“Real world” use of a highly reliable imaging sign: “T2-FLAIR mismatch” for identification of IDH mutant astrocytomas

Abstract

AbstractThe T2-FLAIR (fluid attenuated inversion recovery) mismatch sign is an easily detectable imaging sign on routine clinical MRI studies that suggests diagnosis of isocitrate dehydrogenase (IDH)–mutant 1p/19q non-codeleted gliomas. Multiple independent studies show that the T2-FLAIR mismatch sign has near-perfect specificity, but low sensitivity for diagnosing IDH-mutant astrocytomas. Thus, the T2-FLAIR mismatch sign represents a non-invasive radiogenomic diagnostic finding with potential clinical impact. Recently, false positive cases have been reported, many related to variable application of the sign’s imaging criteria and differences in image acquisition, as well as to differences in the included patient populations. Here we summarize the imaging criteria for the T2-FLAIR mismatch sign, review similarities and differences between the multiple validation studies, outline strategies to optimize its clinical use, and discuss potential opportunities to refine imaging criteria in order to maximize its impact in glioma diagnostics.

The revised World Health Organization (WHO) 2016 classification for adult diffuse gliomas has implemented several somatic mutations into the diagnosis of patients with these cancers, highlighting the importance of genetic alterations in the biology of glioma. Accompanying this classification update has been a burgeoning interest in correlating preoperative radiologic features with glioma genomics, leading to the rapid growth in the field of glioma “radiogenomics.”

Among promising biomarkers within the nascent field of radiogenomics is the “T2-FLAIR (fluid attenuated inversion recovery) mismatch” sign, an imaging feature detectable on routine clinical MRIs that allows preoperative diagnosis of IDH-mutant astrocytomas (harboring IDH mutation but not 1p/19q codeletion) with a level of specificity that is almost unrivaled in brain tumor imaging.¹ While stringent application of the sign identifies only a minority of IDH-mutant astrocytomas and hence suffers from low sensitivity, multiple independent researchers have validated this sign.^2–6

The purpose of this review is to provide detailed methodology for identifying the T2-FLAIR mismatch sign, including explicit description of the inclusion and exclusion criteria as well as various limitations and exceptions, and to describe the similarities and differences in the multiple independent reports validating this sign with the goal of facilitating application of the T2-FLAIR mismatch sign to “real world” clinical practice. Given the validated high specificity of this radiogenomic biomarker and the ease of identification using routine clinical MRI, the T2-FLAIR mismatch sign has the potential for widespread clinical use and to positively impact clinical care and preoperative decision/analysis of diffuse adult gliomas.

Contemporary Glioma Classification

Traditional pathological diagnosis of primary brain tumors is based on features that are assessed at microscopy. Even as knowledge of the molecular and genetic features of gliomas rapidly increased in the early 2000s, this molecular information was mainly used to provide supplementary prognostic information for tumors that were defined by their histologic features, and in certain circumstances for treatment selection. This situation changed with the release of the 2016 update of the WHO classification system for central nervous system tumors, when molecular markers were integrated into the definitions of several primary brain tumor types.^7,8 Now, infiltrating gliomas are subdivided by the presence of IDH mutation and 1p/19q codeletion into (anaplastic) oligodendrogliomas (IDH mutant and 1p/19q codeleted), IDH-mutant (anaplastic) astrocytomas (IDH mutant but 1p/19q non-codeleted), IDH-wildtype grades II and III astrocytomas, and IDH-wildtype and IDH-mutant glioblastoma.

These molecular subtypes have different prognoses and treatment implications, and a non-invasive method that provides an accurate preoperative diagnosis has the potential to improve patient counseling and treatment planning from initial presentation. For example, definitive knowledge that a tumor is an IDH-mutant glioma may allow for greater time in planning surgery given the more prolonged natural history and slower growth rate of these tumors. Knowledge that a glioma is IDH-mutant 1p/19q intact would favor a more aggressive surgical resection, as emerging data suggest that greater extent of resection independently correlates with survival in IDH mutant astrocytic gliomas.^9–12 Additionally, non-neoplastic lesions that mimic low-grade gliomas are encountered frequently in clinical practice, and highly specific non-invasive diagnostics should have significant impact in limiting diagnostic uncertainty in such cases.

MR spectroscopy is another imaging technique that has been reported to identify IDH mutation in gliomas with high specificity through detection of 2-hydroxyglutarate (2HG), which is abundant in IDH mutant gliomas.^13,14 However, 2HG detection by MR spectroscopy has been difficult to implement in routine clinical practice due to many technical factors, including complex spectral overlap by a number of other metabolites (such as glutamate, glutamine, and gamma-aminobutyric acid) found in abundance in normal brain tissue. These factors confound the identification and detection of 2HG as well as compromise accurate quantification of metabolite concentration, especially at low levels of 2HG.¹⁵

Definition of the T2-FLAIR Mismatch Sign

While the phenomenon of “T2-FLAIR suppression” was previously noted in protoplasmic astrocytomas,¹⁶ Patel and colleagues published the first article specifically linking this neuroimaging feature to IDH-mutant, 1p/19q non-codeleted astrocytomas in 2017.¹ In their study of diffuse lower grade gliomas (WHO grades II/III), “T2-FLAIR mismatch” was defined by the presence of 2 distinct MRI features (Fig. 1) as follows:

Fig. 1.

Examples of the T2-FLAIR mismatch sign in IDH-mutant, 1p/19q non-codeleted astrocytomas. (A, B) A 31-year-old female with a left frontal lobe mass. (C, D) A 33-year-old male with a left temporal lobe mass. In both examples, the T2-weighted images (A, C) display striking, near-uniform hyperintense signal throughout the lesions. On the FLAIR sequences (B, D) the lesions display relatively hypointense signal throughout the majority of the lesions compared with T2-weighted images, with the exception of a peripheral rim of hyperintense signal. Note that the degree of hypointensity on FLAIR imaging can be uniform (B) or inhomogeneous (D). Additionally, note that the peripheral high signal rim on FLAIR imaging typically appears as a thin, smooth contour circumscribing the central volume of the mass.

1. Tumor displays complete or near-complete and almost homogeneous hyperintense signal on T2-weighted images.

2. Tumor displays relatively hypointense signal on the T2-weighted FLAIR sequence except for a hyperintense peripheral rim.

This definition of the T2-FLAIR mismatch sign remains the currently accepted one and has been adopted in subsequent independent validation studies.^2,3 Several practical aspects relevant to the application of these rules in routine clinical practice are discussed below.

It is crucial to appreciate the context in which the T2-FLAIR mismatch sign was originally described and subsequently validated. Most crucially, prior studies analyzed the T2-FLAIR mismatch sign using largely similar cohorts.^1–5 Namely, all studies retrospectively studied proven WHO grades II and III diffuse gliomas. None included WHO grade I or IV gliomas or nonglial neoplasms (eg, metastasis, lymphoma), entities that commonly demonstrate contrast enhancement. Prior studies have almost exclusively included adult patients (reported age range of all studies combined is 17‒86 y). Other selection criteria were variably applied, such as the exclusion of patients with contrast-enhancing disease,³ or the selection of only patients with IDH-mutant gliomas.² Collectively, these design differences leave open the question: how well does the T2-FLAIR mismatch sign perform in routine clinical practice where patients may harbor a variety of primary or secondary neoplasms, or neoplasm mimics?

Validation of the T2-FLAIR Mismatch Sign and Literature Review

Although the T2-FLAIR mismatch sign was only recently described, literature on this topic is expanding quickly. The high diagnostic specificity of the sign has been replicated in multiple studies using independent patient cohorts and anecdotally is currently used in neuroradiology and neuro-oncology clinical practice worldwide. Supplementary Table 1 summarizes the literature regarding the test characteristics of the T2-FLAIR mismatch sign.

Prior to the formal description of the T2-FLAIR mismatch sign, the first group to associate the similar “T2-FLAIR suppression” imaging appearance with any subtype of glioma was Tay and colleagues in 2011 in a small series of protoplasmic astrocytomas.¹⁶ In 6 out of their 8 patients they noted “T2-FLAIR suppression” of greater than 50% of the lesion cross-section on preoperative MRI. Protoplasmic astrocytomas were previously classified as a rare WHO grade II histologic variant of diffuse astrocytoma that typically affected young adults and followed a relatively indolent course.^17–19 Although it is possible that such lesions largely comprised IDH-mutant astrocytomas, this remains speculative as their diagnoses were based purely on histopathology without genomic assessment. In 2016, the WHO eliminated protoplasmic astrocytomas from the classification of CNS neoplasms.⁸

In the initial report of the T2-FLAIR mismatch sign, Patel and colleagues reviewed MR imaging in 125 patients with WHO grades II and III gliomas from The Cancer Imaging Archive (TCIA) with corresponding clinical and genomic data supplemented via   The Cancer Genome Atlas (TCGA).¹ Fifteen cases were positive for the T2-FLAIR mismatch sign (15/125; 12%), all of which were IDH-mutant, 1p/19q non-codeleted astrocytomas. As a validation step, they analyzed the imaging of 60 additional adult patients with molecularly characterized WHO grades II and III gliomas from a single institution (NYU Langone Health). Among the validation cohort, 10 cases displayed the T2-FLAIR mismatch sign and all were IDH-mutant, 1p/19q non-codeleted astrocytomas. In both groups, presence of T2-FLAIR mismatch was 100% specific for IDH-mutant, 1p/19q non-codeleted astrocytoma, but the sensitivity of the sign was limited (22–46%). Interrater reliability of T2-FLAIR mismatch sign assessment between the 2 study neuroradiologists was substantial (ĸ = 0.728–0.747).

Lasocki and colleagues published the first independent validation of the T2-FLAIR mismatch sign.⁵ They retrospectively evaluated multiple imaging predictors of 1p/19q status in 69 patients (training cohort n = 10, validation cohort n = 59) with grade II or III gliomas from their institution and found perfect specificity of T2-FLAIR mismatch for non-codeleted glioma with high interrater agreement (ĸ = 0.88). Sensitivity of the sign was 36.8%, thus similar to the report of Patel and colleagues. The only other imaging feature that approached the specificity of the T2-FLAIR mismatch sign in this study was tumor calcification, which was highly associated with 1p/19q codeleted tumors (ie, oligodendrogliomas).

Broen and colleagues evaluated the performance of the T2-FLAIR mismatch sign in a multicenter retrospective study of 154 adult patients with non-enhancing supratentorial WHO grade II or III gliomas.³ As in previous studies, the authors reported 100% specificity of the T2-FLAIR mismatch sign for IDH-mutant, 1p/19q non-codeleted astrocytomas. Interrater agreement between the reviewers, a neuroradiologist and a neurologist, was substantial (ĸ = 0.75). Among the 75 patients with IDH-mutant, 1p/19q non-codeleted tumors, presence (38/75) or absence (37/75) of the T2-FLAIR mismatch sign was not associated with differences in age, sex, WHO grade, or tumor location.

More recently, Batchala and colleagues used the T2-FLAIR mismatch sign along with a number of other imaging features to develop a classification algorithm for predicting 1p/19q codeletion status in IDH-mutant lower grade gliomas.² In the first part of their study, they analyzed 102 cases of adult IDH-mutant WHO grade II or III glioma obtained from TCIA/TCGA to develop a multivariate classification model. In the second part, the classification model was applied to 106 patients with IDH-mutant WHO grade II or III glioma from a single institution for independent validation. In both parts of the study, the T2-FLAIR mismatch sign achieved 100% specificity and positive predictive value (PPV) for diagnosing IDH-mutant, 1p/19q non-codeleted astrocytomas superior to the other tested imaging metrics. Although the interrater agreement for the T2-FLAIR mismatch sign in the validation phase was lower than in previous reports (ĸ = 0.56), both readers nonetheless independently assigned the T2-FLAIR mismatch sign to IDH-mutant non-codeleted astrocytomas in all instances (even those where they disagreed on the presence of T2-FLAIR mismatch).

The first publication to demonstrate less than 100% specificity of the T2-FLAIR mismatch sign for IDH-mutant, 1p/19q non-codeleted glioma was the study by Juratli and colleagues in 2019.⁴ They evaluated the sign in 133 adult patients with WHO grades II and III gliomas collected from TCIA/TCGA as well as 2 other institutions. They observed the T2-FLAIR mismatch sign in a much higher percentage of IDH-mutant, 1p/19q intact gliomas (73%, 60/82 cases) compared with previous studies. Correspondingly, they reported false positive cases with the T2-FLAIR mismatch sign. The “false positive” cases all occurred among a subset (29%, 12/42) of IDH-mutant 1p/19q codeleted oligodendrogliomas. Detailed analysis and personal correspondence with the authors revealed that the authors applied more “relaxed” criteria for T2-FLAIR mismatch compared with earlier studies. For example, some gliomas with heterogeneous signal on T2-weighted imaging or incomplete “suppression” on FLAIR were not strictly excluded from meeting the criteria of T2-FLAIR mismatch. They also included contrast-enhancing gliomas, unlike Broen et al. Even though their results do not mention how many of the T2-FLAIR mismatch cases also showed contrast enhancement, any tumor contrast enhancement will not meet strict criteria for the mismatch sign based on previous studies which showed 100% specificity of the mismatch sign and hence suggesting that Juratli et al in fact used relaxed criteria for the sign. Other issues such as technical differences related to MRI sequence acquisition parameters may have also contributed to discordant results of this study compared with prior publications. As a result of these differences, Juratli et al failed to achieve the 100% specificity/PPV for diagnosing IDH-mutant astrocytoma reported in previous studies. Strikingly, however, their version of the T2-FLAIR mismatch sign was still 100% predictive of IDH-mutant glioma and none of the IDH-wildtype gliomas showed the T2-FLAIR mismatch sign. These results raise the question of whether a modified form of the T2-FLAIR mismatch sign with “relaxed” inclusion/exclusion criteria could prove useful in excluding IDH-wildtype gliomas, a development that if validated could have clinical utility, albeit at the cost of sacrificing the diagnostic specificity for IDH-mutant, 1p/19q non-codeleted astrocytoma.

Exceptions to the Rule, False Positive Cases

Johnson and colleagues reported a series of 5 patients with false positive T2-FLAIR mismatch sign collected from clinical practice at 3 academic medical centers.⁷ Only one case occurred in an adult with a diffuse lower grade glioma (oligodendroglioma, IDH-mutant and 1p/19q codeleted). The 4 remaining cases occurred in children aged 2 to 18 years harboring rare pediatric-type neoplasms (n = 3) and a nonneoplastic lesion (n = 1). An earlier study by Parmar et al described a “FLAIR Ring Sign” in a pediatric cohort (ages 4–18) with dysembryoplastic neuroepithelial tumors, an imaging finding that can resemble the T2-FLAIR mismatch sign (Supplementary Figure 1).²⁰ Although such reports do not allow for evaluation of the sensitivity or specificity of the T2-FLAIR mismatch sign, they suggest that while false positives are relatively rare in adult patients, the T2-FLAIR mismatch sign should be used cautiously, if at all, in pediatric patients as some non-infiltrative gliomas (typically WHO grade I) may show this sign.

How to Use the T2-FLAIR Mismatch Sign in Clinical Practice

As noted previously, the core features of T2-FLAIR mismatch sign use are a stepwise ascertainment of: (i) complete or near-complete and homogeneous hyperintense signal on T2-weighted MR images, and (ii) hypointense signal on the T2-weighted FLAIR sequence except for a hyperintense peripheral rim (Table 1). To meet the first criterion, the tumor should demonstrate striking, diffuse, and an almost homogeneous high signal on T2-weighted images with only subtle and very small regions of internal hypointensity permitted. Any significant internal signal hypointensity or heterogeneity on T2-weighted images fails to meet the first criterion (Fig. 2). Notably, when tumors are wrapped underneath the cortex, interposed gray matter can create the false impression of relatively hypointense regions within an otherwise hyperintense tumor on T2-weighted imaging (Supplementary Figure 2). Obtaining images in different planes helps to clarify such cases.

Table 1.

T2-FLAIR mismatch sign: key points

Strict inclusion and exclusion criteria

• T2-weighted sequence: Complete or near-complete and homogeneous hyperintense signal.

• FLAIR: Hypointense signal except for a hyperintense thin peripheral rim.

Additional imaging features help to accurately identify the T2-FLAIR mismatch sign

• Necrotic cavities do not represent the T2-FLAIR mismatch sign; small cysts are not sufficient for meeting the criteria of T2-FLAIR mismatch.

• T2-FLAIR mismatch sign is typically accompanied by little or no contrast enhancement.

• The degree of FLAIR signal suppression may be inhomogeneous within the tumor.

• Common imaging correlates include: homogeneous hypointensity on non-contrast T1-weighted images; markedly elevated ADC values; low blood volume on perfusion maps; diffuse hypodensity on CT.

Tips to avoid potential pitfalls

• Avoid using the T2-FLAIR mismatch sign in pediatric patients (age ≤18).

• On T2-weighted imaging, enveloped cortical gray matter within tumor may demonstrate relatively hypointense signal; this finding should not exclude the T2-FLAIR mismatch sign.

Tips to expand the scope of a modified/partial T2-FLAIR mismatch sign

• The presence of glioma subregions displaying T2-FLAIR mismatch appears to effectively exclude IDH-wildtype gliomas; further validation is required.

Fig. 2.

A 49-year-old male with an oligodendroglioma, IDH-mutant and 1p/19q codeleted without the T2-FLAIR mismatch sign. (A) T2-weighted images and (B) FLAIR display an infiltrative right frontal lobe mass. Although the mass contains small regions of hypointense signal on the FLAIR sequence (arrows) relative to the T2-weighted images, the majority of the mass shows high signal on FLAIR similar to the T2-weighted images. Moreover, there are regions of internal hypointensity on the T2-weighted images. Therefore, this case does not meet the definition of the T2-FLAIR mismatch sign.

For the second criterion, by far the majority of the tumor should demonstrate hypointense signal on FLAIR relative to T2-weighted images, although the degree of FLAIR signal suppression may be inhomogeneous within the tumor. Crucially, small intratumoral regions of high signal on T2-weighted images and corresponding low signal on FLAIR, as seen with intratumoral cysts or necrotic cores, should not be confused with the criteria of the T2-FLAIR mismatch sign (Fig. 3).

Fig. 3.

A 28-year-old female with an oligodendroglioma without the T2-FLAIR mismatch sign. A macrocystic component was confirmed with (A) FLAIR, (B) T2-weighted images, and (C) post-contrast T1-weighted images, and hence the tumor does not display a T2-FLAIR mismatch sign.

Notably, in their validation study of the T2-FLAIR mismatch sign, Broen and colleagues excluded contrast-enhancing gliomas.³ Regions of contrast-enhancement within gliomas often correspond to relatively hypointense signal on T2-weighted images and corresponding hyperintense signal on FLAIR images. As such, gliomas with contrast enhancement often fail to meet the strict criteria for the T2-FLAIR mismatch sign as established by Patel et al, although this has not been rigorously established. Furthermore, it remains to be seen whether the appearance of “T2-FLAIR mismatch” in subregions of gliomas (eg, Fig. 4) has diagnostic significance with respect to underlying molecular status.

Fig. 4.

A 34-year-old female with a glioblastoma, IDH-mutant (and 1p/19q non-codeleted) with partial T2-FLAIR mismatch sign. (A) FLAIR, (B) T2, and (C) contrast-enhanced T1-weighted images display a right frontoparietal mass. The tumor displays the T2-FLAIR mismatch sign, although with a small nodule of enhancement and proven to be an IDH-mutant glioblastoma.

Beyond contrast enhancement on T1-weighted images, there may be findings on other imaging sequences and modalities that commonly associate with, or are exclusive of, the T2-FLAIR mismatch sign. For instance, Lasocki and colleagues showed that presence of glioma calcification and T2-FLAIR mismatch are essentially exclusive of one another,⁵ which is concordant with the observation that most calcified gliomas are oligodendrogliomas, IDH-mutant and 1p/19q codeleted. The T2-FLAIR mismatch sign is typically accompanied by markedly elevated apparent diffusion coefficient values (“facilitated diffusion”) on diffusion-weighted imaging, homogeneous hypointensity on non-contrast T1-weighted images, homogeneous hypodensity on CT imaging, and low blood volume on perfusion maps (Supplementary Figure 3). As with contrast enhancement, the relationship between such imaging findings and the T2-FLAIR mismatch sign warrants further evaluation.

The optimal stringency for applying the T2-FLAIR mismatch sign criteria may depend on the goals of the reader. Several studies^1–3,5 have clearly demonstrated that if the primary goal is to achieve high specificity and PPV for the diagnosis of IDH-mutant and 1p/19q non-codeleted astrocytoma, then the T2-FLAIR mismatch sign should be used with the strict guidelines suggested by Patel et al and Broen et al. The T2-FLAIR mismatch sign in such cases should only be applied to adult patients harboring intracranial masses highly suspicious for diffuse glioma and which show little or no contrast enhancement. Any tumor with nodular areas of T2 hypointense signal and corresponding FLAIR hyperintensity (except thin peripheral rim) should not be assigned as having a T2-FLAIR mismatch positive sign (Fig. 2). On the other hand, if the goal is to predict IDH status (regardless of 1p/19q status), it appears that IDH-wildtype lower grade gliomas can be excluded with high confidence when glioma subregions display a mismatched appearance on T2-weighted imaging and FLAIR as suggested by the results of Juratli and colleagues (Fig. 4).⁴ Explicit definition criteria and further diagnostic testing is required to establish the performance of this “relaxed” version of the T2-FLAIR mismatch sign, however if done correctly it could have significant clinical impact by excluding IDH-wildtype gliomas.

Notably, all studies evaluating the T2-FLAIR mismatch sign include MRI examinations acquired in a variety of scanners with field strengths of 1.5T and 3T and variable acquisition parameters. Fluid suppression on FLAIR depends on the timing of a 180-degree inversion pulse that precedes the 90-degree radiofrequency excitation pulse used in spin-echo MR imaging. The degree of fluid suppression on FLAIR may vary depending on the precise timing of this inversion pulse, field strength, and repetition time between radiofrequency excitations,²¹ and these parameters likely varied across cases analyzed in the studies reported to date. As such, the appearance of the T2-FLAIR mismatch sign may significantly depend on image acquisition parameters (Fig. 5) and possibly also on manual windowing of the display screen. Nevertheless, independent reproduction of 100% specificity for IDH-mutant, 1p/19q non-codeleted astrocytoma using strict eligibility guidelines set by Patel et al despite the use of diverse scanners demonstrates the robustness of the T2-FLAIR mismatch sign and its potential for rapid and widespread clinical implementation.

Fig. 5.

A 27-year-old male with a left insular diffuse astrocytoma, IDH-mutant, displaying the T2-FLAIR mismatch sign. (A) T2-weighted images and (B) FLAIR images from the original 1.5T MRI shows an expansile left insular mass with near uniform hyperintense signal on T2-weighted images and subtle hypointense signal on FLAIR except a thin peripheral rim. (C) A subsequent FLAIR sequence acquired on a 3T MRI performed one month later for surgical planning shows a greater degree of hypointensity on the FLAIR sequence, but no other changes on the other imaging sequences (not shown). The inversion times and repetition times were 12 000/2713 msec for the original 1.5T FLAIR sequence (b), and 9000/2500 msec on the subsequent 3T FLAIR sequence (C), differences that potentially impacted the glioma appearance.

Future Directions

The identification of the T2-FLAIR mismatch sign marks a significant finding in glioma imaging and radiogenomics representing the first imaging marker that has near-perfect specificity for a mutation-defined glioma subtype. A further advantage is that the sign can be readily identified using clinical MRIs already routinely used worldwide without need for advanced imaging methods. As the T2-FLAIR mismatch sign provides diagnostic information that can be obtained prior to neurosurgery, clinical application has the potential to influence patient counsel and management early in the disease course.

Nevertheless, there is ample room for the development of further improved diagnostic imaging to supplement the diagnostic information provided by the T2 FLAIR mismatch sign or identify other genetic subtypes of brain tumors. Notably, although the sign interpreted strictly is highly specific for IDH-mutant, 1p/19q non-codeleted astrocytoma, many of these tumors do not display the sign, and an imaging marker with greater sensitivity and equal specificity would increase clinical utility. Other closely related glioma molecular subtypes remain without specific imaging biomarkers, for example IDH-mutant, 1p/19q codeleted oligodendrogliomas. Heterogeneous texture features, presence of calcifications, and indistinct tumor margins have been shown to be associated with oligodendrogliomas—however, not achieving the specificity that allows for definitive diagnosis.^2,22–28 Similarly, frontal lobe location²⁹ as well as non-enhancing tumor component^30,31 have been shown to be associated with IDH-mutated gliomas, but again without high enough specificity for diagnostic use.

Additionally, although genetic classification has improved prognostic accuracy in glioma, heterogeneity of treatment responses and survival remains within the major glioma molecular subtypes, including within IDH-mutant, 1p/19q non-codeleted astrocytomas, and no study has shown the prognostic value of the T2-FLAIR mismatch sign (Supplementary Figure 4). With genomic characterization now commonplace in glioma, novel prognostic molecular signatures that further subdivide currently defined major glioma molecular subtypes are being identified,³² and imaging markers that associate with these newly described genomic alterations could further improve early diagnostic and prognostic assessment. Of note, contrast enhancement has been shown to be associated with poor prognosis in IDH-mutant astrocytoma and in oligodendroglioma.³³

A central unanswered question regarding the T2-FLAIR mismatch sign is the pathophysiologic nature that accounts for it. In their original report, Patel et al found a trend for tumors with abundant microcysts on histopathology to display the T2-FLAIR mismatch sign, although the finding did not achieve statistical significance and the numbers of samples were limited. In addition, mechanistic target of rapamycin pathway gene expression and protein levels were found to be enriched in gliomas positive for T2-FLAIR mismatch. Although these findings remain to be validated and their mechanistic etiology to be determined, these preliminary observations demonstrate potential for further mutation-specific signs to reveal pathogenic mechanisms. Future research in this field could also explore advanced imaging modalities³⁴ as well as quantitative MRI, including, for instance, T1 and T2 relaxation time measurements, which are generally independent of MRI acquisition methods and hence could be more robust imaging markers than qualitative conventional MRI features.³⁵

Summary

In conclusion, preoperative identification of the T2-FLAIR mismatch sign using routine clinical MRI has been independently shown to be a highly specific marker for IDH-mutant astrocytoma (1p/19q non-codeleted). Strict application of the imaging criteria results in high specificity for the diagnosis of IDH-mutant astrocytomas among adult diffuse glioma. Recognizing imaging findings that commonly associate with, or are exclusive of, the T2-FLAIR mismatch sign, as well as the appropriate clinical context for its use, limits false positives and optimizes its clinical performance. Modifications to the imaging criteria for this sign might expand its role for predicting IDH status. Future investigation into the molecular correlates underlying this distinct imaging sign is warranted.

Funding

This work was supported by a Radiological Society of North America research scholar grant (#RSCH1819 to S.H.P.) and NIH grant (#P50CA165962 to D.P.C.).

Conflict of interest statement. A.S.C.: employee of Mirati Therapeutics; served on the scientific advisory board of Cota Healthcare.