A clinical trial of intraoperative near-infrared imaging to assess tumor extent and identify residual disease during anterior mediastinal tumor resection

Abstract

Background: The management of most solid tumors of the anterior mediastinum involves complete resection. Because of their location near mediastinal structures, wide resection is not possible; therefore, surgeons must use subjective visual and tactile cues to determine disease extent. This clinical trial explored intraoperative near-infrared (NIR) imaging as an approach to improving tumor delineation during mediastinal tumor resection.

Methods: Twenty-five subjects with anterior mediastinal lesions suspicious for malignancy were enrolled in an open-label feasibility trial. Subjects were administered indocyanine green (ICG) at a dose of 5 mg/kg, 24 hours before resection (via a technique called TumorGlow). The NIR imaging systems included Artemis (Quest, Middenmeer, the Netherlands) and Iridium (VisionSense Corp, Philadelphia, Pennsylvania). Intratumoral ICG uptake was evaluated. The clinical value was determined via an assessment of the ability of NIR imaging to detect phrenic nerve involvement or incomplete resection. Clinical and histopathologic variables were analyzed to determine predictors of tumor fluorescence.

Results: No drug-related toxicity was observed. Optical imaging added a mean of 10 minutes to case duration. Among the subjects with solid tumors, 19 of 20 accumulated ICG. Fluorescent tumors included thymomas (n = 13), thymic carcinomas (n = 4), and liposarcomas (n = 2). NIR feedback improved phrenic nerve dissection (n = 4) and identified residual disease (n = 2). There were no false-positives or false-negatives. ICG preferentially accumulated in solid tumors; this was independent of clinical and pathologic variables.

Conclusions: NIR imaging for anterior mediastinal neoplasms is safe and feasible. This technology may provide a real-time tool capable of determining tumor extent and specifically identify phrenic nerve involvement and residual disease.

Keywords: anterior mediastinum; indocyanine green (ICG); intraoperative imaging; optical imaging; surgery; thymoma.

Figure 1:. ICG accumulation within anterior mediastinal neoplasms generate NIR signal upon intraoperative fluorescent imaging.

Representative images of anterior mediastinal neoplasms are provided: thymic carcinoma, liposarcoma, hematologic malignancy (Castleman’s Disease), and thymoma. First Column-preoperative CT; Second Column-standard white light view; Third Column-NIR merged view.

Figure 2:. ICG preferentially accumulates within tumors and generates tumor-specific signal.

All specimens underwent fluorescent tomographic analysis to quantify tumor-specific fluorescence intensity. Subject 23 is provided as a representative example (a): NIR merged images were analyzed by quantifying the mean fluorescent intensity of (b) tumors and (c) background. (d) Mean fluorescent intensity of tumors were compared to background and plotted for all patients (n=20) with solid tumors. (e) Tumor-to-background fluorescence ratios (TBRs) were calculated and then plotted for the cohort.

Figure 3:

Anterior Mediastinal Tumors accumulate ICG.All resected specimens underwent a series of brightfield and NIR analyses to confirm intratumoral ICG accumulation. Subject 23 (thymoma) is displayed as a representative example. As can be seen by comparing H&E (a) to NIR point scanning (b), ICG accumulation is predominantly observed within the tumor. Upon anti-CD31 IHC, we note the presence of endothelial cells within anterior mediastinal tumors (c and d).

Figure 4:. NIR imaging identifies unresected disease in the postoperative wound bed.

Following resection, the postoperative wound bed was inspected using NIR imaging. In 18 of 20 subjects with solid tumors, there was no evidence of residual disease (Subject 15 as representative example). In two subjects, residual macroscopic tumor deposits were identified along the aortic groove, pericardium and pleural surface (Subjects 4 and 14).

Figure 5:. Fluorescent imaging provides real-time information during dissection of tumor form phrenic nerve.

In four subjects, mediastinal tumors were found in close proximity the phrenic nerve. Using fluorescent information, tumors were carefully dissected thus preserving the phrenic nerve. Data from Subject 13 is provided as a representative example. Preoperative CT (a) and intraoperative bright light views (b) of a 7.1cm thymoma. During resection, the tumor displayed high fluorescence relative to the phrenic nerve (c). Using real-time fluorescent information, the tumor was carefully dissected from the nerve (d). No residual tumor was identified after tumor resection (e).

Figure 6:. Clinical and histopathologic variables predicting in situ fluorescence:

(a) TBR as a function of tumor type, (b) TBR as a function of tumor size, (c) TBR as a function tumor subject age, (d) TBR as a function of subject gender, (e) TBR by tumor histology, and (f) TBR by time to imaging.