Near-infrared fluorescence-guided resection of colorectal liver metastases

Abstract

Background: The fundamental principle of oncologic surgery is the complete resection of malignant cells. However, small tumors are often difficult to find during surgery using conventional techniques. The objectives of this study were to determine if optical imaging, using a contrast agent already approved for other indications, could improve hepatic metastasectomy with curative intent, to optimize dose and timing, and to determine the mechanism of contrast agent accumulation.

Methods: The high tissue penetration of near-infrared (NIR) light was exploited by use of the FLARE (Fluorescence-Assisted Resection and Exploration) image-guided surgery system and the NIR fluorophore indocyanine green in a clinical trial of 40 patients undergoing hepatic resection for colorectal cancer metastases.

Results: A total of 71 superficially located (< 6.2 mm beneath the liver capsule) colorectal liver metastases were identified and resected using NIR fluorescence imaging. Median tumor-to-liver ratio was 7.0 (range, 1.9-18.7) and no significant differences between time points or doses were found. Indocyanine green fluorescence was seen as a rim around the tumor, which is shown to be entrapment around cytokeratin 7-positive hepatocytes compressed by the tumor. Importantly, in 5 of 40 patients (12.5%, 95% confidence interval = 5.0-26.6), additional small and superficially located lesions were detected using NIR fluorescence, and were otherwise undetectable by preoperative computed tomography, intraoperative ultrasound, visual inspection, and palpation.

Conclusions: NIR fluorescence imaging, even when used with a nontargeted, clinically available NIR fluorophore, is complementary to conventional imaging and able to identify missed lesions by other modalities.

Keywords: colorectal cancer; fluorescence; image-guided surgery; indocyanine green; liver neoplasms; near-infrared.

Figure 1. NIR fluorescence imaging of colorectal liver metastases

A colorectal liver metastasis (arrow) is clearly identified by a rim around the tumor in vivo (top row), 24 h after injection of 10-mg ICG. Normal liver tissue (arrowhead) shows minimal background uptake of ICG. In 5 patients, small, superficial, otherwise occult metastases (middle row, arrow) were identified by NIR fluorescence imaging. Benign lesions (bottom row, dashed arrow) could be differentiated from malignant lesions by a lack of a fluorescent rim around the lesion.

Figure 2. Methods of detection of colorectal liver metastases

Venn diagram showing how the 97 hepatic metastases were detected as a function of each modality alone or in combination.

Figure 3. Pathologic examination of the tumor border

A. After resection and slicing of the same specimen, the rim around the tumor can be visualized ex vivo. B. Shown are hematoxylin and eosin (HE) staining with a pseudo-colored green NIR fluorescence overlay of a 20 µm tissue section of a colorectal liver metastasis using a 5 × objective. The fluorescent rim in stromal tissue appears in the transition zone between tumor (T) and normal liver tissue (L). C. Shown is liver tissue located in the fluorescent rim of a colorectal liver metastasis. Consecutive frozen sections (5 µm) are stained with hematoxylin and eosin (HE) and for CD68, CD31, and CK7. Microscopic color images (left column), NIR fluorescence images (middle column), and a pseudo-colored green merge (right column) were obtained (100× zoom). The NIR fluorescence signal is mainly located intracellularly and shows a high correlation with CK7 staining.