Utility of methylthioadenosine phosphorylase immunohistochemical deficiency as a surrogate for CDKN2Ahomozygous deletion in the assessment of adult-type infiltrating astrocytoma

Homozygous deletion (HD) of CDKN2Ais one of the most promising biomarkers for predicting poor prognosis of IDH-mutant diffuse gliomas. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recommendations propose that IDH-mutant lower-grade astrocytomas with CDKN2A/BHD be classified as grade IV tumors. Loss of methylthioadenosine phosphorylase (MTAP) immunohistochemistry staining has been proposed as a surrogate of CDKN2AHD in various tumors but its performance has not been fully investigated in diffuse glioma. This study determined whether MTAP immunoreactivity could serve as a proxy for CDKN2AHD in adult-type diffuse glioma, thereby contributing to stratifying patient outcome. MTAP immunohistochemistry staining using clone EPR6893 was scored in 178 diffuse glioma specimens consisting of 77 IDH-mutant astrocytomas, 13 IDH-mutant oligodendrogliomas, and 88 IDH-wildtype glioblastomas. The use of MTAP immunohistochemical deficiency to predict CDKN2AHD was good for IDH-mutant astrocytomas (sensitivity, 88%; specificity, 98%) and IDH-wildtype glioblastomas (sensitivity, 89%; specificity, 100%), but poor for IDH-mutant oligodendrogliomas (sensitivity, 67%; specificity, 57%). Both CDKN2AHD and MTAP immunohistochemical deficiency were significant adverse prognostic factors of overall survival for IDH-mutant astrocytoma (P< 0.001 each), but neither were prognostically significant for oligodendroglioma or IDH-wildtype glioblastoma. IDH-mutant lower-grade astrocytoma with CDKN2AHD and deficient MTAP immunoreactivity exhibited overlapping unfavorable outcome with IDH-mutant glioblastoma. MTAP immunostaining was easily interpreted in 61% of the cases tested, but scoring required greater care in the remaining cases. An alternative MTAP antibody clone (2G4) produced identical scoring results in all but 1 case, and a slightly larger proportion (66%) of cases were considered easy to interpret compared to using EPR6893. In summary, loss of MTAP immunoreactivity could serve as a reasonable predictive surrogate for CDKN2AHD in IDH-mutant astrocytomas and IDH-wildtype glioblastomas and could provide significant prognostic value for IDH-mutant astrocytoma, comparable to CDKN2AHD.