Fluorescence Guidance in Glioma Surgery: A Narrative Review of Current Evidence and the Drive Towards Objective Margin Differentiation

Abstract

Fluorescence-guided surgery (FGS) was pioneered for glioma and is now established as the standard of care. Gliomas are infiltrative tumours with diffuse margins. FGS provides improved intra-operative identification of tumour margins based on tumour-specific emission visible to the operating surgeon, resulting in increased rates of gross total resection. Multiple fluorescence agents may be used including 5-ALA, fluorescein sodium, and indocyanine green (ICG). This review details the indication, required equipment, mechanism of action, evidence base, limitations, and regulatory issues for each fluorophore as utilised in current clinical practice. FGS for glioma is limited by a reliance on subjective interpretation of visible fluorescence, which is often not present in low-grade glioma (LGG) or at the infiltrative tumour margin. Consequently, there has been a drive to develop enhanced, objective FGS techniques utilising both quantitative fluorescence (QF) imaging systems and novel fluorophores. This review provides an overview of emerging QF imaging systems for FGS. The pipeline for novel fluorophore development is also summarised.

Keywords: 5-ALA; ICG; PpIX; fluorescein; fluorescence; fluorescence-guided surgery; glioma; quantitative fluorescence.

Figure 1

5-ALA fluorescence-guided surgery. (a) White-light visualisation of glioblastoma involving cortical surface. (b) Surgical field under blue (405 nm) light, demonstrating avid red/pink tumour fluorescence. (c) White-light visualisation of WHO Grade 2 oligodendroglioma involving cortical surface. (d) Blue-light imaging, demonstrating lack of visible tumour fluorescence. Images courtesy of Neuro PPEye study team, King’s College London, UK (NCT05397574).

Figure 2

Simplified schematic of PpIX synthesis in heme biosynthetic pathway. ABCG2: ATP-binding cassette G2; ABCB6: ATP-binding cassette B6; CPOX: coproporphyrinogen oxidase; PPOX: protoporphyrinogen oxidase.

Figure 3

Fluorescein fluorescence guided surgery (a) White-light visualisation of infiltrated gyrus. (b) Surgical field under yellow (560 nm) light, demonstrating green fluorescence at areas of tumour infiltration. Images courtesy of Mr Ryan Mathew, University of Leeds, UK.

Figure 4

ICG angiography during glioma surgery. (a) White-light visualisation of resection cavity showing skeletonized cortical and tumour associated vessels. (b) IR imaging of surgical field with 800 nm excitation light, demonstrating abnormal tumour vessels and preserved flow in overlying cortical vessels. Images courtesy of Neuro PPEye study team, King’s College London, UK (NCT05397574).

Figure 5

Chemical structures and optical emission spectra of key fluorophores used in, and under investigation for, glioma FGS [188]. Excitation spectra are shown in blue, and emission spectra are shown in red. IRDye800CW spectra courtesy of Mr Jean-Romain Lotthe, Kings College London.