T2/FLAIR-mismatch sign for noninvasive detection of IDH-mutant 1p/19q non-codeleted gliomas: validity and pathophysiology

Abstract

Background: This study aimed to assess the validity and pathophysiology of the T2/FLAIR-mismatch sign for noninvasive identification of isocitrate dehydrogenase (IDH)-mutant 1p/19q non-codeleted glioma.

Methods: Magnetic resonance imaging scans from 408 consecutive patients with newly diagnosed glioma (113 lower-grade gliomas and 295 glioblastomas) were evaluated for the presence of T2/FLAIR-mismatch sign by 2 independent reviewers. Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were calculated to assess the performance of the T2/FLAIR-mismatch sign for identifying IDH-mutant 1p/19q non-codeleted tumors. An exploratory analysis of differences in contrast-enhancing tumor volumes, apparent diffusion coefficient (ADC) values, and relative cerebral blood volume (rCBV) values in IDH-mutant gliomas with versus without the presence of a T2/FLAIR-mismatch sign (as well as analysis of spatial differences within tumors with the presence of a T2/FLAIR-mismatch sign) was performed.

Results: The T2/FLAIR-mismatch sign was present in 12 cases with lower-grade glioma (10.6%), all of them being IDH-mutant 1p/19q non-codeleted tumors (sensitivity = 10.9%, specificity = 100%, PPV = 100%, NPV = 3.0%, accuracy = 13.3%). There was a substantial interrater agreement to identify the T2/FLAIR-mismatch sign (Cohen's kappa = 0.75 [95% CI, 0.57-0.93]). The T2/FLAIR-mismatch sign was not identified in any other molecular subgroup, including IDH-mutant glioblastoma cases (n = 5). IDH-mutant gliomas with a T2/FLAIR-mismatch sign showed significantly higher ADC (P < .0001) and lower rCBV values (P = .0123) as compared to IDH-mutant gliomas without a T2/FLAIR-mismatch sign. Moreover, in IDH-mutant gliomas with T2/FLAIR-mismatch sign the ADC values were significantly lower in the FLAIR-hyperintense rim as compared to the FLAIR-hypointense core of the tumor (P = .0005).

Conclusions: This study confirms the high specificity of the T2/FLAIR-mismatch sign for noninvasive identification of IDH-mutant 1p/19q non-codeleted gliomas; however, sensitivity is low and applicability is limited to lower-grade gliomas. Whether the higher ADC and lower rCBV values in IDH-mutant gliomas with a T2/FLAIR-mismatch sign (as compared to those without) translate into a measurable prognostic effect requires investigation in future studies. Moreover, spatial differences in ADC values between the core and rim of tumors with a T2/FLAIR-mismatch sign potentially reflect specific distinctions in tumor cellularity and microenvironment.

Keywords: biomarkers; glioma; isocitrate dehydrogenase; magnetic resonance imaging.

Figure 1.

Two cases with the presence of a T2/FLAIR-mismatch sign and their corresponding ADC image (E and F). (A and B) IDH-mutant 1p/19q non-codeleted anaplastic astrocytoma (WHO °III) in a 31-year-old man and (C and D) IDH-mutant 1p/19q non-codeleted anaplastic astrocytoma (WHO °III) in a 56-year-old woman. Both cases show tumors located in the left frontal lobe with a homogeneously hyperintense signal on T2-w images (left side), coupled with a homogeneously hypointense signal on FLAIR images except for a small hyperintense peripheral rim (right side).

Figure 2.

Absence of a T2/FLAIR-mismatch sign in a 36-year-old woman with a left temporal IDH-mutant 1p/19q non-codeleted anaplastic astrocytoma (WHO °III). The tumor demonstrates a near-complete homogeneous hyperintense signal on both T2-w and FLAIR images (right). No peripheral hyperintense rim is visible on FLAIR images.

Figure 3.

Boxplot of contrast-enhancing tumor volumes (cm³) comparing patients with IDH-mutant gliomas who present the T2/FLAIR-mismatch sign (green color) and who did not (blue color). The left side of the figure zooms to the range of 0–3 cm³, whereas the right side shows the full range of data (0–60 cm³). There was no significant difference in contrast-enhancing tumor volumes between patients who present the T2/FLAIR-mismatch sign and patients who did not (P = .2728).

Figure 4.

Boxplot of mean ADC and rCBV values comparing patients with IDH-mutant gliomas who present the T2/FLAIR-mismatch sign (green color) and those who did not (blue color). Analysis of all IDH-mutant gliomas (ie, including astrocytoma, oligodendroglioma, and glioblastoma cases—top row) and separate analysis for the subset of patients with IDH-mutant astrocytomas (bottom row) were performed. The median ADC values were significantly higher in both IDH-mutant gliomas (P < .0001) and in the subset of IDH-mutant astrocytomas (P < .0001) without the T2/FLAIR-mismatch sign as compared those with a T2/FLAIR-mismatch sign (left column). The median rBCV values were significantly lower in IDH-mutant gliomas (P = .0123) with the presence of a T2/FLAIR-mismatch sign, whereas only borderline significance was found within the subset of IDH-mutant astrocytomas (P = .0757) (right column).

Figure 5.

Boxplot of mean ADC and rCBV values comparing the FLAIR-hypointense core (green color) versus the FLAIR-hyperintense rim (blue color) in patients with a T2/FLAIR-mismatch sign. ADC values were significantly lower in the rim as compared to the core (P = .0005) whereas there was no significant difference in rCBV values (P = .4258).