Intraoperative Visualization of Hepatocellular Carcinoma with Indocyanine Green: Revealing the Mechanisms behind the Glowing Tumor

Abstract

Reliable intraoperative detection of tumors is important in the surgical management of malignant disease. In hepatocellular carcinoma (HCC), for instance, it is well known that failure to achieve R0 resections results in recurrence and reduced survival. Beyond the tactile and visual senses of the surgeon, additional tools are needed to reveal the extent of tumors and their involvement with nearby anatomy in order to achieve safe, curative resections. However, the technologies used to provide such anatomical and functional information for guiding resections have not changed considerably over the years and are based largely on conventional imaging modalities used preoperatively. Of these, intraoperative ultrasound (IOUS) remains the most common form of imaging available to visualize intra-abdominal tumors, although other modalities like intraoperative magnetic resonance and computed tomography have been tried in neurosurgery. To exploit fully the pre-operative advantages of these modalities inside the operating room, many scientific, engineering, and logistical challenges remain to be solved. One problem is that these imaging systems typically discriminate malignant from benign tissues on the basis of their physical properties (e.g. density, vascular flow, etc.) and generally not on their actual biology (e.g. tumor-specific proteins, genetic mutations, etc.). Another problem is that the images seen on a two-dimensional monitor are presented without the three-dimensional context of the actual patient and must be reoriented back in the operative field in order to be useful. Although systems exist to map pre-operative scans onto the intra-operative scene, these technologies are still being evaluated. Without addressing these problems, such images would only serve to suggest a possible tumor in a possible location, requiring the surgeon to explore and sample the tissue to confirm a tumor. In this issue, Ishizawa et al. have explored the use of indocyanine green (ICG) in vivo to make HCCs fluorescent for direct visualization intraoperatively. Unlike the imaging methods described above, the authors demonstrate that the tumor retention of ICG is based, in part, on its biology and that the tumor fluorescence is directly visible intraoperatively in nearly every patient of a fairly large series. As a historical note, ICG was first described in liver surgery, not as a tumor marker but as a means of assessing peri-operative liver function via the clearance of the marker by the organ. ICG rapidly binds albumin upon administration and is then transported to the liver, where it is excreted into the biliary system. Later, ICG was also shown to fluoresce in the near-infrared (NIR) wavelength and was often used as an indicator dye in angiography. This fluorescent property makes ICG and other similar dyes attractive for intra-operative use because its detection is not based on ionizing radiation. Furthermore, at the wavelength at which ICG is excited, the surrounding tissues do not contribute to background auto-fluorescence, allowing ICG to be detected with a high signal-to-noise ratio. Another property of ICG that engendered its clinical use is that it is relatively non-toxic, with few side effects, although the application of ICG as an imaging agent is still considered off-label use. It was against this historical backdrop that the preferential retention of ICG in HCC was accidentally discovered. Nevertheless, the mechanism by which this retention occurred remains unknown. It was hypothesized that ICG retention was a product of disruption in biliary excretion and from leaky portal vasculature near the tumor. Despite these uncertainties, multiple applications of ICG in oncologic surgeries have since been reported. Society of Surgical Oncology 2013