The Value of 5-Aminolevulinic Acid in Low-grade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features: An Analysis Based on Fluorescence, Magnetic Resonance Imaging, 18F-Fluoroethyl Tyrosine Positron Emission Tomography, and Tumor Molecular Factors

Abstract

Background: Approximately 20% of grade II and most grade III gliomas fluoresce after 5-aminolevulinic acid (5-ALA) application. Conversely, approximately 30% of nonenhancing gliomas are actually high grade.

Objective: The aim of this study was to identify preoperative factors (ie, age, enhancement, 18F-fluoroethyl tyrosine positron emission tomography [F-FET PET] uptake ratios) for predicting fluorescence in gliomas without typical glioblastomas imaging features and to determine whether fluorescence will allow prediction of tumor grade or molecular characteristics.

Methods: Patients harboring gliomas without typical glioblastoma imaging features were given 5-ALA. Fluorescence was recorded intraoperatively, and biopsy specimens collected from fluorescing tissue. World Health Organization (WHO) grade, Ki-67/MIB-1 index, IDH1 (R132H) mutation status, O-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and 1p/19q co-deletion status were assessed. Predictive factors for fluorescence were derived from preoperative magnetic resonance imaging and F-FET PET. Classification and regression tree analysis and receiver-operating-characteristic curves were generated for defining predictors.

Results: Of 166 tumors, 82 were diagnosed as WHO grade II, 76 as grade III, and 8 as glioblastomas grade IV. Contrast enhancement, tumor volume, and F-FET PET uptake ratio >1.85 predicted fluorescence. Fluorescence correlated with WHO grade (P < .001) and Ki-67/MIB-1 index (P < .001), but not with MGMT promoter methylation status, IDH1 mutation status, or 1p19q co-deletion status. The Ki-67/MIB-1 index in fluorescing grade III gliomas was higher than in nonfluorescing tumors, whereas in fluorescing and nonfluorescing grade II tumors, no differences were noted.

Conclusion: Age, tumor volume, and F-FET PET uptake are factors predicting 5-ALA-induced fluorescence in gliomas without typical glioblastoma imaging features. Fluorescence was associated with an increased Ki-67/MIB-1 index and high-grade pathology. Whether fluorescence in grade II gliomas identifies a subtype with worse prognosis remains to be determined.

FIGURE 1

Examples of gliomas without imaging features characteristic for glioblastomas and the different types of enhancement. A, no enhancement: glioma WHO grade II; Ki-67/MIB-1 index, 5%; IDH1; 1p/19q status not determined; no MGMT promoter methylation; ¹⁸F-FET PET uptake ratio, 2.0; ALA+ with a weak patch of fluorescence in hot spot. B, patchy enhancement: anaplastic astrocytoma WHO grade III; Ki-67/MIB-1 index, 40%; no 1p/19q co-deletion; no MGMT promotor methylation; IDH1, wild type; PET uptake ratio, 2:6; ALA+ (patchy fluorescence). C, weak enhancement: anaplastic astrocytoma grade III; Ki-67/MIB-1 index, 30%; no MGMT promotor methylation; IDH1, wild type; ¹⁸F-FET PET uptake ratio, 3.7; ALA weak homogeneous fluorescence. D, strong enhancement: anaplastic astrocytoma; Ki-67/MIB-1 index, 30%; IDH1, wild type; 1p19q-, IDH1-, no MGMT promotor methylation; ¹⁸F-FET PET uptake ratio, 4.2; ALA+ with strong fluorescence. ALA, aminolevulinic acid; ¹⁸F-FET PET, 18F-fluoroethyl tyrosine positron emission tomography; MGMT, O⁶-methylguanine DNA methyltransferase; WHO, World Health Organization.

FIGURE 2

Example of a GBM without typical imaging features of a GBM. This particular tumor showed no enhancement. The ¹⁸F-FET PET hot spot, which was located with neuronavigation, showed strong fluorescence (Ki-67/MIB-1 index, 25%; IDH1, wild type; 1p/19q status not determined; no O⁶-methylguanine DNA methyltransferase promotor methylation; ¹⁸F-FET PET uptake ratio, 3.7). ¹⁸F-FET PET, 18F-fluoroethyl tyrosine positron emission tomography; GBM, glioblastoma multiforme. Color version available online only.

FIGURE 3

Classification and regression tree analysis for analyzing predictors of fluorescence in gliomas. Contrast enhancement was the strongest discriminator. For enhancing tumors, age and volume were additional discriminators. For nonenhancing tumors, the ¹⁸F-fluoroethyl tyrosine positron emission tomography (FET-PET) uptake ratio was the only discriminator. SUV, standardized uptake value.

FIGURE 4

Receiver-operating characteristic curves demonstrating the relationship of the ¹⁸F-fluoroethyl tyrosine positron emission tomography uptake ratio as a diagnostic indicator of intraoperative fluorescence. The accuracy of positron emission tomography for predicting fluorescence was 69% (left) and 70% for nonenhancing tumors (right). Note the threshold of 1.85 for nonenhancing tumors. Fluorescence was only observed above this threshold. AUC, area under the curve. Color version available online only.

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