Bithalamic gliomas may be molecularly distinct from their unilateral high-grade counterparts

Abstract

Bithalamic gliomas are rare cancers diagnosed based on poorly defined radiologic criteria. Infiltrative astrocytomas account for most cases. While some previous studies reported dismal outcomes for patients with bithalamic gliomas irrespective of therapy and histologic grade, others described better prognoses even without anticancer therapy. Little is known about their molecular characteristics. We reviewed clinical, radiologic, and histologic features of patients with bithalamic gliomas treated at our institution over 15 years. Targeted sequencing of mutational hotspots in H3F3A, HIST1H3B, IDH1/2, and BRAF, and genome-wide analysis of DNA methylation and copy number abnormalities was performed in available tumors. Eleven patients with bithalamic gliomas were identified. Their median age at diagnosis was 4.8 years (range: 1-15.7). Additional involvement of the brainstem, basal ganglia, and cerebral lobes occurred in 11, 9, and 3 cases, respectively. All patients presented with hydrocephalus. Two-thirds of the patients had a histologic diagnosis of anaplastic astrocytoma. Despite aggressive therapy, our youngest patient, the only one diagnosed before 1 year of age, is the sole long-term survivor. DNA methylation could be performed in seven tumors, all of which clustered with the RTK I 'PDGFRA' subgroup by unsupervised hierarchical analysis of methylation array against a previously published cohort of 59 pediatric high-grade gliomas. Sequencing of hotspots mutations could be done in 10 tumors, none of which harbored H3F3A p.K27 and/or the respective DNA methylation signature, and any other hotspot mutations. Amplification of MDM4 (n = 2), PDGFRA (n = 2), and ID2 combined with MYCN (n = 1) were observed in 7 tumors available for analysis. In comparison with the previously published experience with unilateral high-grade thalamic astrocytomas where H3F3A p.K27 was present in two-thirds of cases, the absence of this molecular subgroup in bithalamic gliomas was striking. This finding suggests that unilateral and bithalamic high-grade gliomas may represent two distinct molecular entities.

Keywords: bithalamic; children; high-grade glioma; infiltrative; molecular characteristics.

Figure 1

Axial T₂‐weighted brain MRI of patient 11 showing symmetrical bithalamic involvement (A). This patient was also found to have hydrocephalus based on symptoms and enlargement of lateral ventricles with transependymal flow in their frontal horns. Coronal T₂‐weighted brain MRI of same patient showing symmetrical bithalamic and midbrain involvement (B).

Figure 2

Representative histomorphology and immunophenotype of bithalamic gliomas demonstrating infiltrative growth and moderate cytologic pleomorphism. While tumors lacked immunoreactivity for H3K27M, p53 expression was mostly seen in a minority of tumor cells. The proliferative fraction, as assessed by Ki67/Mib‐1 immunolabeling, was variable from moderately to very high frequency. The scale bars represent 200 μm.

Figure 3

Heatmap representation of unsupervised hierarchical clustering analysis of 450 k methylation array profiles in 7 pediatric patients with bithalamic gliomas in comparison with a dataset of 59 previously published pediatric high‐grade gliomas.

Figure 4

Axial T₂‐weighted brain MRI of the only long‐term survivor (patient 1) at diagnosis. A tumor biopsy was obtained from the T₂ hyperintense anterior portion of the right thalamus.