The clinical significance of the T2-FLAIR mismatch sign in grade II and III gliomas: a population-based study.
ABSTRACT: BACKGROUND:The T2-FLAIR mismatch sign is an imaging finding highly suggestive of isocitrate dehydrogenase mutated (IDH-mut) 1p19q non-codeleted (non-codel) gliomas (astrocytomas). In previous studies, it has shown excellent specificity but limited sensitivity for IDH-mut astrocytomas. Whether the mismatch sign is a marker of a clinically relevant subtype of IDH-mut astrocytomas is unknown. METHODS:We included histopathologically verified supratentorial lower-grade gliomas (LGG) WHO grade II-III retrospectively during the period 2010-2016. In the period 2017-2018, patients with suspected LGG radiologically were prospectively included, and in this cohort other diagnoses than glioma could occur. Clinical, radiological and molecular data were collected. For clinical evaluation we included all patients with IDH-mut astrocytomas. In the 2010-2016 cohort DNA methylation analysis with Infinium MethylationEPIC BeadChip (Illumina) was performed for patients with an IDH-mut astrocytoma with available tissue. We aimed to examine the association of the T2-FLAIR mismatch sign with clinical factors and outcomes. Additionally, we evaluated the diagnostic reliability of the mismatch sign and its relation to methylation profiles. RESULTS:Out of 215 patients with LGG, 135 had known IDH-mutation and 1p19q codeletion status. Fifty patients had an IDH-mut astrocytoma and 12 of these (24.0%) showed a mismatch sign. The sensitivity and specificity of the mismatch sign for IDH-mut detection were 26.4 and 97.6%, respectively. There were no differences between patients with an IDH-mut astrocytoma with or without mismatch sign when grouped according to T2-FLAIR mismatch sign with respect to baseline characteristics, clinical outcomes and methylation profiles. The overall interrater agreement between neuroradiologist and clinical neurosurgeons for the T2-FLAIR mismatch sign was significant when all 215 MRI examination assessed (??=?0.77, p?
Project description:Background:The purpose of this study was to assess the reproducibility of the previously described T2-fluid attenuated inversion recovery (FLAIR) mismatch sign as a specific imaging marker in non-enhancing isocitrate dehydrogenase (IDH) mutant, 1p/19q non-codeleted lower-grade glioma (LGG), encompassing both diffuse and anaplastic astrocytoma. Methods:MR scans (n = 154) from 3 separate databases with genotyped LGG were evaluated by 2 independent reviewers to assess (i) presence/absence of "T2-FLAIR mismatch" sign and (ii) presence/absence of homogeneous signal on T2-weighted images. Interrater agreement with Cohen's kappa (κ) was calculated, as well as diagnostic test performance of the T2-FLAIR mismatch sign to identify IDH-mutant astrocytoma. Results:There was substantial interrater agreement for the T2-FLAIR mismatch sign [κ = 0.75 (0.64-0.87)], but only fair agreement for T2 homogeneity [κ = 0.38 (0.25-0.52)]. The T2-FLAIR mismatch sign was present in 38 cases (25%) and had a positive predictive value of 100%, negative predictive value of 68%, a sensitivity of 51%, and a specificity of 100%. Conclusions:With a robust interrater agreement, our study confirms that among non-enhancing LGG the T2-FLAIR mismatch sign represents a highly specific imaging marker for IDH-mutant astrocytoma. This non-invasive marker may enable a more informed patient counsel and can aid in the treatment decision processes in a significant proportion of patients presenting with non-enhancing, LGG-like lesions.
Project description:PURPOSE:With the updated World Health Organization (WHO) 2016 neuropathological diagnostic criteria, radiographic prognostic associations in lower-grade gliomas (LGG, WHO grade II and III) are undergoing re-evaluation. METHODS:We identified 316 LGG patients (151 grade II and 165 grade III) for a combined cohort from three independent databases. We analyzed the preoperative axial FLAIR, axial T2-weighted and post-gadolinium volumetric T1-weighted MR images. The molecular data collected included the status of IDH1/2, TP53, TERT promoter and ATRX mutations, in addition to 1p/19q co-deletions. In a subset of cases (n?=?133), we assessed the "T2-FLAIR mismatch" sign. RESULTS:Gliomas were assigned to one of the three molecular groups: Group O (IDH-mutant, 1p/19q co-deleted oligodendrogliomas, n?=?95), Group A (IDH-mutant, ATRX inactivated astrocytomas, n?=?175) and Group G (IDH wild-type, GBM-like, n?=?46). A contrast-enhancing tumor was seen in 98 patients (31%), most frequently in Group G (n?=?28/45, 57%), when compared to Group A (n?=?49/175, 28%) and Group O (n?=?24/95, 25.3%) tumors (p?=?0.008 and p?=?0.0011, respectively). Consistent with previous reports, T2-FLAIR mismatch was preferentially found in Group A tumors (73.1%, 60 of 82), although its presence was not associated with survival, after controlling for molecular group. False positive mismatch sign was noted in 28.5% (12/42) Group O tumors, but none of the tumors in Group G. A combination of all three factors: age under 40 years at first diagnosis, a tumor size larger than 6 cm and T2-FLAIR mismatch was highly specific for IDH mutant astrocytoma (Group A). CONCLUSION:We identify radiographic correlates of molecular groups in lower-grade gliomas, which join clinical demographic features in defining the characteristic presentation of these tumors. Radiographic correlates of prognosis in LGG require re-evaluation within molecular group.
Project description:AbstractBackgroundThis 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.MethodsMagnetic 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.ResultsThe 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).ConclusionsThis 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.
Project description:BACKGROUND AND PURPOSE:Isocitrate dehydrogenase (IDH)-mutant lower grade gliomas are classified as oligodendrogliomas or diffuse astrocytomas based on 1p/19q-codeletion status. We aimed to test and validate neuroradiologists' performances in predicting the codeletion status of IDH-mutant lower grade gliomas based on simple neuroimaging metrics. MATERIALS AND METHODS:One hundred two IDH-mutant lower grade gliomas with preoperative MR imaging and known 1p/19q status from The Cancer Genome Atlas composed a training dataset. Two neuroradiologists in consensus analyzed the training dataset for various imaging features: tumor texture, margins, cortical infiltration, T2-FLAIR mismatch, tumor cyst, T2* susceptibility, hydrocephalus, midline shift, maximum dimension, primary lobe, necrosis, enhancement, edema, and gliomatosis. Statistical analysis of the training data produced a multivariate classification model for codeletion prediction based on a subset of MR imaging features and patient age. To validate the classification model, 2 different independent neuroradiologists analyzed a separate cohort of 106 institutional IDH-mutant lower grade gliomas. RESULTS:Training dataset analysis produced a 2-step classification algorithm with 86.3% codeletion prediction accuracy, based on the following: 1) the presence of the T2-FLAIR mismatch sign, which was 100% predictive of noncodeleted lower grade gliomas, (n = 21); and 2) a logistic regression model based on texture, patient age, T2* susceptibility, primary lobe, and hydrocephalus. Independent validation of the classification algorithm rendered codeletion prediction accuracies of 81.1% and 79.2% in 2 independent readers. The metrics used in the algorithm were associated with moderate-substantial interreader agreement (? = 0.56-0.79). CONCLUSIONS:We have validated a classification algorithm based on simple, reproducible neuroimaging metrics and patient age that demonstrates a moderate prediction accuracy of 1p/19q-codeletion status among IDH-mutant lower grade gliomas.
Project description:The "integrated diagnosis" for infiltrating gliomas in the 2016 revised World Health Organization (WHO) classification of tumors of the central nervous system requires assessment of the tumor for IDH mutations and 1p/19q codeletion. Since TERT promoter mutations and ATRX alterations have been shown to be associated with prognosis, we analyzed whether these tumor markers provide additional prognostic information within each of the five WHO 2016 categories. We used data for 1206 patients from the UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) with infiltrative glioma, grades II-IV for whom tumor status for IDH, 1p/19q codeletion, ATRX, and TERT had been determined. All cases were assigned to one of 5 groups following the WHO 2016 diagnostic criteria based on their morphologic features, and IDH and 1p/19q codeletion status. These groups are: (1) Oligodendroglioma, IDH-mutant and 1p/19q-codeleted; (2) Astrocytoma, IDH-mutant; (3) Glioblastoma, IDH-mutant; (4) Glioblastoma, IDH-wildtype; and (5) Astrocytoma, IDH-wildtype. Within each group, we used univariate and multivariate Cox proportional hazards models to assess associations of overall survival with patient age at diagnosis, grade, and ATRX alteration status and/or TERT promoter mutation status. Among Group 1 IDH-mutant 1p/19q-codeleted oligodendrogliomas, the TERT-WT group had significantly worse overall survival than the TERT-MUT group (HR: 2.72, 95% CI 1.05-7.04, p = 0.04). In both Group 2, IDH-mutant astrocytomas and Group 3, IDH-mutant glioblastomas, neither TERT mutations nor ATRX alterations were significantly associated with survival. Among Group 4, IDH-wildtype glioblastomas, ATRX alterations were associated with favorable outcomes (HR: 0.36, 95% CI 0.17-0.81, p = 0.01). Among Group 5, IDH-wildtype astrocytomas, the TERT-WT group had significantly better overall survival than the TERT-MUT group (HR: 0.48, 95% CI 0.27-0.87), p = 0.02). Thus, we present evidence that in certain WHO 2016 diagnostic groups, testing for TERT promoter mutations or ATRX alterations may provide additional useful prognostic information.
Project description:Diffuse IDH-mutant astrocytoma mostly occurs in adults and carries a favorable prognosis compared to IDH-wildtype malignant gliomas. Acquired mismatch repair deficiency is known to occur in recurrent IDH-mutant gliomas as resistance mechanism towards alkylating chemotherapy. In this multi-institutional study, we report a novel epigenetic group of 32 IDH-mutant gliomas with proven or suspected hereditary mismatch repair deficiency. None of the tumors exhibited a combined 1p/19q deletion. These primary mismatch repair-deficient IDH-mutant astrocytomas (PMMRDIA) were histologically high-grade and were mainly found in children, adolescents and young adults (median age 14 years). Mismatch repair deficiency syndromes (Lynch or Constitutional Mismatch Repair Deficiency Syndrom (CMMRD)) were clinically diagnosed and/or germline mutations in DNA mismatch repair genes (MLH1, MSH6, MSH2) were found in all cases, except one case with a family and personal history of colon cancer and another case with MSH6-deficiency available only as recurrent tumor. Loss of at least one of the mismatch repair proteins was detected via immunohistochemistry in all, but one case analyzed. Tumors displayed a hypermutant genotype and microsatellite instability was present in more than half of the sequenced cases. Integrated somatic mutational and chromosomal copy number analyses showed frequent inactivation of TP53, RB1 and activation of RTK/PI3K/AKT pathways. In contrast to the majority of IDH-mutant gliomas, more than 60% of the samples in our cohort presented with an unmethylated MGMT promoter. While the rate of immuno-histochemical ATRX loss was reduced, variants of unknown significance were more frequently detected possibly indicating a higher frequency of ATRX inactivation by protein malfunction. Compared to reference cohorts of other IDH-mutant gliomas, primary mismatch repair-deficient IDH-mutant astrocytomas have by far the worst clinical outcome with a median survival of only 15 months irrespective of histological or molecular features. The findings reveal a so far unknown entity of IDH-mutant astrocytoma with high prognostic relevance. Diagnosis can be established by aligning with the characteristic DNA methylation profile, by DNA-sequencing-based proof of mismatch repair deficiency or immunohistochemically demonstrating loss-of-mismatch repair proteins.
Project description:Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 are among the first genetic alterations observed during the development of lower-grade glioma (LGG). LGG-associated IDH mutations confer gain-of-function activity by converting ?-ketoglutarate to the oncometabolite R-2-hydroxyglutarate (2HG). Clinical samples and gene expression data from The Cancer Genome Atlas (TCGA) demonstrate reduced expression of cytotoxic T lymphocyte-associated genes and IFN-?-inducible chemokines, including CXCL10, in IDH-mutated (IDH-MUT) tumors compared with IDH-WT tumors. Given these findings, we have investigated the impact of IDH mutations on the immunological milieu in LGG. In immortalized normal human astrocytes (NHAs) and syngeneic mouse glioma models, the introduction of mutant IDH1 or treatment with 2HG reduced levels of CXCL10, which was associated with decreased production of STAT1, a regulator of CXCL10. Expression of mutant IDH1 also suppressed the accumulation of T cells in tumor sites. Reductions in CXCL10 and T cell accumulation were reversed by IDH-C35, a specific inhibitor of mutant IDH1. Furthermore, IDH-C35 enhanced the efficacy of vaccine immunotherapy in mice bearing IDH-MUT gliomas. Our findings demonstrate a mechanism of immune evasion in IDH-MUT gliomas and suggest that specific inhibitors of mutant IDH may improve the efficacy of immunotherapy in patients with IDH-MUT gliomas.
Project description:Background:Tumor infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) are targets of immune checkpoint inhibitors. Methods:Forty-three World Health Organization (WHO) grade II/III gliomas (39 IDH-mutant [mut], 4 IDH-wildtype [wt]) and 14 IDH-mut glioblastomas (GBM) were analyzed for TIL (CD3+; PD1+) infiltration and PD-L1 expression. Results were compared with the data of a previously published series of 117 IDH-wt glioblastomas. PD-L1 gene expression levels were evaluated in 677 diffuse gliomas grades II-IV from The Cancer Genome Atlas (TCGA) database. Results:TIL and PD-L1 expression were observed in approximately half of WHO grade II/III gliomas. IDH-wt status was associated with significantly higher TIL infiltration and PD-L1 expression among all (grades II-IV) cases (n = 174, P < 0.001) and within the cohort of glioblastomas (n = 131, P < 0.001). In low-grade glioma (LGG) and glioblastoma cohorts of TCGA, significantly higher PD-L1 gene expression levels were evident in IDH-wt compared with IDH-mut samples (LGG: N = 516; P = 1.933e-11, GBM: N = 161; P < 0.009). Lower PD-L1 gene expression was associated with increased promoter methylation (Spearman correlation coefficient -0.36; P < 0.01) in the LGG cohort of TCGA. IDH-mut gliomas had higher PD-L1 gene promoter methylation levels than IDH-wt gliomas (P < 0.01). Conclusions:The immunological tumor microenvironment of diffuse gliomas differs in association with IDH mutation status. IDH-wt gliomas display a more prominent TIL infiltration and higher PD-L1 expression than IDH-mut cases. Mechanistically this may be at least in part due to differential PD-L1 gene promoter methylation levels. Our findings may be relevant for immune modulatory treatment strategies in glioma patients.
Project description:BACKGROUND:Surgical resection and irradiation of diffuse glioma are guided by standard MRI: T2/fluid attenuated inversion recovery (FLAIR)-weighted MRI for non-enhancing and T1-weighted gadolinium-enhanced (T1G) MRI for enhancing gliomas. Amino acid PET has been suggested as the new standard. Imaging combinations may improve standard MRI and amino acid PET. The aim of the study was to determine the accuracy of imaging combinations to detect glioma infiltration. METHODS:We included 20 consecutive adults with newly diagnosed non-enhancing glioma (7 diffuse astrocytomas, isocitrate dehydrogenase [IDH] mutant; 1 oligodendroglioma, IDH mutant and 1p/19q codeleted; 1 glioblastoma IDH wildtype) or enhancing glioma (glioblastoma, 9 IDH wildtype and 2 IDH mutant). Standardized preoperative imaging (T1-, T2-, FLAIR-weighted, and T1G MRI, perfusion and diffusion MRI, MR spectroscopy and O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET) was co-localized with multiregion stereotactic biopsies preceding resection. Tumor presence in the biopsies was assessed by 2 neuropathologists. Diagnostic accuracy was determined using receiver operating characteristic analysis. RESULTS:A total of 174 biopsies were obtained (63 from 9 non-enhancing and 111 from 11 enhancing gliomas), of which 129 contained tumor (50 from non-enhancing and 79 from enhancing gliomas). In enhancing gliomas, the combination of apparent diffusion coefficient (ADC) with [18F]FET PET (area under the curve [AUC], 95% CI: 0.89, 0.79?0.99) detected tumor better than T1G MRI (0.56, 0.39?0.72; P < 0.001) and [18F]FET PET (0.76, 0.66?0.86; P = 0.001). In non-enhancing gliomas, no imaging combination detected tumor significantly better than standard MRI. FLAIR-weighted MRI had an AUC of 0.81 (0.65-0.98) compared with 0.69 (0.56-0.81; P = 0.019) for [18F]FET PET. CONCLUSION:Combining ADC and [18F]FET PET detects glioma infiltration better than standard MRI and [18F]FET PET in enhancing gliomas, potentially enabling better guidance of local therapy.
Project description:Background:Extensive resections in low-grade glioma (LGG) are associated with improved overall survival (OS). However, World Health Organization (WHO) classification of gliomas has been completely revised and is now predominantly based on molecular criteria. This requires reevaluation of the impact of surgery in molecularly defined LGG subtypes. Methods:We included 228 adults who underwent surgery since 2003 for a supratentorial LGG. Pre- and postoperative tumor volumes were assessed with semiautomatic software on T2-weighted images. Targeted next-generation sequencing was used to classify samples according to current WHO classification. Impact of postoperative volume on OS, corrected for molecular profile, was assessed using a Cox proportional hazards model. Results:Median follow-up was 5.79 years. In 39 (17.1%) histopathologically classified gliomas, the subtype was revised after molecular analysis. Complete resection was achieved in 35 patients (15.4%), and in 54 patients (23.7%) only small residue (0.1-5.0 cm3) remained. In multivariable analysis, postoperative volume was associated with OS, with a hazard ratio of 1.01 (95% CI: 1.002-1.02; P = 0.016) per cm3 increase in volume. The impact of postoperative volume was particularly strong in isocitrate dehydrogenase (IDH) mutated astrocytoma patients, where even very small postoperative volumes (0.1-5.0 cm) already negatively affected OS. Conclusion:Our data provide the necessary reevaluation of the impact of surgery in molecularly defined LGG and support maximal resection as first-line treatment for molecularly defined LGG. Importantly, in IDH mutated astrocytoma, even small postoperative volumes have negative impact on OS, which argues for a second-look operation in this subtype to remove minor residues if safely possible.