Diffuse non-midline glioma with H3F3A K27M mutation: a prognostic and treatment dilemma
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KeywordsDiffuse Glioma Midline Structure K27M Mutation IDH1 R132H Eosinophilic Granular Body
Recent studies have identified that K27M mutation in either the H3F3A or HIST1H3B genes, which encode the histone H3 variants H3.3 and H3.1, define the majority of diffuse gliomas arising in midline structures including the thalamus, brainstem, and spinal cord in both children and adults [8, 10]. These “diffuse midline gliomas, H3 K27M-mutant” are associated with poor prognosis regardless of histologic grade and were thus designated as a grade IV entity in the 2016 WHO Classification . Here we illustrate that H3 K27M mutation can occur in cortically-based diffuse gliomas not arising in midline structures and discuss the uncertainties regarding grading and prognostic classification for such tumors.
While common in diffuse midline gliomas, H3 K27M mutation appears to be a rare genetic alteration in diffuse gliomas arising peripherally in the cerebral hemispheres. Initial reports documented that diffuse midline gliomas with H3 K27M mutation are associated with a uniformly poor prognosis; however, these tumors are centered in critical midline structures such as the brainstem and spinal cord, thereby preventing surgical resection in most cases. It is unclear to what extent the poor prognosis of these tumors is due to the inability of resection versus the biologic behavior caused by the H3 K27M mutation. As some cortically-based diffuse gliomas can be gross totally resected (as was the case in this patient), the prognosis and need for aggressive adjuvant therapy in this setting is therefore uncertain. Also of note is a recent study suggesting that diffuse thalamic gliomas in adults harboring H3 K27M mutation are not associated with a uniformly poor prognosis , as well as a few reports of circumscribed low-grade glial neoplasms centered in midline structures that harbor H3 K27M mutation. These cases histologically resembled ganglioglioma or pilocytic astrocytoma and were associated with more indolent disease course than typical diffuse midline gliomas [4, 5, 6]. Together with these reports, this patient demonstrates that H3 K27M mutation is not limited to diffuse midline gliomas and that more studies are need to define the prognosis and optimal treatment for the growing spectrum of both midline and non-midline tumors that harbor this critical oncogenic mutation. We suggest that immunostaining for H3 K27M mutant protein be considered in all IDH-wildtype diffuse gliomas in young patients, not just those centered in midline structures. However, we emphasize that only those diffuse gliomas centered in midline structures harboring H3 K27M mutation fulfill the diagnostic criteria for the entity “diffuse midline glioma, H3 K27M-mutant” classified as grade IV per the 2016 WHO Classification. As the prognosis for those circumscribed gliomas or diffuse non-midline gliomas with H3 K27M mutation remains uncertain at present, these tumors should not be designated as WHO grade IV.
MSB provided neurosugical management. NAOB provided neuro-oncology management. GL, AP, and DAS performed pathologic assessment. DAS performed genomic analysis. GL and DAS wrote the manuscript and created the figures. All authors read and approved the final manuscript.
D.A.S. is supported by NIH Director’s Early Independence Award (DP5 OD021403). The authors declare that they have no competing interests.
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