Diagnostic utility of bronchoscopy for newly emerging peripheral pulmonary lesions after pulmonary resection

Introduction

Lung cancer is one of the most common cancers worldwide (1). Among patients with early-stage lung cancer, the recurrence rate is reported to be 20–55% despite the curative intent of therapies (2,3). In addition to recurrence, the incidence of second primary lung cancer is estimated to be 1–2% per patient per year (4,5). In addition, the lungs are the most frequent sites of metastasis for many other malignant tumors (6), for which repeated metastasectomies are often performed. Therefore, optimal management of these newly emerging pulmonary lesions is essential to provide favorable survival for patients with a history of malignancy.

Bronchoscopy is a well-established procedure for obtaining tissue samples, with a relatively low risk of complications. The use of radial endobronchial ultrasound (R-EBUS) under X-ray fluoroscopic support, which can confirm the ideal location for bronchoscopic sampling in real time, has increased the diagnostic yield over conventional bronchoscopy for peripheral pulmonary lesions (PPLs) (7). According to the American College of Chest Physicians guidelines, the pooled diagnostic yield of R-EBUS-guided bronchoscopy was 73%. In addition, R-EBUS has been noted to be safe, with complication rates of 0–7.4%, without requiring intervention or death (7,8).

However, the efficacy and safety of bronchoscopic diagnosis of PPLs after pulmonary resection have not been established. As the structural changes in the residual lung after pulmonary resection are often significant (9-13), the negative influence of surgery on bronchoscopic diagnostic performance is concerning. Ueda et al. reported that 41% of patients showed ipsilateral bronchial kinks in postoperative screening using three-dimensional computed tomography (CT) after lobectomy (10). Displacement of the remaining lobe after lobectomy can sometimes be dynamic; in fact, some cases of dyspnea due to obstruction of the main bronchus after right or left upper lobectomy have been reported (11,12). Thus, prior pulmonary resection may cause distortion or stenosis of the ipsilateral bronchi, reducing the bronchoscopic approachability of newly emerging PPLs.

On the other hand, sublobar resection has been actively introduced in recent years as an alternative to standard lobectomy, for lung cancer with certain criteria (14,15). During follow-up after sublobar resection, staple line thickening occasionally occurs, and differentiating between local recurrence and granulation is important issue (9). However, resection changes the architecture of the peripheral bronchi by stapling across the lung parenchyma, which may prevent a bronchoscopic approach (9).

Therefore, this single-center retrospective study aimed to investigate the diagnostic utility of bronchoscopy for newly emerging PPLs after pulmonary resection of malignant tumors. Since surgery is considered to directly influence the architecture of the peripheral bronchi, specifically on the ipsilateral side, we compared the clinical characteristics and diagnostic results between the groups of patients after ipsilateral and contralateral pulmonary resections. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-948/rc).

Methods

Patients

The data of consecutive patients who underwent R-EBUS-guided transbronchial biopsy for PPLs at National Cancer Center Hospital, Tokyo, Japan between January 2017 and December 2022 were reviewed retrospectively. PPLs were defined as endobronchially invisible lesions located in the peripheral lungs.

Data of patients with a history of pulmonary resection for malignant tumors were extracted by dividing them into two groups: (I) ipsilateral biopsy group (i.e., those who underwent biopsy for the PPLs on the ipsilateral side of the prior pulmonary resection) and (II) contralateral biopsy group (i.e., the rest). Patients with bilateral pulmonary resections and those who underwent rebiopsy for previously diagnosed cases were excluded. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by National Cancer Center Institutional Review Board (No. 2018-090) and individual consent for this retrospective analysis was waived.

Procedures

Prior to bronchoscopy, virtual bronchoscopic navigation (VBN) was reconstructed by a workstation (Ziostation2, Ziosoft Ltd., Tokyo, Japan) using thin-section CT (TSCT) images with a slice thickness of ≤1 mm (16). Virtual fluoroscopy was simultaneously reconstructed to reflect the navigation route (17).

All bronchoscopies were performed using R-EBUS under moderate-to-deep sedation, maintaining spontaneous breathing using a nasal cannula and local anesthesia. An endotracheal tube was used in cryobiopsy cases. The procedures were performed using a flexible bronchoscope [BF-1T260 (outer diameter: 5.9 mm), BF-1TQ290 (6.0 mm), BF-P260F (4.0 mm), BF-P290 (4.2 mm), or BF-MP290F (3.0 mm); Olympus Ltd., Tokyo, Japan] combined with an R-EBUS probe (UM-S20-17S or UM-S20-20S; Olympus Ltd.). An R-EBUS probe, with or without a guide sheath (K-201 or K-203; Olympus Ltd.), was advanced through the working channel of the bronchoscope to the target bronchus, and its location was confirmed using R-EBUS and X-ray fluoroscopy. R-EBUS findings were categorized as within, adjacent to, or invisible, based on the relationship between the lesion and bronchus, as reported elsewhere (16,18).

After confirming the location of the target lesions, sampling was performed using a forceps, a brush, an aspiration needle, and/or a cryoprobe. Forceps biopsy was repeated five or more times as possible to ensure adequate diagnostic yield (19). An aspiration needle (NA-1C-1 or N-2C-1; Olympus Ltd.) was frequently used to target lesions where R-EBUS findings indicated that the lesion was adjacent to or invisible. Both were guided under X-ray fluoroscopy, with the former being transbronchial and the latter being transparenchymal. The ERBECRYO^® 2 (Erbe Elektromedizin GmbH, Tübingen, Germany) with a 1.7- or 1.9-mm cryoprobe was used for cryobiopsy, which was generally performed only once. The two-scope bronchoscope technique was used to stop bleeding after sampling by preparing an auxiliary bronchoscope (20).

Variables

The following clinical variables were collected: age, sex, lesion size, morphology, side, lobe, location, distance from the costal pleura, bronchus sign, visibility on radiography, and type of prior pulmonary resection. The lesion size was indicated by the longest diameter, and the distance from the costal pleura was measured as the shortest perpendicular length from the lateral border of the lesion to the costal pleura. The location was defined as “outer” if the lesion was in the outer third ellipse or “inner” if the rest. The bronchus sign was defined as positive if some bronchi led directly to or were contained within the detected target lesion (21,22). All imaging findings were evaluated by TSCT.

The diagnostic yield was calculated as the number of diagnostic cases divided by the overall number of cases. Diagnostic cases were determined as follows: malignant tumors with malignant pathological findings, or benign lesions with specific pathological findings such as organizing pneumonia, tuberculosis, nontuberculous mycobacterial infection, fungal infection, granuloma, and benign tumors [strict definition according to the recently published consensus definition of diagnostic yield (23)]. The final diagnosis was made by referring to reports obtained through bronchoscopy, surgery, or size changes on CT. Regarding the benign lesions that were non-diagnostic by bronchoscopy, the diagnosis was established by re-biopsy or surgery for suspected malignancy. PPLs that were reduced in size were deemed to be inflammation, not otherwise specified (NOS); otherwise, they were unknown.

On the other hand, all potential complications associated with bronchoscopy were extracted. Severe or life-threatening bleeding, according to standardized definitions (24), was counted as major events.

Statistical analysis

Descriptive statistics were presented as numbers and frequency percentages, and numerical data were presented as medians (ranges). Univariable analyses were performed using the Fisher’s exact test. In addition, a multivariable logistic regression analysis was performed using selected variables with P values <0.2 through the univariable analyses. All tests were two-sided and P values <0.05 were considered statistically significant. All statistical analyses were performed using JMP^® 17 (SAS Institute Inc., Cary, NC, USA).

Results

During the study period, 3,670 patients underwent R-EBUS-guided transbronchial biopsy under X-ray fluoroscopic support for PPLs. Of them, 220 were included in the analyses: 110 (50.0%) each in the ipsilateral biopsy and contralateral groups (Figure 1).

Figure 1 Flow diagram displaying patient inclusion. R-EBUS, radial endobronchial ultrasound.

The baseline characteristics of the patients are shown in Table 1. The median lesion size was relatively larger in the ipsilateral biopsy group than in the contralateral biopsy group (25.1 vs. 20.2 mm, P=0.21). Differences were also observed in the side and lobe distributions of the lesions. Lesions were more common on the right side (71.8% vs. 52.7%, P=0.005) and relatively fewer in the right upper lobe/left upper segment (31.8% vs. 46.4%, P=0.04) in the ipsilateral biopsy group. Other variables were comparable between the two groups. Lobectomies accounted for approximately half of the prior pulmonary resection types in both groups, while other resections were included with various frequencies.

The diagnostic results are presented in Table 2. The overall number of diagnostic cases was 158 of 220 (71.8%), and the diagnostic yield was significantly lower in the ipsilateral biopsy group than in the contralateral biopsy group (62.7% vs. 80.9%, P=0.004). If we included cases of two granuloma and nine inflammation, NOS, which followed clinical courses consistent with diagnostic success [i.e., the intermediate definition (23)], the overall diagnostic yield would be 76.8% (ipsilateral biopsy group: 70.0% vs. contralateral biopsy group: 83.6%, P=0.03). The ipsilateral biopsy group had significantly more benign lesions than the contralateral biopsy group (27.3% vs. 12.7%, P=0.01); details of the final diagnosis are listed in Table S1. According to the lobe-specific comparisons, the ipsilateral biopsy group showed a significantly lower diagnostic yield than the contralateral biopsy group in the middle lobe/lingula (45.8% vs. 85.7%, P=0.02).

Regarding complications, one case (0.9%) in the contralateral biopsy group who was taking antiplatelet agents experienced severe bleeding and required temporary selective intubation after biopsy, but none of the cases were life-threatening. Pneumothorax occurred in one case (0.9%) in the contralateral biopsy group and two cases (1.8%) in the contralateral biopsy group, of which one in the contralateral biopsy group required hospitalization for drainage. In addition, three cases (2.7%) in the contralateral biopsy group developed pulmonary infections.

Table 3 summarizes the factors affecting the diagnostic yield. In the multivariable analysis, in addition to the bronchus sign (negative against positive), visibility on radiography (not visible against visible), the lesion lobe (others against the right upper lobe/left upper segment), the biopsy group (ipsilateral against contralateral) was significantly associated with a lower diagnostic yield (adjusted odds ratio, 0.41; 95% confidence interval: 0.21–0.79; P=0.008).

Discussion

The present study investigated the diagnostic utility of bronchoscopy for PPLs that develop after the pulmonary resection of malignant tumors. Because of the different effects of prior pulmonary resections on the bronchi toward lesions ipsilateral and contralateral to the resected lung, we compared the diagnostic performance of the ipsilateral and contralateral biopsy groups. The results revealed that the ipsilateral biopsy group had a significantly lower diagnostic yield than the contralateral biopsy group (62.7% vs. 80.9%, P=0.004). The diagnostic yield in the contralateral biopsy group was comparable to those reported in previous reports (7,20,25,26), suggesting that the impact of prior surgery was minimal, whereas that in the ipsilateral biopsy group, although relatively low, was comparable to the cumulative diagnostic yield for PPLs reported in the guidelines (7), suggesting the diagnostic yield in the ipsilateral biopsy group is still at an acceptable level for clinical practice.

Multivariable analysis showed that the bronchus sign, visibility on radiography, the lesion lobe, and biopsy group were significantly associated with the diagnostic yield. Among them, a negative bronchus sign and lesion invisibility on radiography have been reported to be robustly associated with lower diagnostic yields in several previous studies (25-29). In addition, ipsilateral biopsy was a significant factor in reducing the diagnostic yield, suggesting its importance in measuring the efficacy of bronchoscopic diagnosis. This may be partly due to the differences in the proportions of malignant tumors and benign lesions between the two biopsy groups. Thickening of the staple line after sublobar resection may occur (9), and granulation is one of the main differential diagnoses. However, this situation was only observed in the ipsilateral biopsy group, which may have resulted in a higher proportion of benign lesions. Benign lesions are more difficult to diagnose on bronchoscopy than malignant tumors (26), leading to a lower diagnostic yield in the ipsilateral biopsy group.

Another factor that may have led to the lower diagnostic yield in the ipsilateral biopsy group is the direct effect of surgery on the architecture of the peripheral bronchi. This study found a markedly lower diagnostic yield for postoperative PPLs in the middle lobe/lingula (Table 2). Figure 2 shows the actual deformation of the middle lobe after right upper lobectomy in a non-diagnostic case. In the postoperative adaptations after pulmonary resections, residual lungs are often displaced irregularly, causing distortion and/or stenosis of the peripheral bronchi (9-12). The resulting airflow inhibition can cause atelectasis, which occurs more frequently in the middle lobes (30,31). Additionally, right middle lobar torsion, a severe complication that specifically occurs after right upper lobectomy (13), suggests that postoperative shift in the middle lobar bronchi is particularly significant. Surgery can make the residual middle lobe and its peripheral bronchi anatomically unstable, thus preventing bronchoscopic access.

Figure 2 Reconstructed CT images of the middle lobe and its bronchus of a non-diagnostic case after right upper lobectomy. (A) Anterior view. (B) Right view. The images show an irregular curvature of right middle bronchus (arrow) and over-expansion of the lobe (painted in cream). The target lesion is painted yellow in the middle lobe. CT, computed tomography.

In fact, a detailed comparison of lobe-specific diagnostic yields revealed a markedly lower diagnostic yield for the middle lobe/lingula in the ipsilateral biopsy group (Table 2). While some previous studies have discussed the influence of lesions in the upper or lower lobe on diagnostic yields (25,32,33), there has been little discussion regarding the middle lobe/lingula. Therefore, it is unusual for a significant difference to be limited to the middle lobe/lingula in the ipsilateral biopsy group, and it is reasonable to assume that bronchial deviation due to prior pulmonary resection may have affected the outcome.

In contrast, although lesion size has been demonstrated to be a robust predictive factor for the diagnostic yield of PPLs (25,26,32), it was not statistically significant in this study. The reasons may be multifactorial, but may be influenced by benign lesions that arise postoperatively. These benign lesions, typically granulomas, often grow along the staple line (9,10,34). Although these lesions are first followed up, it is difficult to differentiate them from local recurrences on imaging modalities, including ¹⁸F-fluorodeoxyglucose positron emission tomography (35), and biopsy is considered if they continue to grow. Therefore, these lesions are often large at the time of biopsy. Figure 3 shows a representative case of a granuloma along the staple line that was suspected to be a local recurrence. Indeed, in this study, relatively large lesions (>20.0 mm) tended to be included more frequently as benign lesions than as malignant tumors (66.0% vs. 54.6%). However, as mentioned above, the bronchoscopic diagnosis of benign lesions is more difficult than that of malignant tumors, which may offset the effect of lesion size.

Figure 3 A representative case with postoperative granuloma initially suspected of local recurrence along the staple line. (A) High-resolution CT shows a 65.3-mm lesion along the staple line (double arrow). (B) Forceps biopsy was performed referring the view on radiography where radial endobronchial ultrasound indicated within the lesion (bottom right corner). (C) The tissue sample obtained by forceps biopsy (hematoxylin and eosin stain, ×200 magnification). Scale bar: 100 µm. (D) At a higher magnification [boxed area in (C), ×100 magnification], extensive fibrosis with inflammatory reaction is observed but no malignancy cells are proven. Scale bar: 100 µm. CT, computed tomography.

Regarding safety, seven patients (3.2%) experienced complications, none of which were life-threatening. The complication rates were not statistically different between the ipsilateral and contralateral biopsy groups (0.9% vs. 5.5%, P=0.12) and were comparable to those in previous studies of R-EBUS-guided bronchoscopy (0–7.4%), despite decreased respiratory function after prior pulmonary resection (7,8). On the other hand, surgical lung biopsy has been reported to cause complications in 3.6–12.9% of cases, even in the initial diagnosis without prior resection (30,31). In particular, there is a certain amount of risk associated with repeated pulmonary resections (20). Another diagnostic method, transthoracic needle biopsy (TTNB), has been reported to have a better yield than bronchoscopy, but also a higher complication rate (36). Notably, pneumothorax is a frequent complication which occurs in 10–40% of TTNB cases, requiring drainage in 1.1% of patients, and can be fatal in patients who have undergone lung resection. Therefore, it is reasonable to attempt a bronchoscopic diagnosis first. Recently, two randomized controlled trials, CALGB-140508 and JCOG-0802, reported non-inferior survival rates of sublobar resection compared to lobectomy for Stage IA lung cancer (14,15). Therefore, the number of sublobar resections is expected to increase in the future. However, local recurrence rates are reportedly higher than lobectomy (15,37). Thus, in the future, an accurate evaluation of postoperative lesions suspected of local recurrence will be increasingly required in clinical practice. In this study, the ipsilateral biopsy group had a significantly lower diagnostic yield than the contralateral biopsy group but was still at a practical level. Considering the current situation in which it is almost impossible to distinguish benign lesions from local recurrences using imaging modalities (35), bronchoscopy is a useful option.

This study has several limitations. First, owing to the retrospective nature of the study performed at a single cancer center, the possibility of selection bias cannot be excluded. Second, the type of bronchoscope and sampling device to be used were discussed at the pre-conference, but the final decision was left to the discretion of each bronchoscopist, depending on the situation during the bronchoscopy. Third, all bronchoscopies were performed under the same setting combined with VBN, R-EBUS, and X-ray fluoroscopy. Essentially, there should not be much difference in terms of the transbronchial approach; caution may be needed regarding the external validity for other advanced modalities, such as electromagnetic navigational bronchoscopy and robotic-assisted bronchoscopy (38,39). Fourth, as we could not refer all patients with newly emerging PPLs after pulmonary resection, the cohort of this study included only patients for whom bronchoscopy was ordered at the discretion of their physicians. The current results should be validated in multicenter prospective cohorts with newly established criteria for patient enrollment.

Conclusions

This study demonstrated that bronchoscopy has sufficient diagnostic yield and safety for newly emerging PPLs after the pulmonary resection of malignant tumors. Although the diagnostic performance was reduced in biopsies ipsilateral to prior resections, it was still at a practical level, and diagnostic bronchoscopy would be useful for PPLs.

Acknowledgments

We would like to thank Editage (www.editage.com) for English language editing.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-948/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-948/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-948/prf

Funding: This study was partially supported by the National Cancer Center Research and Development Fund (29-A-13, 2020-A-12, and 2023-A-15).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-948/coif). Y.M. receives research funds from Hitachi; consulting fees from INTUITIVE; and lecture fees from Olympus, AstraZeneca, Novartis, COOK, AMCO, Thermo Fisher Scientific, Erbe Elektromedizin GmbH, Fujifilm, Chugai, Eli Lilly, Merck, Takeda, and ETHICON. H.F. receives research funds from Hitachi High-Tech Corporation and lecture fees from Erbe Elektromedizin GmbH and AstraZeneca. K.U. reports grants from Japan Society for the Promotion of Science (JSPS) KAKENHI (grant Nos. JP22K15698, JP19K16966), and receives payments for lectures from Novartis, Thermo Fisher Scientific, AstraZeneca and Chugai. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by National Cancer Center Institutional Review Board (No. 2018-090) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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