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Abstract

Background:

Although electromagnetic navigation bronchoscopy (ENB) is highly sensitive in the diagnosis of peripheral pulmonary nodules (PPNs), its diagnostic yield for subgroups of smaller PPNs is under evaluation.

Objectives:

Diagnostic yield evaluation of biopsy using ENB for PPNs <2 cm.

Design:

The diagnostic yield, sensitivity, specificity, positive predictive value, and negative predictive value of the ENB-mediated biopsy for PPNs were evaluated.

Methods:

Patients who had PPNs with diameters <2 cm and underwent ENB-mediated biopsy between May 2015 and February 2020 were consecutively enrolled. The final diagnosis was made via pathological examination after surgery.

Results:

A total of 82 lesions from 65 patients were analyzed. The median tumor size was 11 mm. All lesions were subjected to ENB-mediated biopsy, of which 29 and 53 were classified as malignant and benign, respectively. Subsequent segmentectomy, lobectomy, or wedge resection, following pathological examinations were performed on 64 nodules from 57 patients. The overall sensitivity, specificity, positive predictive value, and negative predictive value for nodules <2 cm were 53.3%, 91.7%, 92.3%, and 51.2%, respectively. The receiver operating curve showed an area under the curve of 0.721 (p < 0.001). Additionally, the sensitivity, specificity, positive predictive value, and negative predictive value were 62.5%, 100%, 100%, and 42.9%, respectively, for nodules with diameters equal to or larger than 1 cm; and 30.8%, 86.7%, 66.7%, and 59.1%, respectively, for nodules less than 1 cm. In the subgroup analysis, neither the lobar location nor the distance of the PPNs to the pleura affected the accuracy of the ENB diagnosis. However, the spiculated sign had a negative impact on the accuracy of the ENB biopsy (p = 0.010).

Conclusion:

ENB has good specificity and positive predictive value for diagnosing PPNs <2 cm; however, the spiculated sign may negatively affect ENB diagnostic accuracy. In addition, the diagnostic reliability may only be limited to PPNs equal to or larger than 1 cm.

Keywords

2 cm diagnostic yield ENB PPNs

Introduction

Lung cancer is the global leading cause of cancer-related death.¹ Early diagnosis and treatment are pivotal to improve patient survival and reduce socioeconomic costs. Routine radiological examination of malignant nodules is usually accompanied by a series of ‘malignant’ features, such as lobulated sign, spiculated sign, vacuole sign, pleural indentation, and vessel convergence. However, these radiological signs are not obvious when the nodules are small, which complicates radiological diagnosis. Furthermore, studies have developed a series of evaluative scoring systems, such as the Mayo, Brock, and Veterans Affairs classification, to achieve an accurate radiological diagnosis of peripheral pulmonary nodules (PPNs). Nevertheless, studies comparing these classifications have shown mediocre area under the curve (AUC) performances^2,3 for which a diagnostic strategy with higher accuracy is required. The NELSON trial found that the probabilities of lung cancer for nodules measured 5–10 mm and 11–20 mm were 1.3% and 13.2%, respectively.⁴ Therefore, the application of approaches with high diagnostic yield remains a key issue in the management of smaller PPNs.

Pathological examination is the gold standard for diagnosing oncological diseases. For nodules close to the central airways, a pathological diagnosis can be achieved using endobronchial ultrasound needle aspiration (EBUS-TBNA). In contrast, PPN biopsy depends on computed tomography (CT)-or electromagnetic navigation bronchoscopy (ENB)-guided strategies. Compared to CT-guided biopsy, ENB has the advantage of decreasing the incidence of pneumothorax,⁵ and provides an efficient one-step method for minimally invasive surgery to handle PPNs.^6,7 The NAVIGATE study revealed that ENB-aided diagnosis had a diagnostic yield of 73% and a low complication rate.⁸ Additionally, a recent meta-analysis found that ENB had pooled diagnostic yields of approximately 70% and was influenced by lesion location, dimension, and presence of a bronchus sign.^9,10 Nonetheless, the median diameter of the PPNs in NAVIGATE or a couple of retrospective cohort studies was larger than or equal to 2 cm.^11–13 Compared with transbronchial biopsy, Taton et al. showed that ENB-guided biopsy could achieve five times larger sample volume and provide a higher diagnostic yield for PPNs <2 cm in diameter.¹⁴ ENB is a promising technique for the diagnosis of PPN; however, its diagnostic yield for smaller nodules requires further evaluation.

In the study, we conducted a retrospective observational study enrolling consecutive patients who underwent ENB for the diagnosis of PPNs <2 cm. The objective of this study was to assess the diagnostic yield, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

Methods

Patients

In this study, we retrospectively enrolled 65 consecutive patients with 82 pulmonary nodules treated between May 2015 and February 2020 at Sun Yat-sen Cancer Center. Preoperative routine examinations, including blood tests, pulmonary and cardiac function evaluations, bronchoscopy, chest, and abdominal CT with contrast, and cranial magnetic resonance imaging were performed in all cases. If mediastinal metastasis is suspected, EBUS or EBUS-fine-needle aspiration can be performed. Only patients without mediastinal lymph node metastases underwent video-assisted segmentation, lobectomy, or wedge resection.

The inclusion criteria were as follows: (1) nodule diameter of the long axis was <2 cm; (2) suspicion of malignancy as assessed by clinicians; and (3) PPNs located beyond the visible range of flexible bronchoscopy. Exclusion criteria included: (1) ENB-aided lung nodule location or dye marking without biopsy; (2) existence of a pacemaker or implantable cardioverter defibrillator due to expectant hazards of the electromagnetic field; and (3) pregnancy or nursing. The study was designed following the STARD guideline.¹⁵

Pre-procedure and procedure

The SuperDimension™ navigation system, software version 6.0 or 7.0 (Medtronic, Minneapolis, MN), was used to conduct all ENB procedures. All patients underwent CT scans of the chest configured with slices of 1 mm thickness at 1 mm intervals in the digital imaging and communications in medicine (DICOM) format.

All patients were administered general anesthesia. An adult-size therapeutic bronchoscope (Fujinon, Tokyo, Japan) was used. Once registration was completed, the sensor probe was attached to the lesion through an extended working channel. Successful navigation was defined as the closest distance of <1 cm between the sensor tip and the lesion center, irrespective of the size of the nodule. When the navigation was completed, the steerable probe was removed, leaving an extendable working channel through which brushing, catheter aspiration, and biopsy were performed.

Brushing or catheter aspiration was performed following biopsy using forceps. The forceps were withdrawn every three attempts at biopsy, and the position of the sensor probe relative to the target lesion was checked. The catheter aspiration technique included moving the catheter back and forth, while continued suction was applied using a 10 mL syringe. Brushing was performed in all cases, whereas needle aspiration was performed only when the target could not be placed directly in front of the sensor. Cytological and histological specimens were obtained independently from the pathology department.

After the ENB procedure, nodules with malignant or suspected malignant biopsy results were removed via wedge or lobe resection. Thus, the diagnosis of ENB was confirmed based on the postoperative pathology. If the nodules were located in different lobes, the largest nodule was removed, and the rest were followed up. CT surveillance was performed for the nodules without resection. The nodules that grew over time were considered malignant, whereas the stable nodules were benign.

Endpoints

The primary endpoint was the ENB-guided biopsy diagnostic yield, which was calculated as true positive and true negative for pathological or CT follow-up-identified malignancies. The secondary endpoints were sensitivity, specificity, PPV, and NPV. The calculations were based on comparisons between ENB-guided biopsy and postoperative pathology plus CT follow-up for nodules without surgery.

Definitions

(1) Malignant nodule in biopsy

Pathological report of ENB-guided biopsy shows adenocarcinoma, minimally invasive adenocarcinoma, squamous cell carcinoma, atypical adenomatous hyperplasia or other types of lung malignancy.

(2) Dyskaryosis

When ENB-guided biopsy finds pathological features, including nuclear atypia, active cell proliferation, cribriform/cord cellular arrangement, or stroma invasion, it usually suggests dyskaryotic cells that tend to be tumors, and the nodule is considered a ‘suspicious malignancy’. Biopsy samples without these pathological features were considered benign nodules.

(3) Benign nodule in biopsy

Pathological report of ENB-guided biopsy shows alveolar epithelial hyperplasia, normal pulmonary tissue, inflammatory cells, simply dyskaryotic cells, or interstitial fibrous proliferation.

(4) Spiculated sign

The description of the bronchus sign of PPNs with a spiculated margin (also usually described as a corona radiata sign).

Statistical analysis

All statistical analyses were performed using SPSS version 15 (SPSS Inc., Chicago, IL, USA). Descriptive statistics for all continuous variables were summarized as means, medians, and standard deviations. Discrete variables are presented using frequency distributions and cross-tabulations. Comparisons between groups of categorical data were performed using Fisher’s exact test and the chi-squared goodness-of-fit test. A p-value <0.05 indicated statistical significance.

Results

Cohort characteristics

A total of 82 lesions in 65 patients were included in the analysis. All patients successfully underwent ENB biopsy, and no cases of pneumothorax or uncontrolled bleeding occurred. The median tumor size was 11 mm (range, 2–19 mm). All lesions were subjected to ENB-mediated biopsy, of which 29 and 53 were classified as malignant and benign nodules respectively. According to the pretest probability calculated by the Mayo model,¹⁶ nearly three-quarters of the nodules (70.7%) were at intermediate risk, 26.8% were at low risk and only two cases were at high risk. The detailed patient and nodular characteristics are shown in Table 1.

Table 1.

Patient demographics and lesion features in study cohort.

Demographics	N = 65 subjects
Age (Mean ± SD)	55.3 ± 11.1
Gender (M/F)	30/35
Smoking history(Y/N)	20/45
Cancer history (Y/N)	8/57
Treatment
Surgical/non-surgical	57/8
Lesion features	N = 82 lesions in 65 subjects
Average size (cm)	1.10
Tumor location
LU/LL/RU/RM/RL	16/9/36/4/17
Distance to pleura
Inner/middle/outer	4/24/54
Spiculated sign (Y/N)	15/67
Solidary state
pGGO/sub-solid/solid	41/25/16
Biopsy
Benign/malignant	53/29
Treatment
Surgical/non-surgical	64/18
Surgical pathology
Benign/malignant	20/44
Risk of Mayo model
High/median/low	2/58/22

cm, centimeter; LU/LL/RU/RM/RL, left upper lobe/left lower lobe/right upper lobe/right middle lobe/right lower lobe; M/F, male/female; Inner/middle/outer, inner one-third/middle one-third/outer one-third of the chest cavity in each side; pGGO, pure ground-glass opacity; SD, standard deviation; Y/N, yes/no.

All 82 nodules were identified and a cytological diagnosis was obtained through brushing or catheter aspiration in the ENB procedure. Fourteen nodules were confirmed as adenocarcinoma, 15 nodules with dyskaryotic cells (tended to be malignant, Supplemental Table 1) were suspected to be malignant, and the remaining 53 nodules were negative. The distribution of biopsy diagnoses of the 53 negative nodules is shown in Supplemental Table 2.

Subsequently, VATS segmentation, lobectomy, or wedge resection, and subsequent pathological examinations were performed on 64 nodules from 57 patients. Of the 64 nodules removed, 44 (67.2%) were considered malignant, including 42 adenocarcinoma and two typical adenomatous hyperplasia (AAH). Of the remaining 20 nodules, 17 had chronic inflammation, and two had cryptococcosis. For the 18 nodules without surgical treatment, the one-month and 12-month chest CT surveillance was completed for 66.7% (12/18) and 27.8% (5/18) of the nodules, respectively. Based on the 12-month follow-up CT scan, all five nodules were confirmed to be benign.

The diagnostic yield of ENB-guided biopsy

The total diagnostic yield of ENB-guided biopsy was 66.7%. The overall sensitivity, specificity, PPV, and NPV for nodules <2 cm were 53.3%, 91.7%, 92.3%, and 51.2%, respectively (Table 2). The receiver operating characteristic (ROC) curve showed an AUC of 0.721 (p < 0.001). Neither the lobar location nor the distance of PPNs from the pleura affected the diagnostic yield of ENB. Moreover, the pretest risk of the Mayo model did not correlate with the diagnostic yield. However, the spiculated sign had a negative impact on the diagnostic yield of ENB biopsy (p = 0.010, Table 3).

Table 2.

Diagnostic yield of ENB-mediated biopsy.

Biopsy identified malignancy	Pathological identified malignancy		CT follow-up identified malignancy		Pathological or CT follow-up identified malignancy
Biopsy identified malignancy	Yes (N = 44)	No (N = 20)	Yes (N = 0)	No (N = 5)	Yes (N = 44)	No (N = 25)
Nodules <2 cm
Yes/No	23/21	0/20	0/0	2/3	23/21	2/23
1 cm ⩽ Nodules<2 cm
Yes/No	19/12	0/10	0/0	0/0	19/12	0/10
Nodules < 1 cm
Yes/No	4/9	0/10	0/0	2/3	4/9	2/13

Table 3.

Associations between CT features and diagnostic yield of ENB-mediated biopsy.

CT features	Accuracy of ENB-mediated biopsy		p-Value
CT features	Yes (N = 46)	No (N = 23)	p-Value
Spiculated sign			0.010
Yes/no	5/41	9/14
Lobar location			0.329
LU/LL/RU/RM/RL	11/4/22/2/7	4/5/8/0/6
Distance to pleura			0.713
Inner/middle/outer	1/14/31	0/5/18
Solidary state			1.000
pGGO/sub-solid/solid	23/15/8	12/7/4
Risk of Mayo model			0.603
High/median/low	1/30/15	0/18/5

CT, Computed tomography; Inner/middle/outer, inner one-third/middle one-third/outer one-third of the chest cavity in each side; LU/LL/RU/RM/RL, left upper lobe/left lower lobe/right upper lobe/right middle lobe/right lower lobe; pGGO, pure ground-glass opacity.

Subgroup analysis

In the subgroup analysis, a trend of higher diagnostic yield was identified in lesions with diameters equal to or larger than 1 cm (70.7% versus 60.7%, p = 0.386). The sensitivity, specificity, PPV, and NPV were 62.5%, 100%, 100%, and 42.9%, respectively, for nodules with diameters equal to or larger than 1 cm and 30.8%, 86.7%, 66.7%, and 59.1%, respectively, for nodules <1 cm (Table 2). The AUC values were 0.806 (p < 0.001) and 0.587 (p = 0.280), respectively.

Discussion

Rapid and precise diagnosis of suspicious lesions is crucial for determining the optimal treatment for PPNs found on chest CT imaging. ENB allows clinicians to access peripheral lung lesions beyond the scope of conventional bronchoscopy. In this study, we found that the diagnostic yield of ENB-guided was 66.7% without significant complications. Moreover, the diagnostic yield was independent of lesion location, distance to the pleura, and pretest probability of malignancy. In addition, ROC analysis revealed a higher reliability of ENB-guided diagnosis for nodules with diameters equal to or larger than 1 cm than for nodules smaller than 1 cm.

ENB-guided biopsy has advantages for the sampling of PPNs. Conventional flexible bronchoscopy has poor accuracy for the pathological diagnosis of PPNs.¹⁷ Steinfort et al.¹⁸ identified that the pooled diagnostic yield of radial endo-bronchial ultrasound (r-EBUS) was 56.3% (95% CI 51–61%) for lesions 20 mm or less. Several retrospective studies have shown that the diagnostic yield of r-EBUS is approximately 60.0%.^19,20 CT-guided percutaneous needle biopsy of pulmonary lesions has a diagnostic yield ranging from 59% to 96%.^21–23 However, the main limitation is complications, including pneumothorax (8.6–45.3%) and hemorrhage (2.9–54.5%).²⁴ Compared to CT-guided needle biopsy, no cases of pneumothorax or bleeding requiring intervention occurred in our cohort. As a minimally invasive approach, ENB has the advantage of precisely arriving at the peripheral lesion and avoiding adverse effects.

Gex et al. conducted a meta-analysis and found that the pooled accuracy, sensitivity, and specificity of ENB-guided biopsies were 73.9%, 82%, and 100%, respectively.¹⁰ However, the mean diameter of the nodules included in these studies was >2 cm. For peripheral nodules <2 cm, the diagnostic accuracy was 66.7%. It appears that a larger lesion can achieve a higher diagnostic accuracy. Lamprecht et al.¹² showed that diagnostic yield was achieved in 76% of lesions smaller than 2 cm and 89.6% of those larger than 2 cm, with the combination of ENB, PET scan, and rapid on-site evaluation. Diagnostic accuracy was defined by strictly comparing the confirmed diagnoses containing true positives and negatives. In fact, we established a difference between 5–10 mm and 11–20 mm nodules, and a diagnostic yield of 70.7% for nodules between 11 and 20 mm. In contrast, the diagnostic yield was only 60.7% for nodules between 5 and 10 mm. Therefore, diagnostic accuracy could vary depending largely on the number of smaller nodules. Although the size of the nodules may not influence the diagnostic accuracy when reaching the lesion successfully, a smaller size may decrease the accuracy of the sampling approaches. Moreover, ENB is based on virtual spatial reconstruction; therefore, a mismatch between the virtual and actual locations of the electromagnetic guide may decrease the diagnostic accuracy of ENB, despite what appears to be the success of navigation. Alexander et al. suggested that the average lesion motion was 17.6 mm between inspiratory and expiratory CT scans and that the motion could be greater when the PPN was located in the lower lobes than in the upper lobes.²⁵ The preoperative CT scan with maximal inspiratory phase is therefore required before the ENB planning in our center. Then the maximal inspiratory state can be simulated to decrease the CT to body divergence via setting ventilation machine with tidal volume of the individual patient during the ENB procedure.

Although only the ENB-guided approach was used, our study yielded comparable results. The NAVIGATE study revealed that ENB-aided diagnosis had a diagnostic yield of 73% for all size lesions.⁸ Supplemental Data 5b of the NAVIGATE article further showed a diagnostic yield of 67.3% in the <20 mm subgroup, which was similar to our diagnostic yield of 66.7%. As we were dealing with small PPNs, a few methods were attempted in our previous study to improve the accuracy. Our experience suggests that these two major tips may provide a better diagnostic yield. First, the re-check technique used, in which the position of the sensor probe in relation to the target lesion was checked every three attempts of biopsy, could help increase the diagnostic yield effectively. Second, the anesthesia colleague helped to perform breathing pauses during the biopsy, which might also be a method to improve the procedure.

As recommended by the American College of Chest Physicians Lung Cancer Guidelines, the pretest probability of malignancy of pulmonary nodules was evaluated to determine the next treatment. The Mayo model is used commonly.²⁶ For nodules with an intermediate risk of malignancy, a minimally invasive alternative to surgery is ideal as the initial diagnostic approach.²⁷ CT surveillance is preferable for low-risk nodules. Mayo scores were calculated for each nodule to classify the nodules into different risk categories. However, we found that the risk results of the Mayo model did not correlate with the diagnostic accuracy of ENB-aided biopsy. Therefore, the Mayo score cannot be used to predict ENB biopsy results, and these are two different methods for nodule evaluation. Although CT surveillance is noninvasive and convenient, psychological distress about nodules, along with long-term surveillance, has a negative impact on the quality of life. Some patients may have been lost to follow-up, resulting in a missed diagnosis of early lung cancer. Therefore, ENB may be a suitable alternative to CT surveillance for the detection of low-risk nodules.

The bronchus signs including spiculated sign, lobar location, solidary state, and distance to pleura were considered in the analysis. The results showed that spiculated signs negatively impacted the diagnostic yield of ENB biopsy. After reviewing all preoperative plans in the SuperDimension™ navigation system, nodules with spiculated signs were found to be given a wide range of targets covering all burrs. With larger targets, it is usually more difficult to locate the true lesions. Therefore, the target range may be set more effectively by simply shrinking to omit the burrs. Or, smaller targets with diameters of 1–2 mm at the planned biopsy sites could be a good choice. Other bronchus signs, such as the lobulated sign, vacuole sign, vessel convergence, and pleural indentation are difficult to be identified in small PPNs <2 cm, and therefore are not taken into consideration in our cohort.

This study had some limitations. First, it was retrospective and not prospective in nature. Second, compared to the NAVIGATE study, the enrolled cohort was relatively smaller. Further studies with more samples are required to confirm the diagnostic results for small PPNs using the ENB-guided approach alone.

Conclusion

This study suggests that ENB is an effective and safe modality for the diagnosis of peripheral pulmonary lesions measuring <2 cm. It has a higher diagnostic efficiency for nodules with diameters equal to or larger than 1 cm compared with nodules less than 1 cm. Further randomized prospective studies are required to investigate the diagnostic ability of low-risk nodules.

Supplemental Material

sj-docx-1-tar-10.1177_17534666241249150 – Supplemental material for Diagnostic yield using electromagnetic navigation bronchoscopy for peripheral pulmonary nodules <2 cm

Supplemental material, sj-docx-1-tar-10.1177_17534666241249150 for Diagnostic yield using electromagnetic navigation bronchoscopy for peripheral pulmonary nodules <2 cm by Jun-Ying Chen, Han Yang, Xiao-Dan Lin, Hong Yang, Jing Wen, Qian-Wen Liu, Lan-Jun Zhang, Peng Lin, Jian-Hua Fu, Chang-Sen Leng, Rong Yi and Kong-Jia Luo in Therapeutic Advances in Respiratory Disease

Supplemental Material

sj-docx-2-tar-10.1177_17534666241249150 – Supplemental material for Diagnostic yield using electromagnetic navigation bronchoscopy for peripheral pulmonary nodules <2 cm

Supplemental material, sj-docx-2-tar-10.1177_17534666241249150 for Diagnostic yield using electromagnetic navigation bronchoscopy for peripheral pulmonary nodules <2 cm by Jun-Ying Chen, Han Yang, Xiao-Dan Lin, Hong Yang, Jing Wen, Qian-Wen Liu, Lan-Jun Zhang, Peng Lin, Jian-Hua Fu, Chang-Sen Leng, Rong Yi and Kong-Jia Luo in Therapeutic Advances in Respiratory Disease

Supplemental Material

sj-docx-3-tar-10.1177_17534666241249150 – Supplemental material for Diagnostic yield using electromagnetic navigation bronchoscopy for peripheral pulmonary nodules <2 cm

Supplemental material, sj-docx-3-tar-10.1177_17534666241249150 for Diagnostic yield using electromagnetic navigation bronchoscopy for peripheral pulmonary nodules <2 cm by Jun-Ying Chen, Han Yang, Xiao-Dan Lin, Hong Yang, Jing Wen, Qian-Wen Liu, Lan-Jun Zhang, Peng Lin, Jian-Hua Fu, Chang-Sen Leng, Rong Yi and Kong-Jia Luo in Therapeutic Advances in Respiratory Disease

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Jun-Ying Chen

Supplemental material

Supplemental material for this article is available online.

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Supplementary Material

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