MRI Features Can Predict 1p/19q Status in Intracranial Gliomas

Discussion

The simple MR imaging assessment described was overall moderately accurate for predicting 1p/19q status, but the accuracy of 82% is insufficient to replace formal 1p/19q testing for all patients. The inaccuracy is partly because, in some tumors, none of the key MR imaging features were present. More important for the clinical setting, however, a substantial proportion of tumors demonstrated MR imaging features that can predict 1p/19q status with high specificity, including in cases in which this is not expected from the histologic phenotype. Thus, >50% T2-FLAIR mismatch is strongly predictive of a noncodeleted tumor, while the tumor is likely 1p/19q-codeleted if there are calcifications. Of these 2 MR imaging features, >50% T2-FLAIR mismatch was both more sensitive and more specific than the presence of calcifications. No patients had both features, suggesting that they are mutually exclusive, at least in large part.

Histology remains a crucial first step, both to confirm the diagnosis of glioma (because these MR imaging features can also occur in other tumors and nonneoplastic conditions) and for glioma grading.¹⁴ Nevertheless, once a grade II or III glioma has been diagnosed (and other differentials have been excluded), MR imaging is very useful for predicting 1p19q status. The presence of >50% T2-FLAIR mismatch or calcification may provide a surrogate marker of 1p/19q status in cases in which formal testing cannot be performed, for example due to financial or geographic limitations. This feature would be most useful in patients with an indeterminate histologic phenotype, specifically those labeled as “oligoastrocytoma NOS” according to the updated WHO classification.¹ The MR imaging features may even negate the need for formal 1p/19q testing, especially if the phenotypic appearances are supportive. Figure 3 illustrates a possible combined MR imaging–histology assessment method for cases in which formal 1p/19q testing is not possible. First, the tumor is assessed for the presence of >50% T2-FLAIR mismatch or calcifications. If neither of these features is present or if the results are discordant (likely a very rare occurrence), the diagnosis reverts to the histologic phenotype. While there will be rare exceptions to this method, because not all tumors having calcifications are noncodeleted (as demonstrated by 1 patient in our cohort), our results show that this method is likely to be more accurate than using the histologic phenotype alone.

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Fig 3.

A suggested combined MR imaging–histology method of determining 1p/19q status when formal testing is not possible.

Johnson et al⁶ have shown that noncircumscribed borders correlate with 1p/19q codeletion, but given that this appearance was also present in 45% of noncodeleted tumors, this MR imaging feature is not sufficiently specific to predict codeletion with confidence. Rather, to predict 1p/19q status with high specificity, it may be more useful to use circumscribed borders as predictive of a noncodeleted tumor, albeit with limited sensitivity. The suggested combined assessment method could also potentially be extended to cases in which MR imaging is not available, because CT provides useful information. CT is excellent for the detection of calcifications, while the correlate of T2-FLAIR mismatch on CT is a markedly hypodense tumor. Using these features may also have some value even if formal 1p/19q testing is available. Both of the most common methods of determining 1p/19q status (fluorescence in situ hybridization and polymerase chain reaction–based microsatellite loss of heterozygosity) have been shown to occasionally produce false-positive results,¹⁶ and there is also a small risk of sampling error due to the inherent heterogeneity of glial series tumors.^17⇓–19 In contrast, MR imaging provides the potential to overcome this limitation due to its ability to assess the entire tumor.¹¹ A discrepancy between the MR imaging appearances and formal 1p/19q testing may thus raise the possibility of sampling error or a mixed tumor.

Dominant cortical involvement was the least useful feature in our cohort due to the high interobserver variability and low incidence. In addition, it is likely to be the least specific feature, especially in smaller tumors, because cortical involvement is also frequently present in astrocytomas.^20,21 These limitations of the cortical involvement variable account for some of the inaccuracies in the overall prediction of 1p/19q status. We also assessed the 2 possible thresholds of >50% or >33% for the proportions of T2-FLAIR mismatch and cortical involvement. This assessment is most relevant to T2-FLAIR mismatch, given the limitations of cortical involvement discussed above. Of the 2 thresholds, we think that >50% is the most appropriate. Only 1 tumor had 33%–50% T2-FLAIR mismatch; thus, dropping the threshold to >33% would only slightly increase the sensitivity of MR imaging assessment in identifying a noncodeleted tumor, but at the risk of decreasing the specificity and interobserver correlation.

We acknowledge the presence of selection bias because 1p/19q testing was not performed on all intracranial gliomas during this period, which was largely before the update to the WHO criteria. Because 1p/19q testing was generally performed on the basis of an oligodendroglial component on standard histologic assessment (usually an oligoastrocytoma), one may have expected a relatively large proportion of 1p/19q codeleted tumors, but the proportion of 1p/19q codeleted tumors in our cohort was similar to that in a large series described recently.¹⁵ Presumably this similarity reflects a balance between the relatively small number of histologic astrocytomas and oligodendrogliomas in our cohort, which were not thought to require 1p19q testing at the time. Also related to this selection bias, there was only 1 protoplasmic astrocytoma in our cohort (diagnosed before the recent WHO classification). Nevertheless, the substantial number of patients in our cohort with >50% T2-FLAIR mismatch suggests that this MR imaging feature is not specific to tumors labeled protoplasmic astrocytomas. This may be because a protoplasmic (or microcystic) appearance on histology occurs on a continuum, and the diagnosis was not clearly defined in the previous WHO classification,²² a reason for this entity no longer being recognized in the more recent classification.¹ Whatever the histologic correlate for T2-FLAIR mismatch, however, it is a very useful biomarker.

More definitive IDH mutation testing was not routinely available for patients with immunohistochemistry negative for IDH1, but the addition of ATRX and TP53 immunohistochemistry data overcomes some of this limitation, suggesting some tumors that are likely to harbor non-R132H IDH mutations. Our results thus somewhat support the findings of Patel et al³ that substantial T2-FLAIR mismatch is specific to IDH-mutant astrocytomas rather than IDH wild-type astrocytomas, but we are unable to support this definitively. Of note, the single 1p19q codeleted tumor with immunohistochemistry negative for IDH1 did not demonstrate calcifications or >50% T2-FLAIR mismatch; thus, the uncertainty regarding the exact diagnosis according to the updated WHO criteria does not affect the results.

The single-institution nature of our study is a limitation, though in this context, ours is a large cohort, with the number of codeleted tumors demonstrating >50% T2-FLAIR mismatch being like that reported for the TCGA/TCIA cohort.³ Our study is retrospective, and prospective validation of our results in a different cohort would be important. The targeted nature of our MR imaging assessment is also a potential limitation. We thought that it was important to focus on a small number of MR imaging features, to minimize the chance of finding an association by chance alone. Given the small size of the initial cohort, consisting of only 10 patients, it is possible that some MR imaging features that would have been useful in this context were not identified. In addition, the incidence of calcification is likely to be underestimated in our cohort. First, CTs were not available for all patients, and in patients with only a postoperative CT available, there is the potential for the component containing calcifications to have been resected (and thus not accurately identifiable on the imaging available). Second, susceptibility-weighted imaging was variably available; thus, often calcification could not be accurately differentiated from hemorrhage, in which case tumors were labeled as negative for calcification. We suspect, therefore, that our results underestimate the frequency of calcifications, and the ability of MR imaging to identify codeleted tumors may have been higher if CT and/or susceptibility-weighted imaging had been performed in all patients. This addition has the potential to further increase the value of the method we have outlined.