). Additionally, proceeding straight to surgery in PPLs is not straightforward either because it has been demonstrated that lobectomy without prior histologic confirmation of malignancy is associated with benign pathology in up to a third of cases. This review, therefore, focuses on current indications and techniques for advanced diagnostic and therapeutic bronchoscopy available in concert with traditional thoracic surgery in the management of benign and malignant thoracic disease.
Advanced diagnostic bronchoscopy
Convex Endobronchial Ultrasound
Endobronchial ultrasound (EBUS) and transbronchial needle aspiration (TBNA) revolutionized the approach to lung cancer staging and diagnosis of mediastinal disease. Use of a convex linear ultrasound array positioned at the distal end of a flexible bronchoscope allows visualization of mediastinal lymph structures outside of the airway and real-time sampling ( Fig. 1 ). This technique is associated with a high sensitivity, with tissue acquisition shown to be sufficient for immunohistochemistry and molecular analysis for targetable mutations.
Prior to the advent of EBUS, staging of disease was based on CT, PET imaging, and surgical sampling. CT imaging alone, however, has a sensitivity of 55% for detecting mediastinal lymph node metastasis, and 40% of CT-diagnosed lymph nodes considered malignant are actually benign whereas conversely, 20% of those under 10 mm are proved metastatic. , Fluorodeoxyglucose (FDG)-PET improves on this and currently is the gold standard for detection of extrapulmonary metastases. While conferring 85% sensitivity for mediastinal lymph node metastasis, it does carry a poor specificity for large mediastinal lymph nodes , ; 20% of enlarged FDG-avid lymph nodes are attributable to nonmalignant disease.
The landmark multicenter randomized ASTER trial compared surgical staging to EBUS/endoscopic ultrasound followed by surgical staging. The trial demonstrated greater sensitivity for mediastinal nodal metastases (94% in the EBUS/endoscopic ultrasound group vs 77% in the surgical group) and fewer unnecessary thoracotomies. In another study, compared with mediastinoscopy alone, diagnostic accuracy using EBUS was superior, 91% versus 78%. It must be acknowledged that this may well be in part be due to nonaccessible posteriorly located subcarinal lymph nodes via mediastinoscopy rather than overall decreased accuracy. Furthermore, there has been an effect on timing of progression through patient care pathways to treatment with EBUS. In a UK trial of 133 patients with stages I–IIIa disease, median time to treatment was shorter in those who underwent EBUS-TBNA instead of conventional diagnosis and staging, 14 days versus 29 days, respectively, with a post hoc analysis showing an increase in median survival in non–small cell lung cancer (NSCLC) patients who underwent EBUS ( Fig. 2 ).
Peripheral Pulmonary Lesions
Fluoroscopy
Fluoroscopic imaging during bronchoscopy may adjunctively improve the diagnostic yield when targeting PPLs ( Fig. 3 ). In a meta-analysis of 18 studies encompassing 1687 patients, use of fluoroscopy with bronchoscopy was associated with a 60% diagnostic success rate versus 45% when carried out via bronchoscopy alone. The presence of a bronchus leading directly to a PPL on CT scan, on-site pathology assessment, and lesion size greater than 3 cm were associated with a higher diagnostic yield.
Cone-beam computed tomography
The cone beam-CT (CBCT) method involves the use of an x-ray C-arm scanner, which rotates in real time during the procedure around a patient to produce a CT image. Although the image quality is not that of a diagnostic CT, it is sufficient to allow identification of a PPL and bronchoscopic equipment aimed at targeting this. CBCT in conjunction with other approaches has been shown effective, with a reported diagnostic yield of up to 84% in diagnosing PPLs.
Radial endobronchial ultrasound
The radial EBUS technique consists of a flexible catheter with an oscillating ultrasound probe at its tip, providing a 360º assessment of a distal airway. This may be effective particularly in PPLs where a bronchus sign is present (see Fig. 3 ). Reported diagnostic yields range from 58% to 88% in the literature. One meta-analysis reviewed 16 studies involving 1420 patients undergoing radial EBUS-guided bronchoscopy for investigation of a PPL. The sensitivity rate for detection was 0.73 (0.70–0.76). A subsequent larger meta-analysis of 57 different studies and 7872 PPLs found a diagnostic yield rate of 70.6%, with the presence of malignancy, bronchus sign, or lesion greater than 2 cm associated with a higher success rate. The presence of the probe within a lesion rather than adjacent to it also was more favorable.
Electromagnetic navigational bronchoscopy
Distal targeting of a PPL with a bronchus sign can be limited by inaccessibility due to the physical dimensions of a bronchoscope. Electromagnetic navigational bronchoscopy is a method that can be used to overcome this to diagnose lesions, sample lymph nodes, site treatment catheters (eg, radiotherapy), and place fiducial markers to assist prospective surgery. Prebronchoscopy planning CT and virtual reconstruction can be synchronized with live bronchoscopy to provide navigation ( Fig. 4 ). An electromagnetic plate beneath the plate permits a smaller steerable working channel to be advanced from the bronchoscope once the latter’s limitations are reached to distally access a lesion. The NAVIGATE study demonstrated electromagnetic navigational bronchoscopy is a safe and effective modality in diagnosing PPLs (radial-EBUS assisted in some cases), and to help site fiducial markers for surgery or stereotactic radiotherapy. ,
Bronchoscopic transparenchymal nodule access
The novel approach, bronchoscopic transparenchymal nodule access, employs augmented fluoroscopy after preprocedural planning of a path toward a peripheral parenchymal lesion through an airway wall. It does not rely on the need for a bronchus sign because the procedure involves puncturing an airway wall, dilation, and passage of a catheter through a tract toward a lesion and subsequently sampling to be performed ( Fig. 5 ). A pilot human study in 12 patients demonstrated adequate diagnostic sampling was achieved in 83% of cases. A further small study of 6 patients demonstrated a malignancy diagnosis rate of 100% in the 5 individuals able to undergo the procedure. A multicenter trial across 9 sites aiming to recruit 200 patients currently is under way.
Robotic bronchoscopy
Robotic bronchoscopy represents potentially the most advanced future platform on the horizon, with the possibility of a thinner, more flexible bronchoscope potentially being able to navigate more distally throughout the bronchial tree to interrogate disease. , A small feasibility and safety study assessing its use in investigation of pulmonary lesions in a 15-patient cohort successfully was reported without adverse events encountered.
Autofluorescence bronchoscopy
Autofluorescence bronchoscopy (AFB) can be used to detect preinvasive malignant disease by utilizing the differences between red light and green light absorption demonstrated by abnormal and normal epithelium. In abnormal mucosa, there is an increase in fluorophores, which absorb and emit fluorescence when irradiated with light (see Fig. 5 ). It is associated with a 1.4-fold to 6.3-fold increase in sensitivity in detecting preinvasive disease compared with white light alone, and a meta-analysis showed a pooled sensitivity of 85% for white light bronchoscopy (WLB) combined with AFB versus 43% for WLB alone. A key aspect to consider, however, is that AFB has a lower specificity than WLB because nonspecific airway changes often also can lead to abnormal fluorescence.
Narrow band imaging (NBI) demonstrates similar advantages and is helpful in detecting changes, such as vessel growth, tortuosity, and microvascular patterns associated with angiogenesis, which develop during early phases of premalignant disease (see Fig. 5 ). , This is achieved through emission of blue light and green light bandwidths. The former is absorbed by superficial capillaries in the mucosa and the latter by submucosal blood vessels. The combined effect allows more detailed assessment of the mucosa for signs of angiogenesis, which may accompany premalignant changes or early invasive disease. In 1 meta-analysis of 6 studies, NBI demonstrated improved sensitivity compared with WLB (86% vs 70%) and specificity (81% vs 66%) in detecting early premalignant or invasive airway disease.
Both modalities can prove effective in screening for disease recurrence in cases of previous carcinoma in situ at a surgical margin or in individuals with previously proved dysplastic airway lesions (eg, smokers), which may evolve over time. They also can be used to assess for response to treatment after previous direct endobronchial management, such as debulking and laser therapy.
Transbronchial lung cryobiopsy
Transbronchial lung biopsies have long been hindered by small tissue acquisition and crush artifact distorting analysis. Use of a flexible cryotherapy catheter probe inserted through a bronchoscope to obtain larger transbronchial lung cryobiopsies (TBLCBs) has shown increasing promise. Acquired tissue samples are larger (5–10 mm), with architecture maintained without distortion, allowing more accurate analysis. Surgical lung biopsies (SLBs), although conferring high diagnostic rates, are associated with a 30-day mortality rate of 2% in cases of video-assisted thoracoscopic biopsies and 43% in open lung biopsies. TBLCB also can be performed as a day-case procedure under monitored anesthesia care, thereby reducing risk and minimizing hospital inpatient stay. The main risks are pneumothorax (12%) and significant airway bleeding (39%), the latter managed through use of an endobronchial balloon blocker at sampling to occlude a segmental airway temporarily.
Ravaglia and colleagues compared 150 patients who underwent SLB versus 297 who underwent TBLCB. Mortality rates and length of admission were higher in surgical patients, with diagnostic yield rates of 99% (SLB) and 82.8% (TBLCB). A retrospective review of 117 patients with undiagnosed interstitial lung disease compared outcomes in 58 who underwent TBLCB versus 59 who had SLB. Diagnostic confidence was similar in both groups, at 63% in the TBLCB group and 65% in the SLB group. Contrastingly, a prospective 2-center analysis in 2019 of 21 patients who underwent sequential TBLCB followed by SLB of the same anatomic region noted only a 48% concordance in diagnosis between sampling methods. More recently, however, the COLDICE study, carried out across 9 tertiary interstitial lung disease centers in Australia, pointed to a 70.8% diagnostic agreement between TBLCB and SLB, with this as high as 95% in high-probability/definite diagnosis cases when reviewed by a specialist multidisciplinary team.
TBLCB has a lower risk profile than surgical profile but its role in the diagnostic algorithm of patients with interstitial lung disease remains to be clarified.
Therapeutic bronchoscopy for central airway obstruction
Central airway obstruction (CAO) is defined specifically as obstruction of the central airways, including the trachea, main bronchi, and bronchus intermedius. Symptoms, including cough, dyspnea, wheeze, and stridor, often develop late and may be misdiagnosed as asthma or small airways disease. Late presentation is associated with high morbidity and mortality; hence, clinician awareness is key to prevent potential respiratory failure and asphyxia. Prompt clinical assessment, peak flow measurement (as an indicator of proximal airway airflow), and cross-sectional imaging are paramount to enabling rapid diagnosis and guide management, which often manifests as emergency rescue measures.
CAO can be classified as malignant, in the context of cancer, or as benign/nonmalignant, for example, stricture secondary to vasculitis. A majority of cases are due to primary lung carcinoma, where approximately 20% of patients develop clinically significant CAO. Squamous cell carcinomas account for most of these, but rarer forms, such as adenocystic carcinomas, which classically can affect the central airways, should be noted. The types of CAO are outlined in Fig. 6 . An additional factor to consider when assessing CAO is the presence of viable lower airways and distal lung, which may influence whether intervention is appropriate.
Laser Photoresection
Laser ablation is an important tool in the management of CAO, most importantly endoluminal disease. It can be used to vaporize, coagulate, devascularize, and debulk airway lesions. In benign disease, a laser also can be used in conjunction with balloon dilatation therapy to treat strictures by cutting superficial fibrotic airway bands. The effects of laser therapy are more immediate and, therefore, can be very helpful in the context of palliative disease control and symptom relief. There are several types of lasers, each with different characteristics that in turn may guide their role ( Table 1 ); however, Nd:YAG often is the type used most commonly in bronchoscopy.
| Laser | Wavelength, nm | Penetration Depth | Vaporization | Coagulation | Cutting |
|---|---|---|---|---|---|
| APC | 516 | 1–2 mm | − | ++ | + |
| KTP | 532 | 0.8 mm | ++ | ++ | + |
| Diode | 808 | 8–10 mm | + | ++ | +++ |
| Nd:YAG | 1060 | 4–6 mm | +++ | +++ | + |
| Thulium | 1940 | 0.4 mm | ++ | ++ | +++ |
| CO 2 | 10,600 | 0.3 mm | + | − | +++ |
Bronchoscopic application can be performed through flexible or rigid bronchoscopy and is done best under general anesthesia. Given the potential depth penetration, it is important that application ensures it is fired toward the airway lumen and not perpendicular to the wall ( Fig. 7 ). Protective eyewear is mandatory to avoid retinal injury to operators and health care professionals. The most concerning risk is endobronchial fire, with a Fio 2 below 40% strictly advised in all cases when delivering therapy within the bronchial tree. Short efficient time usage is important for this reason and often improves with operator experience. Other complications include bleeding, airway perforation, pneumothorax, hemorrhage, infection, and fistula formation.
Data on use of laser therapy often are retrospective and not randomized or controlled. Furthermore, it often is used in a multimodality approach with other therapies at the time of bronchoscopy. In 1 study comparing Nd:YAG laser therapy in conjunction with external beam radiotherapy versus control (external beam radiotherapy alone), it was seen that use of additional laser therapy improved survival. A case series assessing laser therapy alone, brachytherapy alone, and both together observed a longer median survival time in the combined cohort, 264 days, versus 111 days and 115 days, respectively. Laser therapy also has been shown effective in treating endobronchial carcinoid disease, negating the need for invasive surgery.
Argon Plasma Photocoagulation
Argon plasma photocoagulation (APC) first was described in the treatment of gastrointestinal bleeding in 1981 and subsequently has been expanded in its uses to various settings. It uses nonionized argon gas to which a voltage electrical current is applied once it is injected on to a target area. This leads to ionization of the argon gas, generating a monopolar current in the target tissue and subsequent heat generation. , Its small-depth penetration means it is best suited for treatment of superficial disease and is effective in achieving hemostasis at mucosal surfaces. Due to the movement of the argon gas around bends, it can be effective to treat disease bifurcation points or distal locations within the bronchial tree. The risks related to APC are similar to those of laser photoresection; Laser therapy has also been shown to be effective in treating endobronchial disease, negating the need for invasive surgery. ,
Small cases series have shown that APC is safe and effective in treating obstructive airway lesions, both malignant and benign. It also has been shown to provide benefit in conjunction with chemotherapy in treatment of tuberculosis with evidence of airway lesions. In 1 case series of 364 patients who underwent bronchoscopy for treatment of airway tumors, APC was shown effective in hemostasis control, stent recanalization, and tumor debulking.
Electrocautery
This is a contact modality that uses an electrical probe to direct a monopolar current in to tissue to cause vaporization and coagulation. The probe tip can come in different forms, such as a snare, to loop a polypoid lesion root, or a knife, to cut through fibrotic webs in a stricture. The depth penetration is more superficial compared with a laser, with the risks similar except that no eye protection is required for operation.
Electrocautery has been shown a safe and effective therapy in treating CAO. , , , In a case series of 94 patients who underwent bronchoscopy with electrocautery for malignant or benign disease, endoscopic improvement was seen in 94% of cases along with 78% radiological improvement in luminal patency on CT and, similarly, lung aeration on both CT (63%) and radiograph (43%). A study by Boxem and colleagues showed electrocautery demonstrated comparable efficacy to Nd:YAG laser therapy in the palliative treatment of symptomatic airway obstruction and was significantly more cost effective.
Cryotherapy and Cryoextraction
Conventional cryotherapy involves repeated free-thaw cycles and can be used to treat airway stenosis, granulation tissue recurrence, and early-grade airway lesions. Freezing cells to subzero temperatures using liquid nitrogen induces cell death by damaging blood vessels, causing ischemia. Formation of ice crystals creates an osmotic gradient, driving water out of cells, resulting in cell rupture.
In acute CAO due to endoluminal disease, debulking of exophytic lesions can be performed using cryoextraction ( Fig. 8 A, B). This allows for larger pieces of tissue to be removed, enabling rapid more efficient debulking. The cryoprobe is positioned on to a target area of tumor before freezing. While the probe tip is adhered to tumor, both it and scope are retracted, shearing off larger chunks of tissue. It is effective, with a review of 16 case series demonstrating an overall success rate for significant recanalization of approximately 80%.
