Adult IDH Wild-type Lower-grade Gliomas Should Be Further Stratified

Abstract

Background:

IDH wild-type astrocytoma is described as a provisional entity within the new WHO classification. Some groups believe that IDH wild-type lower-grade gliomas, when interrogated for other biomarkers, will mostly turn out to be glioblastoma. We hypothesize that not all IDH wild-type lower-grade gliomas have very poor outcomes and the group could be sub-stratified prognostically.

Methods:

718 adult WHO Grade II and III gliomas from our hospitals were re-reviewed and tested for IDH1/2 mutations. 166 IDH wild-type cases were identified for further studies and EGFR and MYB amplifications, mutations of histone H3F3A, TERT promoter and BRAF were examined.

Results:

EGFR amplification, BRAF and H3F3A mutations were observed in 13.8%, 6.9% and 9.5% respectively, in a mutually exclusive pattern in IDH wild-type lower-grade gliomas. TERTp mutations were detected in 26.8% of cases. Favorable outcome was observed in tumors with young age, oligodendroglial phenotype and grade II histology. Independent adverse prognostic values of older age, non-total resection, grade III histology, EGFR amplification, and H3F3A mutation were confirmed by multivariable analysis. Tumors were further classified into “molecularly” high grade (harboring EGFR, H3F3A or TERTp) (median OS=1.23 years) and lower-grade (lacking all of the three) (median OS=7.63 years) with independent prognostic relevance. The most favorable survival was noted in molecularly lower-grade gliomas with MYB amplification.

Conclusion:

Adult IDH wild-type lower-grade gliomas are prognostically heterogeneous and do not have uniformly poor prognosis. Clinical information and additional markers including MYB, EGFR, TERTp and H3F3A should be examined to delineate discrete favorable and unfavorable prognostic groups.

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