Targeted intraoperative fluorescence imaging for the visualization of ground-glass nodules in the lung

The ability to detect small pulmonary nodules has improved with the widespread use of computed tomography (CT) lung screening (1). Minimally invasive surgery, such as video-assisted thoracoscopic surgery (VATS) or robot-assisted thoracoscopic surgery (RATS), is considered to be one of the preferred choices in cases involving an unsuccessful diagnosis via percutaneous transthoracic needle biopsy, or when the resection of small pulmonary nodules is needed. VATS, however, can provide limited identification of small pulmonary nodules due to the inability of a surgeon to visualize or palpate the lesions directly with their own eyes or hands during the procedure (1). In robotic surgery, lesion localization is even more challenging due to the lack of haptic feedback from thoracoscopic palpation (2).

Preoperative localizations, performed using hookwires, microcoils, radiotracers, radio contrasts, and dyes, are currently used in clinical practice to overcome the limitations that may be encountered when attempting to visualize small pulmonary nodules during minimally invasive surgeries (1). These techniques, however, only provide an image of the material, not the tumor itself, making it challenging to identify the resection margins accurately.

Singhal and colleagues first reported that intravenously injected indocyanine green (ICG) could successfully visualize lung cancer under the near-infrared (NIR) fluorescence imaging system (3). This is consistent with our previous studies demonstrating similar results in pulmonary neoplasms, as well as thymoma and esophageal cancer (4-6).

Recent reports from the JCOG0802 trial showed that small ground-glass nodule (GGN) lung cancers with diameters ≤2 cm and a consolidation-to-tumor (C/T) ratio >50% have similar postoperative complication rates and prognostic results after being treated with either lobectomy or segmentectomy (7). Additionally, the 5-year disease-free survival rate, post-surgical resection, of lung adenocarcinoma in situ and minimally invasive adenocarcinoma is 100% (8). The intraoperative visualization of small GGNs, therefore, is crucial for retaining an increased amount of normal lung parenchyma, improving quality of life, and providing a similar prognosis to that of a lobectomy. Because ICG is not a cancer-specific agent (9) and has fast hepatic uptake with a short blood half-life and a low quantum yield dose (10), it is impossible to visualize such early-stage small lung cancer.

The OTL38 NIR tracer was initially designed to target pulmonary adenocarcinomas due to their overexpression of folate receptor alpha, and it has been found that the tracer highlights a broad range of tumors, including squamous cell carcinomas, small cell lung cancers, and even granulomas with hypothetical aid in the expression of folate receptor beta (11). Furthermore, the possibility of visualizing small GGNs using a fluorescence thoracoscope has been demonstrated (12), showing that this procedure could be utilized in RATS, using a new imaging feature with a 785 nm excitation wavelength instead of a conventional one (805 nm). The continuous efforts of Dr. Singhal’s group give us hope that intraoperative molecular imaging techniques may potentially be standardized for minimally invasive oncological surgeries.

Nevertheless, there is ample room for improvement in the present study. First, OTL38 has shorter excitation and emission wavelengths compared to ICG, which requires modifying the optical path and light source of the current imaging systems in clinical settings. This concern would be resolved as wavelength-tunable scopes are developed. Second, OTL38 is not always accurate when discriminating tumors from benign lesions, especially between GGN and pneumonia. Therefore, further studies are required to understand the specific types of GGOs that OTL38 can accurately identify. Third, this technology has well-documented limitations in its penetration depth; however, this was not observed in the currently reported study cohort, which primarily included pleural surface lesions. Fluorescence from the second NIR spectral window (NIR-II; wavelengths of 1,000–1,700 nm) might be one solution, allowing for deep tissue imaging at a high resolution, owing to reduced light scattering, minimal light absorption, and extremely low levels of autofluorescence (9).

Acknowledgments

Funding: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant No. HR14C-0007-060022) and the Korea Medical Device Development Fund grant funded by the Korean government (the Ministry of Science and ICT, Ministry of Trade, Industry and Energy, Ministry of Health & Welfare, Ministry of Food and Drug Safety) (Project No. 1711138151, KMDF-PR-20200901-0094-02).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-751/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.

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/.

References

1. Rho J, Lee JW, Quan YH, et al. Fluorescent and Iodized Emulsion for Preoperative Localization of Pulmonary Nodules. Ann Surg 2021;273:989-96. [Crossref] [PubMed]
2. Hagen ME, Meehan JJ, Inan I, et al. Visual clues act as a substitute for haptic feedback in robotic surgery. Surg Endosc 2008;22:1505-8. [Crossref] [PubMed]
3. Okusanya OT, Holt D, Heitjan D, et al. Intraoperative near-infrared imaging can identify pulmonary nodules. Ann Thorac Surg 2014;98:1223-30. [Crossref] [PubMed]
4. Kim HK, Quan YH, Choi BH, et al. Intraoperative pulmonary neoplasm identification using near-infrared fluorescence imaging. Eur J Cardiothorac Surg 2016;49:1497-502. [Crossref] [PubMed]
5. Rho J, Quan YH, Choi BH, et al. Near-infrared fluorescent imaging with indocyanine green in rabbit and patient specimens of esophageal cancer. J Thorac Dis 2021;13:6314-22. [Crossref] [PubMed]
6. Quan YH, Xu R, Choi BH, et al. Fluorescence Imaging-Guided Identification of Thymic Masses Using Low-Dose Indocyanine Green. Ann Surg Oncol 2022; Epub ahead of print. [Crossref] [PubMed]
7. Saji H, Okada M, Tsuboi M, et al. Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial. Lancet 2022;399:1607-17. [Crossref] [PubMed]
8. Russell PA, Wainer Z, Wright GM, et al. Does lung adenocarcinoma subtype predict patient survival?: A clinicopathologic study based on the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary lung adenocarcinoma classification. J Thorac Oncol 2011;6:1496-504. [Crossref] [PubMed]
9. Choi HS, Kim HK. Multispectral image-guided surgery in patients. Nat Biomed Eng 2020;4:245-6. [Crossref] [PubMed]
10. James NS, Chen Y, Joshi P, et al. Evaluation of polymethine dyes as potential probes for near infrared fluorescence imaging of tumors: part - 1. Theranostics 2013;3:692-702. [Crossref] [PubMed]
11. Kennedy GT, Azari FS, Bernstein E, et al. First-in-human results of targeted intraoperative molecular imaging for visualization of ground glass opacities during robotic pulmonary resection. Transl Lung Cancer Res 2022;11:1567-77. [Crossref] [PubMed]
12. Predina JD, Newton A, Corbett C, et al. Localization of Pulmonary Ground-Glass Opacities with Folate Receptor-Targeted Intraoperative Molecular Imaging. J Thorac Oncol 2018;13:1028-36. [Crossref] [PubMed]