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Page 2 of 7 Chang et al. Mini-invasive Surg 2024;8:15 https://dx.doi.org/10.20517/2574-1225.2023.137

TUMOR IDENTIFICATION
With regard to non-targeted fluorescence techniques, indocyanine green (ICG) fluorescence imaging has
been demonstrated to have diverse applications in the surgical resection of sinonasal tumors. ICG is a
water-soluble tricarbocyanine dye with excellent safety profile that fluoresces when exposed to wavelengths
of light in the near-infrared (NIR) spectrum (peak excitation at 805 nanometers).

When ICG is infused preoperatively via an intravenous line (IV), it can highlight tumor tissue during
surgery, leveraging the differential vascular perfusion patterns between cancer tissue and normal tissue.
Tumor tissue is often characterized by vascular damage and increased permeability, which results in
increased retention of ICG compared to normal tissue . By visualizing tumor with fluorescence, surgeons
[1]
can ensure a more precise and complete resection, minimizing the risk of leaving residual cancerous tissue.
This technology has been validated in benign skull base tumors such as pituitary adenomas . One series
[2,3]
demonstrated that an IV infusion of ICG 24 h prior to surgery generated a significantly high signal-to-
background ratio between tumor tissue and normal tissue for chordomas, craniopharyngiomas, and
[4]
pituitary adenomas . This study found that tumors with high signal intensity on magnetic resonance
imaging (MRI) T1 sequence with gadolinium contrast were the single best predictor of the signal-to-
background ratio. While ICG has been shown to facilitate intraoperative identification of squamous cell
carcinoma and adenoid cystic carcinoma in the head and neck , currently no studies investigate the efficacy
[5]
of ICG to highlight tumor tissue specifically in sinonasal malignancy.

TARGETED FLUORESCENCE
Targeted fluorescence approaches capitalize further on tumor-specific biomarkers to provide signal contrast
during surgery. These approaches, also referred to as “molecular imaging”, are the subject of numerous
trials in oncologic surgery, which are now beginning to expand into sinonasal tumors.

Certain tumors overexpress folate receptors, which has led to the development of folate analogs conjugated
to fluorescent antibodies. For example, pituitary adenomas have demonstrated up to 20-fold overexpression
[6]
of folate receptor alpha . OTL38 is a folate analog conjugated to ICG to allow for fluorescence in NIR.
Among skull base tumors, OTL38 can be used to distinguish pituitary adenomas from normal tissue
intraoperatively, when administered intravenously 4-6 hours preoperatively . Pre-operative confirmation of
[6]
target receptor content is not typically feasible due to limited tissue biopsy, and as such, targeted imaging
typically relies on preclinical validation of target receptor content. While folate receptors have not been
investigated specifically for sinonasal malignancy, in squamous cell carcinoma of the head and neck, tumors
do contain a high population of macrophages that express folate receptors, suggesting that folate-conjugated
[7]
fluorescent dyes may be able to specifically target tumor tissue .

Another molecular target of interest is vascular endothelial growth factor (VEGF), which is overexpressed in
sinonasal papilloma. This target can be identified using the antibody-dye conjugate, bevacizumab-
IRDye800CW. Using a fluorescent grid to quantify fluorescence within a tumor sample, ex vivo, Vonk et al.
calculated the signal-to-background ratio and demonstrated a significantly higher mean fluorescence signal
in SNP compared to normal tissue [77.54 (IQR 50.47-112.30) vs. 35.99 (IQR 21.48-57.81), P < 0.0001] .
[8]
However, despite the higher levels of fluorescence, the authors conclude that clinical utility is limited,
because this higher fluorescence signal could not be detected during endoscopic surgery. VEGF is also
uniquely overexpressed in pituitary neuroendocrine tumors, and is the subject of a clinical trial using
bevacizumab-IRDye800CW (NCT04212793) .
[9]