Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between δ-aminolevulinic acid–induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters

Abstract

Object The aim of this study was to investigate the relationships between intraoperative fluorescence, features on MR imaging, and neuropathological parameters in 11 cases of newly diagnosed glioblastoma multiforme (GBM) treated using protoporphyrin IX (PpIX) fluorescence-guided resection. Methods In 11 patients with a newly diagnosed GBM, δ-aminolevulinic acid (ALA) was administered to enhance endogenous synthesis of the fluorophore PpIX. The patients then underwent fluorescence-guided resection, coregistered with conventional neuronavigational image guidance. Biopsy specimens were collected at different times during surgery and assigned a fluorescence level of 0–3 (0, no fluorescence; 1, low fluorescence; 2, moderate fluorescence; or 3, high fluorescence). Contrast enhancement on MR imaging was quantified using two image metrics: 1) Gd-enhanced signal intensity (GdE) on T1-weighted subtraction MR image volumes, and 2) normalized contrast ratios (nCRs) in T1-weighted, postGd-injection MR image volumes for each biopsy specimen, using the biopsy-specific image-space coordinate transformation provided by the navigation system. Subsequently, each GdE and nCR value was grouped into one of two fluorescence categories, defined by its corresponding biopsy specimen fluorescence assessment as negative fluorescence (fluorescence level 0) or positive fluorescence (fluorescence level 1, 2, or 3). A single neuropathologist analyzed the H & E–stained tissue slides of each biopsy specimen and measured three neuropathological parameters: 1) histopathological score (0–IV); 2) tumor burden score (0–III); and 3) necrotic burden score (0–III). Results Mixed-model analyses with random effects for individuals show a highly statistically significant difference between fluorescing and nonfluorescing tissue in GdE (mean difference 8.33, p = 0.018) and nCRs (mean difference 5.15, p < 0.001). An analysis of association demonstrated a significant relationship between the levels of intraoperative fluorescence and histopathological score (χ2 = 58.8, p < 0.001), between fluorescence levels and tumor burden (χ2 = 42.7, p < 0.001), and between fluorescence levels and necrotic burden (χ2 = 30.9, p < 0.001). The corresponding Spearman rank correlation coefficients were 0.51 (p < 0.001) for fluorescence and histopathological score, and 0.49 (p < 0.001) for fluorescence and tumor burden, suggesting a strongly positive relationship for each of these variables. Conclusions These results demonstrate a significant relationship between contrast enhancement on preoperative MR imaging and observable intraoperative PpIX fluorescence. The finding that preoperative MR image signatures are predictive of intraoperative PpIX fluorescence is of practical importance for identifying candidates for the procedure. Furthermore, this study provides evidence that a strong relationship exists between tumor aggressiveness and the degree of tissue fluorescence that is observable intraoperatively, and that observable fluorescence has an excellent positive predictive...

11C‐methionine uptake and intraoperative 5‐aminolevulinic acid‐induced fluorescence as separate index markers of cell density in glioma

“…In accordance with this finding, limited sensitivity for the detection of tumor area with this method has been reported. 37 The negative predictive value, representing the rate for correct detection of nontumor areas with absence of fluorescence, was reportedly not favorable, whereas the positive predictive value, as the rate of positive tumor detection with positive fluorescence, was high. 37 Therefore, although the clinical utility of 5-ALA fluorescence-guided glioma surgery has already been supported by a randomized controlled multicenter phase 3 trial, 19 additive techniques for delineation of tumor invasion areas are needed for further improvement in cytoreduction surgery for gliomas.…”

“…Several reports have compared 5-ALA-induced fluorescence with radiological findings. [37][38][39][40] A previous report showed that contrast enhancement on MRI was stronger in the fluorescence-positive area than in the fluorescence-negative area, suggesting that image signatures on preoperative MRI are predictive of intraoperative fluorescence. 37 Another 2 reports compared tracer uptake with 5-ALA-induced fluorescence.…”

“…[37][38][39][40] A previous report showed that contrast enhancement on MRI was stronger in the fluorescence-positive area than in the fluorescence-negative area, suggesting that image signatures on preoperative MRI are predictive of intraoperative fluorescence. 37 Another 2 reports compared tracer uptake with 5-ALA-induced fluorescence. 38,39 One of those reports showed that 18 F-FET PET was more sensitive than 5-ALA-induced fluorescence for the detection of glioma tissue.…”

Intraoperative monopolar mapping during 5-ALA–guided resections of glioblastomas adjacent to motor eloquent areas: evaluation of resection rates and neurological outcome

“…36 Although a significant correlation between the degree of infiltration and the intensity of fluorescence has been reported, areas of relatively little infiltration, or even those without infiltration, may show fluorescence of various intensities. 32 5-ALA is therefore inadequate as a stand-alone method for resections adjacent to eloquent areas. In the current study, resection was stopped in 16 patients due to low MTs (mean MT 3 mA) despite persisting 5-ALA fluorescence.…”

Accuracy of High-Field Intraoperative MRI in the Detectability of Residual Tumor in Glioma Grade IV Resections

“…Improved resection grade of contrast-enhancing tissue [1 -7] prolongs the patient survival rate and preserves eloquent brain function and life quality [1 -9]. Studies dealing with the accuracy of fluorescence-guided resection detected a sensitivity of about 90 % and a negative predictive value of 76 -91 % [1,10,11]. However a negative predictive value of 0.26 in the study of Roberts et al also showed that there are deficits in fluorescence-guided resection with respect to the detection of residual tumorous tissue in normal appearing resection borders [11] so that there is a need for additional intraoperative resection control.…”