Intraoperative molecular imaging—a bright navigator for thoracic surgeons in the era of limited resection

Lobectomy or greater pulmonary resection with complete mediastinal lymph nodes dissection is currently the standard surgical procedure for operable non-small cell lung cancer (NSCLC), regardless of tumor size or location (1). However, limited sublobar resection, either segmentectomy or partial resection, is sometimes considered for high-risk patients with small-sized NSCLC who are not suitable for standard resection because of compromised respiratory and/or cardiac function (2). In contrast to these “passive” limited resections, so-called “active” or intentional limited resections for patients with small-sized NSCLCs have also been proposed (3). The feasibility and outcomes of these limited resections have been evaluated by many retrospective studies (4-6). In addition, a nonrandomized confirmatory phase III study (JCOG0804/WJOG4507L) (7) proved that limited resection (mainly partial resection) offered sufficient local control of lung adenocarcinomas with radiologically-predicted noninvasive tumors, i.e., consolidation/tumor ratio of 0.25 or less and tumor size of 2.0 cm or less (8). For other types of small-sized NSCLCs, prospective trials (the JCOG0802/WJOG4607L and JCOG1211 trials) are currently being conducted to evaluate the feasibility of segmentectomy, and the results will be available in the near future.

Thoracic surgeons face two main challenges when performing limited resections, partially due to the widespread use of video-assisted thoracoscopic surgery (VATS) and robot-assisted thoracic surgery (RATS). One issue is the detection or identification of tumor(s), and the other is establishing an adequate distance from the surgical margin to the tumor, which can be greater than the size of the tumor itself (9). Thoracic surgeons usually try to solve these two issues intraoperatively via visual inspection of the pulmonary surface and manual palpation.

The identification of the tumor(s) is sometimes difficult when the tumor(s) mainly consist of ground-glass opacity (GGO). Such tumors are challenging to detect, because they often lack parenchymal abnormalities and tactile irregularities. In the aforementioned clinical trial (JCOG0804/WJOG4507L) (7), partial resection was planned for such GGO tumors in 330 patients; however, 10 of these patients (3%) received segmentectomy, rather than partial resection, solely because the thoracic surgeons could not find the tumors.

The acquisition of adequate surgical margins can become an issue during any limited resection. The edges of a tumor are usually judged by manual palpation; however, the GGO part of tumors is often not palpable. Furthermore, the judgement of adequate surgical margins is complicated by the potential microscopic spread of cancer cells from the edge of tumors, including the spread through air spaces (STAS) (10). In addition to macroscopically checking the distance between the surgical margin and the edge of the tumor, thoracic surgeons often use intraoperative pathological examinations to confirm the negativity of the surgical margins. However, during the surgery, it is virtually impossible to detect the microscopic spread of tumor cells, and to determine the GGO part of the tumor; therefore, final permanent pathological examinations occasionally conclude a closer surgical margin to the tumor than the thoracic surgeons have intended.

Intraoperative molecular imaging is one possible solution to these two issues. Several kinds of molecules have been used to detect tumors intraoperatively. Indocyanine green (ICG) is one of the most widely used agents to detect many kinds of malignancies, including NSCLCs, together with near-infrared (NIR) fluorescence imaging (11,12). Although ICG is not a tumor-specific fluorescence dye, it accumulates in certain types of tumors because of the enhanced permeability and retention effect (13). Intraoperative molecular imaging using ICG is reportedly able to detect small tumors in the lung (12,14); however, hyperplastic or inflammatory nodules may cause false-positive results (12) and ICG cannot distinguish between the tumor itself and the inflamed tissue around the tumor (11). Another potentially useful agent is the folate receptor (FR) targeted NIR tracer (OTL0038) that targets the FR-alpha that is expressed in 90% of pulmonary adenocarcinomas and 70% of squamous cell carcinomas (15,16). OTL0038 has successfully been used by Predina and his colleagues for the intraoperative imaging of several thoracic malignancies, including pulmonary adenocarcinomas (15,16), squamous cell carcinomas (16,17), metastatic lung tumors of osteosarcomas (18), and mesotheliomas (19). However, as intraoperative molecular imaging may be especially useful during limited pulmonary resections, the data of intraoperative molecular imaging for small-sized tumors with/without GGO is clinically important.

Predina and his colleagues have very recently published the data of intraoperative molecular imaging using OTL0038 for pulmonary small nodules with GGO in the Journal of Thoracic Oncology (20). This study recruited 20 patients with 21 pulmonary tumors, comprising nine pure GGOs and 12 GGOs with a solid component, which were suspicious for lung neoplasms. The median tumor size was only 1.3 cm. The participants received 0.025 mg/kg of OTL0038 intravenously 3 to 6 hours prior to the pulmonary resection. Intraoperatively, surgeons first used thoracoscopic visualization and finger palpation to identify known lesions. Next, molecular imaging was applied to confirm lesion fluorescence or to detect lesions that were unidentifiable using the traditional methods. All lesions were wedge resected and imaged ex vivo prior to being submitted for pathological examination to compare the molecular imaging margins and the pathological margins with permanent histopathological analysis. Additional pulmonary parenchyma was resected if the molecular imaging identified close margins.

In this trial, there were no drug-related adverse events observed perioperatively or within 30 days postoperatively (20). Sixteen of 21 tumors with GGO displayed lesion-specific fluorescence during NIR imaging, and the depth from the pleural surface was the sole determinant for the successful detection of lesions by intraoperative molecular imaging. However, 20 of 21 lesions displayed signal upon back-table NIR evaluation; the single exception was an adenocarcinoma lesion that lacked FR-alpha expression by immunohistochemistry, causing the negative result of the molecular imaging on the back-table. The margins assessed by ex vivo molecular imaging and those evaluated by final permanent histology were surprisingly similar, with a median difference in margin length of within 1 mm. Based on the margin evaluation by molecular imaging, three patients received immediate re-resection. All tumors were confirmed to be adenocarcinomas, either invasive adenocarcinoma, minimally invasive mucinous adenocarcinoma (one case), or adenocarcinoma in situ (AIS).

Although these results are encouraging, further evaluation using larger cohorts is necessary before we apply this technique in clinical practice. There are also several clinical questions that need to be addressed. The first question is whether this technique can be applied in patients with “dirty” lungs, such as those with severe pulmonary emphysema, anthracosis, or inflammatory adhesions around the lung. Another question is whether this molecular imaging can detect GGO lesions other than lung adenocarcinomas, as many types of diseases may present with GGO on computed tomography (CT) imaging, including infection, collagen vascular disease, drug toxicity, fibrosis, and pulmonary metastasis from malignant melanoma (although this is rare) (21). In addition, further challenging is essential to improve this technique so that it can detect deeper lesions from the parenchyma surface in vivo, although intraoperative molecular imaging using ICG has the same issue (12)

The widespread use of CT examination, especially in developed countries, enables the early detection of small-sized lung cancers, including AIS. As not all lesions detected in the lung by CT imaging are malignant, several biomarkers that may be able to distinguish lung cancers from benign diseases have been suggested (22). Furthermore, not all adenocarcinoma or atypical adenomatous hyperplasia progresses clinically, and there might be clinical or molecular biomarker(s) that will predict tumor progression (23). The development of surgical instruments for VATS and RATS means that pulmonary resections are becoming safer and less invasive. Furthermore, completed and ongoing large prospective trials will provide the rationale to perform limited pulmonary resection for some small-sized NSCLCs in the near future. I believe that the intraoperative molecular imaging highlighted in this editorial will help thoracic surgeons to perform successful limited resections with adequate surgical margins. I expect that all these efforts will change lung cancer from the leading cause of cancer-related mortality in the world into a curable disease.

Acknowledgements

Funding: This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (18K07336 to K Suda). I thank Dr. Kelly Zammit, BVSc, from Edanz Group (www.edanzediting.com/ac), for editing a draft of this manuscript.

Footnote

Conflicts of Interest: The author has no conflicts of interest to declare.

References

1. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60:615-22; discussion 622-3. [Crossref] [PubMed]
2. Wolf AS, Richards WG, Jaklitsch MT, et al. Lobectomy versus sublobar resection for small (2 cm or less) non-small cell lung cancers. Ann Thorac Surg 2011;92:1819-23; discussion 1824-5.
3. Okada M, Koike T, Higashiyama M, et al. Radical sublobar resection for small-sized non-small cell lung cancer: a multicenter study. J Thorac Cardiovasc Surg 2006;132:769-75. [Crossref] [PubMed]
4. Kates M, Swanson S, Wisnivesky JP. Survival following lobectomy and limited resection for the treatment of stage I non-small cell lung cancer<=1 cm in size: a review of SEER data. Chest 2011;139:491-6. [Crossref] [PubMed]
5. Zhong C, Fang W, Mao T, et al. Comparison of thoracoscopic segmentectomy and thoracoscopic lobectomy for small-sized stage IA lung cancer. Ann Thorac Surg 2012;94:362-7. [Crossref] [PubMed]
6. Tsutani Y, Miyata Y, Nakayama H, et al. Oncologic outcomes of segmentectomy compared with lobectomy for clinical stage IA lung adenocarcinoma: propensity score-matched analysis in a multicenter study. J Thorac Cardiovasc Surg 2013;146:358-64. [Crossref] [PubMed]
7. Suzuki K, Watanabe S, Wakabayashi M, et al. A nonrandomized confirmatory phase III study of sublobar surgical resection for peripheral ground glass opacity dominant lung cancer defined with thoracic thin-section computed tomography (JCOG0804/WJOG4507L). J Clin Oncol 2017;2017;35:abstr 8561.
8. Suzuki K, Koike T, Asakawa T, et al. A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). J Thorac Oncol 2011;6:751-6. [Crossref] [PubMed]
9. Sawabata N, Ohta M, Matsumura A, et al. Optimal distance of malignant negative margin in excision of nonsmall cell lung cancer: a multicenter prospective study. Ann Thorac Surg 2004;77:415-20. [Crossref] [PubMed]
10. Masai K, Sakurai H, Sukeda A, et al. Prognostic Impact of Margin Distance and Tumor Spread Through Air Spaces in Limited Resection for Primary Lung Cancer. J Thorac Oncol 2017;12:1788-97. [Crossref] [PubMed]
11. 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]
12. Mao Y, Chi C, Yang F, et al. The identification of sub-centimetre nodules by near-infrared fluorescence thoracoscopic systems in pulmonary resection surgeries. Eur J Cardiothorac Surg 2017;52:1190-6. [Crossref] [PubMed]
13. Ishizawa T, Masuda K, Urano Y, et al. Mechanistic background and clinical applications of indocyanine green fluorescence imaging of hepatocellular carcinoma. Ann Surg Oncol 2014;21:440-8. [Crossref] [PubMed]
14. Okusanya OT, DeJesus EM, Jiang JX, et al. Intraoperative molecular imaging can identify lung adenocarcinomas during pulmonary resection. J Thorac Cardiovasc Surg 2015;150:28-35.e1. [Crossref] [PubMed]
15. Predina JD, Newton AD, Keating J, et al. A Phase I Clinical Trial of Targeted Intraoperative Molecular Imaging for Pulmonary Adenocarcinomas. Ann Thorac Surg 2018;105:901-8. [Crossref] [PubMed]
16. Predina JD, Newton AD, Keating J, et al. Intraoperative Molecular Imaging Combined With Positron Emission Tomography Improves Surgical Management of Peripheral Malignant Pulmonary Nodules. Ann Surg 2017;266:479-88. [Crossref] [PubMed]
17. Predina JD, Newton AD, Xia L, et al. An open label trial of folate receptor-targeted intraoperative molecular imaging to localize pulmonary squamous cell carcinomas. Oncotarget 2018;9:13517-29. [Crossref] [PubMed]
18. Predina JD, Newton A, Deshpande C, et al. Utilization of targeted near-infrared molecular imaging to improve pulmonary metastasectomy of osteosarcomas. J Biomed Opt 2018;23:1-4. [Crossref] [PubMed]
19. Kennedy GT, Newton A, Predina J, et al. Intraoperative near-infrared imaging of mesothelioma. Transl Lung Cancer Res 2017;6:279-84. [Crossref] [PubMed]
20. 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]
21. Mizuuchi H, Suda K, Kitahara H, et al. Solitary pulmonary metastasis from malignant melanoma of the bulbar conjunctiva presenting as a pulmonary ground glass nodule: Report of a case. Thorac Cancer 2015;6:97-100. [Crossref] [PubMed]
22. Silvestri GA, Tanner NT, Kearney P, et al. Assessment of Plasma Proteomics Biomarker's Ability to Distinguish Benign From Malignant Lung Nodules: Results of the PANOPTIC (Pulmonary Nodule Plasma Proteomic Classifier) Trial. Chest 2018. [Epub ahead of print].
23. Kobayashi Y, Mitsudomi T, Sakao Y, et al. Genetic features of pulmonary adenocarcinoma presenting with ground-glass nodules: the differences between nodules with and without growth. Ann Oncol 2015;26:156-61. [Crossref] [PubMed]