Yifan Fu,Xinyu Yuan,Wenyin Pan,Yijie Lu,Daxiong Zeng,Junhong Jiang
Comparative analysis of the efficacy and safety of electromagnetic navigation bronchoscopy combined with x‐ray or radial endobronchial ultrasound biopsy in the diagnosis of small peripheral pulmonary nodules
biopsy,electromagnetic navigational bronchoscopy,radial endobronchial ultrasound,small peripheral pulmonary lesions
Abstract Objective To compare the clinical value and safety of electromagnetic navigation bronchoscopy (ENB) combined with radial endobronchial ultrasound (R‐EBUS) or x‐ray in the diagnosis of small peripheral pulmonary nodules that cannot be diagnosed by conventional bronchoscopy. Methods Fifty‐six patients with peripheral pulmonary nodules of <3 cm in diameter who underwent bronchoscopy at the First Affiliated Hospital of Soochow University and Dushu Lake Hospital of Soochow University from February 2019 to January 2022 were selected as the study subjects, including 24 patients who underwent ENB combined with x‐ray and 32 patients who underwent ENB combined with R‐EBUS. ENB was used as the guiding method in both groups, and x‐ray group and R‐EBUS group were combined with x‐ray and R‐EBUS, respectively, to determine whether the lesion was reached. In x‐ray group, biopsy and brushing were performed under fluoroscopic guidance. Using the results of surgery, puncture pathology, or clinical follow‐up 1 year as the gold standard, the diagnostic sensitivity, specificity, negative predictive value (NPV), diagnostic yield, negative likelihood ratio (LR‐), Youden index, missed diagnosis rate, success rate, and κ value were compared between the two groups, and the occurrence of postoperative complications was also compared between the two groups. Results The negative predictive value of the R‐EBUS group was significantly better than that of the x‐ray group (p = 0.006). Conclusion Even with smaller nodule diameters, the negative predictive value of ENB combined with R‐EBUS were still higher than that of the x‐ray group.
Comparative analysis of the efficacy and safety of electromagnetic navigation bronchoscopy combined with x‐ray or radial endobronchial ultrasound biopsy in the diagnosis of small peripheral pulmonary nodules

To compare the clinical value and safety of electromagnetic navigation bronchoscopy (ENB) combined with radial endobronchial ultrasound (R‐EBUS) or x‐ray in the diagnosis of small peripheral pulmonary nodules that cannot be diagnosed by conventional bronchoscopy.

Fifty‐six patients with peripheral pulmonary nodules of <3 cm in diameter who underwent bronchoscopy at the First Affiliated Hospital of Soochow University and Dushu Lake Hospital of Soochow University from February 2019 to January 2022 were selected as the study subjects, including 24 patients who underwent ENB combined with x‐ray and 32 patients who underwent ENB combined with R‐EBUS. ENB was used as the guiding method in both groups, and x‐ray group and R‐EBUS group were combined with x‐ray and R‐EBUS, respectively, to determine whether the lesion was reached. In x‐ray group, biopsy and brushing were performed under fluoroscopic guidance. Using the results of surgery, puncture pathology, or clinical follow‐up 1 year as the gold standard, the diagnostic sensitivity, specificity, negative predictive value (NPV), diagnostic yield, negative likelihood ratio (LR‐), Youden index, missed diagnosis rate, success rate, and κ value were compared between the two groups, and the occurrence of postoperative complications was also compared between the two groups.

The negative predictive value of the R‐EBUS group was significantly better than that of the x‐ray group (p = 0.006).

Even with smaller nodule diameters, the negative predictive value of ENB combined with R‐EBUS were still higher than that of the x‐ray group.

Lung cancer remains the malignancy with the highest tumor mortality in the world. With the popularity of low‐dose spiral computed tomography (CT) scanning, more and more peripheral pulmonary nodules are accidentally detected. The National Lung Screening Trial reported low‐dose CT (LDCT) brings a relative risk reduction in lung cancer mortality of 20% (95% CI, 6.8%–26.7%). Because 30% of early lung cancers are located in the peripheral one‐third of the lung, an area not accessible by conventional bronchoscopy, and although ultrathin bronchoscopes with smaller outer diameter have been developed, the diagnostic efficacy of the ultrathin bronchoscope remains low. The overall diagnostic yield of fluoroscopic‐guided ultrathin bronchoscopy compared with standard‐size bronchoscopy was 55.0% versus 80.0%, respectively (p = 0.18), because of complex subsegmental bronchial structures and limited biopsy sample. However, there is a certain probability of malignancy while conventional bronchoscopy is difficult to obtain pathological tissue, so the management of small pulmonary nodules is often follow‐up observation or premature surgical resection. Long‐term follow‐up not only poses a greater risk of radiation exposure to patients, but also psychologically increases patient stress. , From the physician's perspective, determining the nature of these lesions that are difficult to detect by conventional bronchoscopy or imaging is a pressing issue. Navigational bronchoscopy is one of the tools that can help to reach the pulmonary nodules located in the peripheral one‐third of the lung. , Several different navigation systems are now available. These include virtual bronchoscopic navigation (VNB) and electromagnetic navigation bronchoscopy (ENB), both of which use images from CT scans to reconstruct three‐dimensional (3D) maps of the airways, thereby creating visualized bronchoscope access routes through the airway. Guiding sheath (GS) is a bronchoscope accessory to help locate sampling, which can navigate bronchoscope to lock working channel and improve sampling accuracy. The angle of the sheath, the stiffness of the biopsy tool, and the structure of the surrounding lung parenchyma all influence the severity of deflection, which in turn impacts the accuracy of sheath positioning. , In Oki et al.'s study, the diagnostic yield of histological specimens was significantly higher in the GS group than in the non‐GS group (55.3% vs. 46.6%; p = 0.033). High‐resolution chest CT (HRCT) provides finer details of lung architecture and combined with navigation technology provides a roadmap of distal lesions for bronchoscopy. Three‐dimensional reconstruction based on HRCT imaging can construct a virtual 3D map of the pulmonary tracheal system and plan a virtual path for lower level subsegmental bronchial lesions. Combined with real‐time imaging during bronchoscopy, it provides precise localization of difficult to reach targets. ENB is a novel bronchoscopy method based on electromagnetic localization technology, combined with the virtual bronchoscopy, 3D computed tomography imaging, and respiratory gating techniques. ENB‐guided biopsy may save patients from loss of opportunity for surgery at an advanced stage and reduce surgical trauma. In previous studies, ENB combined with x‐ray or radial endobronchial ultrasound (R‐EBUS) has been studied. , There are not many studies on the differences in diagnostic efficacy and safety between ENB combined with x‐ray and R‐EBUS.

Fifty‐six patients with benign or malignant peripheral pulmonary nodules who visited the First Affiliated Hospital of Soochow University and Dushu Lake Hospital of Soochow University from February 2019 to January 2022 were selected as the study subjects. Peripheral pulmonary nodules were difficult to assess by imaging that could not be diagnosed by conventional bronchoscopy. All patients were informed about the study and signed the informed consent form, and the study was reviewed and approved by the hospital ethics committee. It was registered on the China Clinical Trials (ChiCTR2100045573). There was no significant difference in gender, age, height, weight, and smoking history between the two groups (p > 0.05), lesion diameter was significantly smaller in the R‐EBUS group (p < 0.001), as shown in Table 1.

The ENB system we use consists of the following four parts: (1) The electromagnetic navigation bronchial localization system (EMND001A, Changzhou Lung Health Medical Instrument) constructs a 3D lung model by CT data in DICOM format and connecting the magnetic navigation localization plate. (2) The magnetic navigation positioning plate connects the positioning system to provide the magnetic field required for magnetic navigation positioning. (3) The guiding catheter provides the working channel of guiding catheter and fixes the biopsy position in the subsegmental bronchus that cannot be reached by bronchoscope. (4) The positioning catheter is a flexible catheter with magnetic positioning sensor at its end. We used an Olympus bronchoscopy system (model BF‐1TQ290, BF‐Q290 Olympus) and a radial ultrasound probe (model UM‐S20‐17S, Olympus).

Patients were fasted and deprived of water for 6 hours before surgery. Patients were given 5 mL of 2% lidocaine nebulized and intravenous midazolam (0.03‐0.04 mg/kg) and fentanyl (10‐12 µg/kg), and then the patient was placed supine on a magnetic navigation positioning board. Electrocardiogram monitoring and oxygen inhalation were given.

The chest CT data with a slice thickness of 0.5 ~ 1.5 mm were imported into the magnetic navigation bronchus positioning system for 3D bronchial structure reconstruction and planning the path from the main carina to the lesion (Figure 1). The operator inserted the positioning catheter and the guiding catheter into the bronchoscopic working channel and selected the registration point in the patient's main bronchus to complete registration. After reaching the target location under the guidance of the magnetic navigation positioning system, the operator fixed the guiding catheter, withdrawed the positioning catheter and confirmed whether the lesion was reached with the X‐ray or radial ultrasound probe. Then biopsy forceps and cell brushes were placed through the guiding catheter to complete the forceps and brushing (Figures 2 and 3).

Compare the degree of coincidence between the pathological results of biopsy and the final diagnosis between the two methods, and the final diagnosis is based on the results of surgery, puncture pathology, or clinical follow‐up.

Data analysis was performed using SPSS 24.0 software, measurement data were described as mean ± standard deviation (x ± s), t‐test was used, enumeration data were analyzed by χ2 test, and Fisher exact test was used when n < 40. The agreement test between the two methods was performed using the κ test, and p < 0.05 was considered statistically significant. Multivariate logistic regression analysis was performed to explore significant factors influencing diagnostic yield. Diagnostic yield is defined as the rate of true positives (for malignancy) plus true negatives (for malignancy) out of all procedures.

The diagnostic results of all nodules are shown in Table 2.

The sensitivity of ENB combined with x‐ray for suspicious pulmonary nodules biopsy was 47.4% (9/19), specificity was 100% (5/5), negative predictive value was 33.33% (5/15), diagnostic yield was 58.33% (14/24), negative likelihood ratio was 0.526, Youden index was 0.47, missed diagnosis rate was 52.6% (10/19), success rate was 95.8%, κ value was 0.273. The radial ultrasound group had a sensitivity of 50% (6/12), specificity was 100% (20/20), negative predictive value was 76.92% (20/26), diagnostic yield was 81.25% (26/32), negative likelihood ratio was 0.5, Youden index was 0.5, missed diagnosis rate was 50% (6/12), success rate was 87.5%, and κ value was 0.556. The negative predictive value was significantly better in the ENB group than in the x‐ray group (p = 0.006). A multivariate analysis revealed that lesion size was (>20 mm or ≤20 mm) an important factor affecting diagnosis (Tables 3, 4, 5, 6).

No significant complications occurred in the x‐ray group, and three patients in the R‐EBUS group developed mild to moderate pneumothorax.

Into the 21st century, along with the popularization and development of advanced CT scans, the number of patients found to have pulmonary nodules has gradually increased. For nodules <8 mm without obvious malignant signs such as lobulation sign and burr sign, and if the patients have no risk factors such as smoking and family history of cancer, they can be advised to continue follow‐up in clinical practice. For nodules with significantly increased nodule size, increased solid components, or vascular and pleural invasion, the surgical risks and benefits can be assessed in multidisciplinary consultation, and appropriate treatment measures can be developed considering the value and desire of patients. Bronchoscopic lung biopsy is undoubtedly a safe and reliable technique for preoperative diagnosis of pulmonary nodules, but the sensitivity in the diagnosis of a solitary pulmonary nodule via conventional bronchoscopy with fluoroscopy has been low (≈33%), especially for smaller nodules <2 cm in diameter. The sensitivity of transthoracic needle aspiration (TTNA) to malignant disease was excellent, but TTNA was associated with a higher incidence of pneumothorax compared to bronchoscopy, up to 24% in some studies. In a one‐year multicenter study of NAVIGATE, ~73% of patients could be diagnosed under ENB guidance, and in our practice, the combined R‐EBUS group had a higher diagnostic agreement rate, but the combined x‐ray group had a slightly lower diagnostic agreement rate, which, in our opinion, may be related to the size and location of the lesion as well as the patient's respiratory amplitude. Because of the limitation of the number of cases, the specific correlation has not been further studied, and it can be continued to be analyzed after more patients are included in the future. Of the navigation failures in the R‐EBUS group, one failed because the patient was obese and the lesion was located in the lower lobe, with excessive respiratory amplitude during navigation, and three failed because the subsegment bronchi, where the lesion was located, was too thin and steeper and the locatable guide could not reach. Remarkably, navigation success rate is not consistent with diagnostic accuracy. This is also reflected in previous studies. In the study by Steinfort et al. although electromagnetic navigation increases visualization for lesions that could not be located by EBUS + VB (Virtual Bronchoscopy), the addition of electromagnetic navigation resulted in only modest increases in EBUS localization and procedural yield (8% and 4%, respectively). That is, ENB can help to reach lung lesions after unsuccessful EBUS, but is often insufficient to ensure diagnosis. This may be because ENB has a small working channel and requires a biopsy tool with a smaller diameter to pass through, so biopsy sampling is less. The combined use of ENB and cryobiopsy may improve this. In our results, lobar distribution, lesion size, distance from pleura, and presence or absence of pneumatic bronchial sign were included in logistic regression analysis affecting diagnostic yield, and the results showed that lesion size was (>20 mm or ≤20 mm) an important factor affecting diagnosis. Bronchial signs have been mentioned in some existing literature to significantly influence diagnostic yield, which has not been identified in our study. It seems to us that there must be a tracheal pathway associated with the target location that the bronchoscope can reach, whether or not it appears on the image. The size of the lesion may affect the quality of sampling and then the diagnostic yield. For larger lesions, the biopsy tool is easier to obtain tumor cells, and it is difficult to ensure that the appropriate tissue is clamped even if the small lesion reaches the location. The same operator was a strength of this study, which reduced operator excursions. In addition, equipment varies from institution to institution. R‐EBUS combined with ENB is easier to implement in a wider area, there are far more hospitals with EBUS than x‐ray. In addition, x‐ray requires a radiation‐proof operation room, which requires more investment. However, because of the small sample size of this study, this conclusion still needs to be confirmed by a large sample size study. Another limitation, the two groups of patients were not randomized controlled included. Clinicians should closely combine the specific circumstances of patients during the selection of lung nodule biopsy. The diagnostic yield of ENB varies widely in different studies and may be related to operator's experience. In future, electromagnetic navigation combined with robotics, which combines the real‐time localization and route planning of magnetic navigation for peripheral lung lesions with better passing ability of robotic bronchoscopy in tortuous subsegmental bronchi. Biopsy can be performed on lesions that are difficult to reach with a hand‐held bronchoscope (bending angle is more distorted). With the help of engineers, it is expected to reduce the requirements for the experience of bronchoscope operators.

ENB combined with R‐EBUS have achieved higher negative predictive value than with x‐ray. Lesion size may be a critical factor affecting diagnostic yield of ENB.

Yifan Fu: Data analysis and Writing. Xinyu Yuan: Formal analysis. Wenying Pan: Validation. Yijie Lu: Project administration and Resources. Daxiong Zeng: Writing ‐ Review & Editing. Junhong Jiang: Methodology.

The authors declare no conflict of interest.