The T2-FLAIR–mismatch sign as an imaging biomarker for IDH and 1p/19q status in diffuse low-grade gliomas: a systematic review with a Bayesian approach to evaluation of diagnostic test performance

Abstract

<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>With the revised WHO 2016 classification of brain tumors, there has been increasing interest in imaging biomarkers to predict molecular status and improve the yield of genetic testing for diffuse low-grade gliomas (LGGs). The T2-FLAIR–mismatch sign has been suggested to be a highly specific radiographic marker of isocitrate dehydrogenase (<jats:italic>IDH</jats:italic>) gene mutation and 1p/19q codeletion status in diffuse LGGs. The presence of T2-FLAIR mismatch indicates a T2-hyperintense lesion that is hypointense on FLAIR with the exception of a hyperintense rim.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>In accordance with PRISMA guidelines, we performed a systematic review of the Ovid Medline, Embase, Scopus, and Cochrane databases for reports of studies evaluating the diagnostic performance of T2-FLAIR mismatch in predicting the <jats:italic>IDH</jats:italic> and 1p/19q codeletion status in diffuse LGGs. Results were combined into a 2 × 2 format, and the following diagnostic performance parameters were calculated: sensitivity, specificity, positive predictive value, negative predictive value, and positive (LR+) and negative (LR−) likelihood ratios. In addition, we utilized Bayes theorem to calculate posttest probabilities as a function of known pretest probabilities from previous genome-wide association studies and the calculated LRs. Calculations were performed for 1) <jats:italic>IDH</jats:italic> mutation with 1p/19q codeletion (<jats:italic>IDHmut-Codel</jats:italic>), 2) <jats:italic>IDH</jats:italic> mutation without 1p/19q codeletion (<jats:italic>IDHmut-Noncodel</jats:italic>), 3) <jats:italic>IDH</jats:italic> mutation overall, and 4) 1p/19q codeletion overall. The QUADAS-2 (revised Quality Assessment of Diagnostic Accuracy Studies) tool was utilized for critical appraisal of included studies.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>A total of 4 studies were included, with inclusion of 2 separate cohorts from a study reporting testing and validation (n = 746). From pooled analysis of all cohorts, the following values were obtained for each molecular profile—<jats:italic>IDHmut-Codel</jats:italic>: sensitivity 30%, specificity 73%, LR+ 1.1, LR− 1.0; <jats:italic>IDHmut-Noncodel</jats:italic>: sensitivity 33.7%, specificity 98.5%, LR+ 22.5, LR− 0.7; <jats:italic>IDH</jats:italic>: sensitivity 32%, specificity 100%, LR+ 32.1, LR− 0.7; 1p/19q codeletion: sensitivity 0%, specificity 54%, LR+ 0.01, LR− 1.9. Bayes theorem was used to calculate the following posttest probabilities after a positive and negative result, respectively—<jats:italic>IDHmut-Codel</jats:italic>: 32.2% and 29.4%; <jats:italic>IDHmut-Noncodel</jats:italic>: 95% and 40%; <jats:italic>IDH</jats:italic>: 99.2% and 73.5%; 1p/19q codeletion: 0.4% and 35.1%.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>The T2-FLAIR–mismatch sign was an insensitive but highly specific marker of <jats:italic>IDH</jats:italic> mutation and I<jats:italic>DHmut-Noncodel</jats:italic> profile, although significant exceptions may exist to this finding. Tumors with a positive sign may still be <jats:italic>IDHwt</jats:italic> or 1p/19q codeleted. These findings support the utility of T2-FLAIR mismatch as an imaging-based biomarker for positive selection of patients with <jats:italic>IDH</jats:italic>-mutant gliomas.</jats:p></jats:sec>

Impact of Inversion Time for FLAIR Acquisition on the T2-FLAIR Mismatch Detectability for IDH-Mutant, Non-CODEL Astrocytomas

“…On the other hand, the T2-FLAIR mismatch sign is an image-based molecular diagnostic marker that clinicians can readily incorporate into clinical practice, as both T2WI and FLAIR are routine MRI protocols for gliomas. The T2-FLAIR mismatch sign is an imaging surrogate specific for IDH mt, non-CODEL astrocytomas, performance of which several studies have validated ( 13 – 15 , 29 – 31 ). However, the sensitivity and NPV of the T2-FLAIR mismatch sign have been reported to be relatively low, as quite a few IDH mt, non-CODEL astrocytomas do not present the T2-FLAIR mismatch sign ( 13 – 15 ).…”

Thin-Slice Magnetic Resonance Imaging-Based Radiomics Signature Predicts Chromosomal 1p/19q Co-deletion Status in Grade II and III Gliomas

“…Previously, the MRIbased T2-FLAIR mismatch sign was recognized as a visual-based imaging characteristic with good interobserver correlation that may determine the 1p/19q status in LGG. A recent systematic review suggested that the T2-FLAIR mismatch sign displayed a sensitivity and specificity of 30 and 73% in determining IDH mutated with 1p/19q co-deleted tumors, and 34 and 98% for IDH mutated with 1p/19q intact tumors (40). However, such imaging characteristics may be limited in clinical application due to the unbalanced sensitivity and specificity, and highthroughput quantitative features are intensively needed to better illustrate the radiological divergences and further predict the 1p/19q status non-invasively.…”

The Role of the T2–FLAIR Mismatch Sign as an Imaging Marker of IDH Status in a Mixed Population of Low- and High-Grade Gliomas

“…Indeed, Foltyn et al recognized the T2-FLAIR mismatch sign in 12 of 113 cases (10.6%) (Grade II and III gliomas) and in none of the 295 glioblastoma cases [19]. A recent meta-analysis by Goyal et al estimated the pooled accuracy of the T2-FLAIR mismatch sign in predicting IDH mutation based on data extracted from three studies focusing on the prediction of 1p/19q status in patients with LGG [11,14,15,24,25]. The pooled sensitivity and specificity rates were estimated to be as high as 31% and 100%, respectively.…”