Localization strategies for deep lung nodule using electromagnetic navigation bronchoscopy and indocyanine green fluorescence: a technical note

Introduction

The widespread adoption of high-resolution computed tomography (CT) has led to a significant increase in the detection of pulmonary nodules, particularly those located deep within the lung parenchyma (1). While many deep lung nodules are benign, a considerable proportion may represent early-stage malignancies, necessitating accurate localization for timely diagnosis and treatment (2).

However, conventional techniques, such as percutaneous needle localization or intraoperative digital palpation, have limitations in accessing deep nodules, often leading to suboptimal outcomes (3,4). Percutaneous needle localization requires puncturing the chest wall, potentially causing complications such as pneumothorax and bleeding. Moreover, it has certain requirements for the location of the lesion; if the nodule is far from the pleura or near the pulmonary fissure, the puncture needle may not accurately reach the lesion. Intraoperative digital palpation, on the other hand, heavily relies on the surgeon’s experience, and small nodules can be easily missed.

Electromagnetic navigation bronchoscopy (ENB) has emerged as a promising minimally invasive approach for localizing lung nodules. By integrating preoperative CT imaging with real-time electromagnetic tracking, ENB enables precise guidance of specialized tools to the target nodule (5). ENB localization is not restricted by the location of the nodule; even if the lesion is deeply situated, it can be accessed through the bronchial tree, greatly reducing the risk of complications. Additionally, ENB allows for accurate preoperative localization and employs marking techniques such as dye injection, providing clear visual guidance for surgical resection, which facilitates precise resection with adequate margins. The feasibility of ENB-guided video-assisted thoracoscopic surgery (VATS) surgery with common dyes for pulmonary nodule localization have been reported. Mariolo et al. (6) reported 48 patients underwent ENB-guided methylene blue dye localization, and 94% lesions were successfully resected without severe complications. Yang et al. (7) achieved a 100% localization success rate in 12 patients using ENB-guided indocyanine green (ICG) dye localization. These studies demonstrate that ENB-guided dye localization techniques have similarly high safety and effectiveness.

While most studies have focused on the direct lesion marking technique (6,7), the potential of ENB in facilitating other localization strategies for deep lung nodules remains largely unexplored. To address this gap, we propose four distinct ENB-guided localization strategies. These strategies may aid in achieving optimal surgical outcomes, particularly in cases where preserving lung function is crucial. To the best of our knowledge, no prior studies have systematically evaluated these techniques in the context of deep lung nodules.

This technical note aims to bridge this gap by comparatively evaluating the procedural outcomes, accuracy, and clinical implications of these four ENB-guided localization strategies. By providing a comprehensive analysis of their strengths and limitations, we seek to expand the armamentarium of minimally invasive options for managing deep lung nodules, ultimately improving patient care and surgical outcomes. We present this article in accordance with the SUPER reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1303/rc).

Preoperative preparations and requirements

Patients presenting with deep lung nodules were prospectively enrolled in this study based on predefined inclusion criteria: (I) nodules located more than 2 cm from the pleural surface; (II) malignant suspected; and (III) a size ranging from 5 to 20 mm in diameter; exclusion criteria: patients with severe comorbidities or inability to tolerate general anesthesia. Particularly, nodules located at the segmental bronchial orifice or in close proximity to the lung hilum were excluded from this study. These locations pose challenges for ENB-guided localization due to the absence of suitable bronchial access and the potential need for more invasive techniques. Moreover, for nodules very close to the hilum, lobectomy remains the only surgical option, making localization unnecessary.

Step-by-step description

ENB procedures

ENB procedures were performed under general anesthesia using the SuperDimension^TM navigation system (Medtronic, Minneapolis, MN, USA). Preoperative CT images were used to construct a 3D airway map and plan the navigation pathway to the target nodule. Each patient had a single nodule that required localization, even if they had multiple nodules present.

One of the four localization strategies was employed:

• Direct lesion marking: the extended working channel was used to inject 0.1–0.2 mL of ICG dye directly into the nodule (Figure 1).
• Superficial marking: the extended working channel was advanced to the visceral pleura overlying the nodule, and 0.1–0.2 mL of ICG dye was injected to create a visible marking (Figure 2).
• Resection boundary marking: this technique involves placing three to four ICG dye injections in a triangular or rectangular pattern surrounding the nodule. These markings delineate the boundaries within which the resection should be performed, ensuring adequate margins. The dye injections are typically placed 1–2 cm away from the nodule, depending on its size and location (Figure 3).
• Margin sphere marking: in this approach, four ICG dye injections are placed equidistant from the nodule, forming a virtual three-dimensional “sphere” around it. The distance between each injection and the nodule is typically set at 2 cm, providing a standardized resection margin. This technique aims to ensure a consistent and adequate resection margin in all directions (Figure 4).

Figure 1 Direct lesion marking using ENB and indocyanine green fluorescence. (A) Preoperative CT scan showing the target pulmonary nodule (arrow). (B) ENB-guided placement of the indocyanine green dye marker. (C) Intraoperative fluorescence thoracoscopic image demonstrating the precise localization of the nodule (circled). ENB, electromagnetic navigation bronchoscopy; CT, computed tomography.

Figure 2 Superficial marking using ENB and indocyanine green fluorescence. (A) Preoperative CT scan depicting the target pulmonary nodule (arrow). (B) ENB-guided injection of indocyanine green dye at the pleural surface overlying the nodule. (C) Intraoperative fluorescence thoracoscopic image showing the superficial dye marking (circled) guiding the resection of the deeply situated nodule. ENB, electromagnetic navigation bronchoscopy; CT, computed tomography.

Figure 3 Resection boundary marking using ENB and indocyanine green fluorescence. (A) Preoperative CT scan identifying the target pulmonary nodule (arrow). (B) ENB-guided injection of indocyanine green dye at three sites surrounding the nodule, delineating the resection margins. (C) Intraoperative fluorescence thoracoscopic image displaying the resection boundary markings ensuring adequate resection margins. (D) The photograph of tumor specimen (circled). ENB, electromagnetic navigation bronchoscopy; CT, computed tomography.

Figure 4 Margin sphere marking using ENB and indocyanine green fluorescence. (A) Preoperative CT scan localizing the target pulmonary nodule (arrow). (B) Three-dimensional reconstruction of the margin sphere marking strategy, with four indocyanine green dye injections placed equidistant from the nodule. (C) Intraoperative fluorescence thoracoscopic image illustrating the right margin sphere markings (arrow) providing a virtual resection boundary with a 2 cm radius. (D) The photograph of tumor specimen (circled). ENB, electromagnetic navigation bronchoscopy; CT, computed tomography.

Procedures were performed by an experienced team ensuring consistent application of the localization techniques. ENB procedures were performed in a dedicated bronchoscopy suite equipped with the necessary facilities for bronchoscopic examinations and interventions. The room was maintained at a high level of cleanliness to minimize the risk of infection. Although the procedures were not conducted in a formal operating theatre, strict aseptic techniques were followed throughout the process. The procedures were performed by a multidisciplinary team consisting of 1–2 thoracic surgeons, 1 nurse, and 1–2 anesthesiologists. Intraoperative monitoring during ENB procedures followed the standard protocols for general anesthesia. This study was approved by the Ethics Committee of Peking Union Medical College Hospital (I-22PJ1133) and conducted in accordance with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from all the patients for publication of this surgical technique and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Quality control

To ensure the quality and consistency of the ENB-guided dye marking procedures, the following measures were taken: (I) only certified and qualified surgeons who had passed the necessary assessments were allowed to perform the procedures; (II) all patients requiring ENB localization were discussed by at least three thoracic surgeons before the procedure; (III) the volume and concentration of the injected dye, as well as the distance from the pleura for marking, were kept consistent to minimize variations among different cases.

Data collection and analysis

The primary outcomes were the success rate of ENB-guided localization and the resection margin status. The success rate was defined as the successful resection of the nodule within the excised lung tissue with satisfactory margins. Secondary outcomes included procedural time and complications (pneumothorax or hemorrhage).

Categorical variables were expressed as frequencies and percentages, while continuous variables were expressed as means and standard deviations. The Chi-squared test or Fisher’s exact test was used to compare categorical variables, while the Student’s t-test or Mann-Whitney U test was used for continuous variables. A P value <0.05 was considered statistically significant. All analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA).

Postoperative considerations and tasks

After the completion of ENB-guided ICG fluorescence marking and VATS resection, several essential postoperative considerations and tasks should be addressed to ensure optimal patient outcomes and facilitate the evaluation of the marking technique’s effectiveness. These include fluorescence visualization assessment, pathological examination, postoperative monitoring, pain management, chest tube management, follow-up and surveillance.

Tips and pearls

A total of 80 patients with deep lung nodules were enrolled in this study. Patient characteristics and nodule features are shown in Table 1. The mean age was 62.5±10.3 years, and 45 (56.3%) patients were male. There were no significant differences in age, gender, nodule size, distance from pleura, surgical approach or nodule location among the four localization strategy groups. The nodules were distributed across various pulmonary segments, with no significant clustering observed in any particular segment.

The overall success rate of ENB-guided localization was 97.5% (78/80). The success rates for direct lesion marking, superficial marking, resection boundary marking, and margin sphere marking were 95% (19/20), 95% (19/20), 100% (20/20), and 100% (20/20), respectively (P=0.98). The visibility of fluorescence varied among the four marking methods. In the direct lesion marking group, visible fluorescence was observed in 6 out of 20 cases (30%). Both the superficial marking and resection boundary marking groups achieved 100% fluorescence visibility (20/20 cases each). In the margin sphere marking group, although the overall success rate was 100% (20/20), simultaneous clear visualization of all four boundary points was achieved in only 8 out of 20 cases (40%), with most cases showing fusion or absence of certain boundary points. The mean procedural time was 25.6±8.4 minutes, with no significant differences among the four groups (P=0.74).

The surgical approach was determined based on the nodule size, location, and patient’s lung function. As all nodules in this study were deeply located, wedge resection was generally not considered suitable. Instead, segmentectomy was performed in the majority of cases to ensure adequate resection margins while preserving lung function. The number of patients undergoing segmentectomy in each group was as follows: direct lesion marking (16/20), superficial marking (15/20), resection boundary marking (17/20), and margin sphere marking (16/20). No patients underwent lobectomy, as localization was not deemed necessary for this extensive resection.

No severe complications, such as massive hemorrhage or tension pneumothorax, occurred during the ENB procedures. One patient (1.3%) had minor bleeding at the dye injection site. It occurred in a patient from the superficial marking group. During thoracoscopy, we observed a hematoma on the pleural surface, which was likely caused by the dye injection. The hematoma was limited in size and did not compromise patient safety or the smooth progression of the subsequent surgery. The patient had an uneventful postoperative recovery. The complication rates were similar among the four groups (P=0.39).

Successful VATS resection was achieved in all 78 patients with successful ENB-guided localization. Negative resection margins were achieved in all the 78 patients (100%). Malignancy was confirmed in 68 patients (87.2%). Pathological examination of the resected specimens revealed no observable interference from the ICG dye used in the localization methods. The light color and minimal visual presence of ICG allowed for accurate pathological assessment, and no disruption of the tissue architecture or cellular morphology was noted.

Discussion

In this study, we evaluated the efficacy and safety of four ENB-guided localization strategies using ICG fluorescence for deep lung nodules: direct lesion marking, superficial marking, resection boundary marking, and margin sphere marking. Our findings demonstrated that all four techniques achieved high success rates and low complication rates, indicating that ENB combined with fluorescence imaging is a reliable and safe tool for preoperative localization of deep lung nodules.

The overall success rate of ENB-guided localization in our study was 97.5%, which is comparable to or higher than those reported in previous studies (6,7). The results of our study are consistent with the reported feasibility of ENB-guided dye localization in other centers. This high success rate can be attributed to meticulous preprocedural planning and strict adherence to the ENB protocol. The lack of significant differences in success rates among the four groups suggests that all four localization strategies are equally effective in marking deep lung nodules. The use of ICG dye in combination with fluorescence thoracoscopy is a novel aspect of our study.

The use of ICG dye in combination with fluorescence thoracoscopy is a highlight of our study. This approach enhances the visibility of the dye markings during VATS, enabling more precise resection of the targeted nodules (8,9). The high rate of negative resection margins in our study underscores the potential of fluorescence-guided VATS in improving surgical outcomes for deep lung nodules.

Based on our results, we recommend that surgeons prioritize the use of superficial marking and resection boundary marking methods when utilizing ENB-guided localization with ICG dye. These techniques offer superior fluorescence visibility and more consistent outcomes, ensuring precise resection margins and minimizing the risk of incomplete resection.

The choice between superficial marking and resection boundary marking may depend on the nodule characteristics, surgical approach, and the surgeon’s experience and comfort level with each technique. Future studies should focus on further validating the efficacy and reliability of the superficial marking and resection boundary marking methods in larger patient cohorts and across different institutions. Additionally, long-term follow-up data on oncologic outcomes and recurrence rates would provide valuable insights into the clinical impact of these techniques.

Regarding the potential impact of staining agents on pathological results, we did not observe any notable influence in our study. Traditionally used dyes such as methylene blue or methyl violet may affect pathological interpretation. However, the ICG used in our study has a very light color and is difficult to recognize with the naked eye, thus minimizing its impact on pathological assessment. It is also worth noting that only in the direct lesion marking method does the dye come into direct contact with the lesion, further reducing the potential for interference with pathological examination in the other marking methods.

In our study, we encountered two cases of localization failure. One case involved the direct lesion marking method, where the absence of visible fluorescence on the surface led to an initial failure to accurately resect the lesion. This highlights the importance of ensuring adequate dye penetration and visibility on the lesion surface for the success of the direct marking method. The second case of localization failure occurred in a middle lobe nodule using the superficial marking method. The middle lobe’s tendency to collapse and form a thin, flat structure reduced the effectiveness of superficial marking, leading to difficulty in identifying the nodule during the initial resection attempt. These cases underscore the need for careful consideration of nodule location and characteristics when selecting the appropriate localization method. Furthermore, our experience highlights the importance of intraoperative flexibility and adaptability. In cases where the initial localization attempt is unsuccessful, surgeons should be prepared to employ additional techniques or modify their approach to ensure the successful resection of the target nodule.

Notably, our study is the first to systematically investigate the resection boundary marking and margin sphere marking techniques for deep lung nodules. These strategies provide visual guidance for achieving adequate resection margins, which is crucial for preventing local recurrence and improving long-term outcomes (10). The comparable success rates and resection margin status among the four groups indicate that these novel techniques are as effective as the more established direct lesion and superficial marking methods. The low complication rates observed in our study further support the safety of ENB-guided localization. The incidence of adverse events was minimal and comparable to those reported in the literature (11,12). The absence of severe complications highlights the minimally invasive nature of ENB and its suitability for patients with comorbidities or limited pulmonary function.

Recent advancements in imaging modalities have the potential to further enhance the accuracy and effectiveness of ENB-guided localization strategies. As highlighted by Abdelghani et al. (13), the integration of advanced imaging techniques such as cone-beam computed tomography (CBCT), augmented fluoroscopy, and radial endobronchial ultrasound (r-EBUS) with navigational bronchoscopy can provide real-time guidance and confirmation of tool placement. CBCT offers the ability to acquire 3D images during the procedure, allowing for immediate verification of the localization accuracy and reducing the risk of complications. Augmented fluoroscopy overlays the virtual bronchial pathway onto the live fluoroscopic image, facilitating more precise navigation and reducing radiation exposure. Furthermore, r-EBUS enables the visualization of peripheral lung lesions and their relationship to adjacent structures, aiding in the selection of the most appropriate localization strategy. The synergistic use of these advanced imaging modalities with ENB has the potential to streamline the localization process, improve success rates, and expand the range of manageable lesions.

It is worth noting that the navigational success to the lung nodule may vary depending on the navigational modality employed. A recent study by Abdelghani et al. (14) compared the performance of CBCT-guided shape-sensing robotic bronchoscopy and ENB for accessing pulmonary nodules. While both platforms demonstrated high navigational success rates, the robotic system showed superior navigational accuracy. This difference in navigational success could potentially influence the localization success rates when using these platforms for dye marking techniques. However, further studies are needed to directly compare the localization success rates between various navigational modalities (14).

Several limitations of our study should be acknowledged. First, the sample size was relatively small, and the study was conducted at a single institution. Further multicenter studies with larger cohorts are needed to validate our findings. Second, long-term follow-up data on recurrence and survival were not available, precluding an assessment of the oncologic outcomes of the different localization strategies. Third, the cost of the ENB system and its associated disposables is a significant consideration in the implementation and adoption of this technique. The initial capital investment for the equipment, as well as the recurring costs of single-use instruments and maintenance, can be substantial. These costs may present a barrier for some healthcare institutions, particularly those with limited financial resources or lower case volumes. However, it is essential to consider the potential benefits of ENB-guided localization in terms of improved surgical outcomes, reduced complications, and shorter hospital stays. These factors may offset the upfront costs over time. Furthermore, as the technology becomes more widely adopted and competition among manufacturers increases, the costs of ENB systems may decrease, making them more accessible to a broader range of healthcare providers.

Conclusions

In conclusion, our study demonstrates that ENB-guided localization using ICG dye and fluorescence thoracoscopy is a safe and effective technique for the preoperative marking of deep lung nodules. Among the four localization strategies investigated, the superficial marking and resection boundary marking methods achieved the highest success rates and fluorescence visibility, with low complication rates. Future studies should focus on long-term oncologic outcomes, learning curve analysis, and cost-effectiveness evaluation of the superficial marking and resection boundary marking methods to better inform clinical decision-making and optimize patient care.

Acknowledgments

Funding: This research was supported by National High Level Hospital Clinical Research Funding (No. 2022-PUMCH-A-188).

Footnote

Reporting Checklist: The authors have completed the SUPER reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1303/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1303/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1303/coif). The 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. This study was approved by the Ethics Committee of Peking Union Medical College Hospital (I-22PJ1133) and conducted in accordance with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from all the patients for publication of this surgical technique and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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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