Fluorescent Detection of Vestibular Schwannoma Using Intravenous Sodium Fluorescein In Vivo

Abstract

Background: Vestibular schwannoma (VS) are intracranial tumors caused by merlin deficiency. Sodium fluorescein (SF) is a fluorescent compound that accumulates in various intracranial tumors, causing tumors to emit green fluorescence after blue light excitation. Hypothesis: Intravenous SF preferentially deposits in VS, helping surgeons differentiate tumor from surrounding tissue. Methods: Merlin-deficient Schwann cells were grafted onto cochleovestibular nerves of immunodeficient rats. Rats were randomized to receive SF (7.5 mg/kg; n = 5) or saline (n = 3). Tissues were harvested at 1 hour and photographed in white and blue light. Sixteen surgeons identified and marked the tumor-tissue interfaces on images. Fluorescence was measured on tissue specimens using the IVIS imaging system and on tissue cross-sections obtained with confocal microscopy. Western blot was performed to measure levels of organic anion transporting polypeptide (OATP), a drug transporter specific for SF. Results: Under blue light, tumors from SF rats demonstrated bright green fluorescence under direct visualization, higher fluorescence measurements on tissue specimens (p < 0.001), and more SF deposition on tissue cross-sections (p < 0.001), when compared with surrounding tissues and placebo rats. Surgeons were better able to distinguish the tumor-tissue interfaces in SF rats. Furthermore, the expression level of OATP1C1 was significantly higher in tumors than in surrounding tissues (p < 0.0001). Conclusion: In a xenograft model of VS, intravenous SF preferentially deposits in tumors, compared with normal surrounding tissue. Under blue light, tumors emit an intense green fluorescence that can help surgeons differentiate tumor from critical structures nearby, which may improve clinical outcomes in complicated VS surgery.

Potential Molecular Biomarkers of Vestibular Schwannoma Growth: Progress and Prospects

“…First, current available VS animal models have some limitations. The commonly utilized animal models for the study of VS including patient-derived xenograft mice model ( 159 ), merlin-deficient Schwann cell or SC4 cells mouse model ( 160 , 161 ). Nevertheless, merlin-deficient Schwann cells may not accurately reproduce VS ( 162 ), and it takes more than 2 weeks for the construction of mouse model.…”

“…Third, research is urgently needed to address how to obtain tissue expression data in a non-traumatic way. MRI texture analysis have been previously associated with VEGF expression in head and neck squamous cell carcinoma ( 166 ), and might also reflected VEGF levels in VS. A more precise non-invasive in vivo marker expression evaluation technique is targeted molecular imaging [MRI, computed tomography (CT), positron emission computed tomography/single-photon emission computed tomography (PET/SPECT) and fluorescence] ( 161 , 167 – 169 ). Recently, Morrison et al.…”

“…Third, research is urgently needed to address how to obtain tissue expression data in a non-traumatic way. MRI texture analysis have been previously associated with VEGF expression in head and neck squamous cell carcinoma (166), and might also reflected VEGF levels in VS. A more precise non-invasive in vivo marker expression evaluation technique is targeted molecular imaging [MRI, computed tomography (CT), positron emission computed tomography/single-photon emission computed tomography (PET/SPECT) and fluorescence] (161,(167)(168)(169). Recently, Morrison et al injected the covalently linked compounds formed by anti-VEGFR2 or anti-Her2/Neu monoclonal antibodies and near-infrared probe into Schwann cell xenograft models in mice, and observed strong correlations between day 1 tumor fluorescence and eventual maximum tumor volume (170).…”

Fluorescein-Assisted Microsurgical Resection of Vestibular Schwannoma: A Prospective Feasibility Study

“…Confocal microscopy revealed concentration of fluorescence intracellularly, with mild fluorescence in the extracellular space. Increased intracellular uptake was further supported by findings of significantly higher concentrations of an organic anion transporting polypeptide (OATP)-OATP1C1-in tumor cells compared with the brainstem and cerebellum (14). OATPs are transmembrane proteins involved in the transport of drugs, hormones, and various endogenous compounds.…”

“…Accumulation of SF in intra-axial tumors has been attributed to a disrupted blood-brain barrier (2,5,13). Szczupak et al (14) described preferential uptake of SF by VS in rat models. Confocal microscopy revealed concentration of fluorescence intracellularly, with mild fluorescence in the extracellular space.…”