5-ALA in Suspected Low-Grade Gliomas: Current Role, Limitations, and New Approaches

Abstract

Radiologically suspected low-grade gliomas (LGG) represent a special challenge for the neurosurgeon during surgery due to their histopathological heterogeneity and indefinite tumor margin. Therefore, new techniques are required to overcome these current surgical drawbacks. Intraoperative visualization of brain tumors with assistance of 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence is one of the major advancements in the neurosurgical field in the last decades. Initially, this technique was exclusively applied for fluorescence-guided surgery of high-grade glioma (HGG). In the last years, the use of 5-ALA was also extended to other indications such as radiologically suspected LGG. Here, we discuss the current role of 5-ALA for intraoperative visualization of focal malignant transformation within suspected LGG. Furthermore, we discuss the current limitations of the 5-ALA technology in pure LGG which usually cannot be visualized by visible fluorescence. Finally, we introduce new approaches based on fluorescence technology for improved detection of pure LGG tissue such as spectroscopic PpIX quantification fluorescence lifetime imaging of PpIX and confocal microscopy to optimize surgery.

First in patient assessment of brain tumor infiltrative margins using simultaneous time-resolved measurements of 5-ALA-induced PpIX fluorescence and tissue autofluorescence

“…This, combined with PpIX fluorescence, may enable more accurate detection of the infiltration zone of high-grade gliomas, including GBM, as well as low-grade gliomas, in which visible 5-ALA fluorescence intensity has poor sensitivity. 4 Current results demonstrate the ability of intraoperative FLIm to simultaneously detect coregistered PpIX and NAD(P)H fluorescence from the tumor resection margins in an integrated approach with the surgical workflow (i.e., under standard room-light illumination). The presented findings support further studies to establish the relationships between tumor presence and PpIX and NAD(P)H fluorescence lifetime to determine their diagnostic ability.…”

“…This, combined with PpIX fluorescence, may enable more accurate detection of the infiltration zone of high-grade gliomas, including GBM, as well as low-grade gliomas, in which visible 5-ALA fluorescence intensity has poor sensitivity. 4 …”

“…However, for the low-cellularity infiltrating edge of high-grade gliomas and most low-grade gliomas, the PpIX fluorescence intensity decreases below the visible threshold. 4 Current implementations of PpIX fluorescence visualization systems require working in a dark surgical field, hindering simultaneous tumor identification and resection. Additionally, visible PpIX fluorescence suffers from non-specific intensity variations (e.g., non-uniform illumination) that complicate the quantitative assessment of tumor with high accuracy.…”

5-Aminolevulinic Acid-Induced Protoporphyrin IX Fluorescence Imaging for Tumor Detection: Recent Advances and Challenges

“…Regarding the 5-ALA PDD of LGGs, the present technology is limited by the low PpIX FI within pure LGG [ 8 ]. LGGs are grade 1/2 tumors according to the WHO classification.…”

“…The signal intensity of PpIX fluorescence depends on the type and number of tumors; low-grade gliomas (LGGs), invasive margins of high-grade gliomas (HGGs), and gastrointestinal cancers generally emit only weak fluorescence after 5-ALA administration. PpIX fluorescence is reported to be attenuated at the margins of the HGGs, making accurate identification of tumor margins difficult [ 1 , 7 , 8 , 9 , 10 , 11 , 12 ]. In tumors that emit relatively weak PpIX signals, tissue autofluorescence derived from collagen and flavin adenine dinucleotide (FAD) affects their ability to be detected [ 13 ].…”