IDH mutation testing in gliomas—where do we draw the line?

The classification of brain tumors has classically been dependent on histology. However, with the additional understanding of the genetic basis of tumorigenesis, molecular parameters have also now become integrated with histology in the 2016 World Health Organization (WHO) classification of brain tumors.¹ This concept has been integrated in the classification of the diffuse gliomas. For lower-grade gliomas (LGGs; WHO grades II and III), it is known that mutations in isocitrate dehydrogenase genes (IDH1/2) occur in high proportion, and the detection of these mutations has diagnostic, prognostic, and therapeutic implications.^2–4 Mutations in IDH1/2 lead to reduction of alpha-ketoglutarate and to the production of oncometabolite 2-hydroxyglutarate. This gain of function phenotype can be incurred via multiple different mutations. Mutations in codon 132 resulting in substation of arginine to histidine (R132H) is the most common of these mutations (termed "canonical"), accounting for up to 90% of all IDH mutations.² The development of R132H-specific anti-IDH1 antibodies allows for screening of canonical mutations by immunohistochemistry (IHC). In cases where IDH screening by IHC indicates the absence of R132H mutation, genetic sequencing of IDH may be performed to screen for noncanonical mutations. Although genetic sequencing allows for screening of both canonical and noncanonical mutations, the cost associated with testing as well as time constraints can be issues. Nevertheless, in the setting of a diffuse adult LGG that is negative by R132H-IHC, testing for a noncanonical IDH mutation is expected to conform within an integrated histomolecular diagnosis. In the absence of a complete evaluation for noncanonical IDH mutations in these cases, the "NOS" designation may be warranted for diffuse gliomas.