Hemispheric H3K27M-mutant diffuse glioma in an adult: a rare entity with ATRX loss and Oligodendroglioma-like features

Abstract The H3K27M genetic alteration is frequent in diffuse midline gliomas but rare in hemispheric diffuse gliomas. We report a rare case of a hemispheric H3K27M-mutant high-grade glioma in a 21-year-old female who presented with a seizure. Brain MRI revealed a 4.2 cm expansile left insular mass with cortical and subcortical involvement, consistent with a high-grade glial tumor. The patient underwent craniotomy and subtotal tumor resection. Microscopy demonstrated oligodendroglial-like morphology with microvascular proliferation and necrosis. Immunohistochemical analysis showed strong nuclear positivity for H3K27 M, IDH negativity, and loss of ATRX. Following progression on MRI in the left frontotemporal region, she underwent a redo craniotomy and debulking, which reproduced the previous histomorphology. The patient was subsequently referred for standard-of-care adjuvant chemoradiation, including external-beam radiation therapy with concurrent and adjuvant temozolomide, which represents the current recommended treatment approach for high-grade gliomas harboring H3K27M mutations. Additional therapeutic options, such as clinical trial enrollment, targeted agents, and immunotherapy, are increasingly considered for these aggressive tumors. This unusual hemispheric H3K27M-mutant tumor morphologically mimicked an oligodendroglioma. We recommend routine H3K27M testing in IDH-wildtype hemispheric gliomas with ATRX loss.