Case of the Month

Answer to August’s Case of the Month.

B. It often lacks high-grade histologic features, but is still considered grade IV.

The entity called “diffuse midline glioma, H3K27M mutant” was added to the World Health Organization (WHO) Classification of Tumours of the Central Nervous System in 2016 and constitutes most of the diffuse gliomas in the brainstem. They are considered WHO grade IV despite the lack of high-grade histological features and have a dismal prognosis. Most common in children, they typically occur in the pons (comprising most tumors previously called “diffuse pontine infiltrating gliomas”) and thalamus, but can be seen anywhere in the midline.

The clinical features vary by tumor location, but commonly include headache, ataxia, and sensory disturbance. MRI typically shows T2 hyperintensity and a heterogeneously enhancing infiltrative mass with T1 hypointensity. Microscopic examination reveals a variably cellular neoplasm with elongated irregular nuclei infiltrating the underlying brain parenchyma. Histologically, the differential diagnosis includes other infiltrating astrocytomas (IDH wildtype or mutant), as well as different low-grade glial neoplasms such as pilocytic astrocytoma. Like this case, many tumors show high-grade morphology (nuclear pleomorphism, mitotic activity, necrosis, and/or microvascular proliferation), but others may appear low-grade by histology. The tumor cells are usually positive for glial markers (GFAP, Olig2) and negative for neuronal markers (synaptophysin, NeuN), supporting their glial origin.

The diagnosis requires the tumor to be a diffusely infiltrating midline glioma with the H3K27M mutation (1). The most frequently used and readily available diagnostic test is immunohistochemistry with an antibody that detects the mutation in the histone 3 gene from a lysine (K) to a methionine (M) at position 27, although molecular testing can also be used. The mutant protein is located in the tumor nuclei. It is crucial to use the mutation-specific antibody and not the trimethylation-specific antibody in this same position (H3K27Me3, normally expressed in most cells), because the trimethylated label will be lost in the nuclei of tumors with the H3K27M mutation. Both can be used in combination. Importantly, the H3K27M mutation can be detected in other primary brain neoplasms including glial, glioneuronal, and ependymal tumors. In those examples, however, the mutation does not carry the dismal prognosis assigned to this entity, so caution is warranted when making this diagnosis (2,3). In pediatric patients (but potentially not in adult patients), this mutation is associated with a poorer prognosis (4).

Submitted by Rawia Mubarak Mohamed and Najla Saleh Ben Gashir, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates. Discussion by Maria Martinez-Lage, Massachusetts General Hospital, Boston, Massachusetts, USA.