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

Martha Foltyn; Karen Natalia Nieto Taborda; Ulf Neuberger; Gianluca Brugnara; Annekathrin Reinhardt; Damian Stichel; Sabine Heiland; Christel Herold-Mende; Andreas Unterberg; Jürgen Debus; Andreas von Deimling; Wolfgang Wick; Martin Bendszus; Philipp Kickingereder

doi:10.1093/noajnl/vdaa004

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

Neurooncol Adv. 2020 Jan 10;2(1):vdaa004. doi: 10.1093/noajnl/vdaa004. eCollection 2020 Jan-Dec.

Authors

Martha Foltyn¹, Karen Natalia Nieto Taborda¹, Ulf Neuberger¹, Gianluca Brugnara¹, Annekathrin Reinhardt², Damian Stichel², Sabine Heiland¹, Christel Herold-Mende³, Andreas Unterberg³, Jürgen Debus^{4

5}, Andreas von Deimling^{2

6}, Wolfgang Wick^{7

8}, Martin Bendszus¹, Philipp Kickingereder¹

Affiliations

¹ Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany.
² Department of Neuropathology, University of Heidelberg Medical Center, Heidelberg, Germany.
³ Department of Neurosurgery, University of Heidelberg Medical Center, Heidelberg, Germany.
⁴ Department of Radiation Oncology, University of Heidelberg Medical Center, Heidelberg Institute of Radiation Oncology and National Center for Radiation Research in Oncology, Heidelberg, Germany.
⁵ Division of Molecular and Translational Radiation Oncology, National Center for Tumor Diseases, Heidelberg University Hospital and DKFZ, Heidelberg, Germany.
⁶ Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷ Neurology Clinic, University of Heidelberg Medical Center, Heidelberg, Germany.
⁸ Clinical Cooperation Unit Neuro-oncology, DKTK, DKFZ, Heidelberg, Germany.

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.