Due to the rare incidence of spinal cord astrocytomas, their molecular features remain unclear. Here, we characterized the landscapes of mutations in H3 K27M, isocitrate dehydrogenase 1 (IDH1) R132H, BRAF V600E, and the TERT promoter in 83 diffuse spinal cord astrocytic tumors. Among these samples, thirty-five patients had the H3 K27M mutation; this mutant could be observed in histological grade II (40%), III (40%), and IV (20%) astrocytomas. IDH1 mutations were absent in 58 of 58 cases tested. The BRAF V600E mutation (7/57) was only observed in H3-wildtype astrocytomas, and was associated with a better prognosis in all histological grade II/III astrocytomas. TERT promoter mutations were observed in both H3 K27M-mutant (4/25) and-wildtype (9/33) astrocytomas, and were associated with a poor prognosis in H3-wildtype histological grade II/III astrocytomas. In the 2016 WHO classification of CNS tumors, H3 K27M-mutant diffuse midline gliomas, including spinal cord astrocytomas, are categorized as WHO grade IV. Here, we noticed that the median overall survival of histological grade II/III H3 K27M-mutant cases (n = 28) was significantly longer than that of either the total histological grade IV cases (n = 12) or the H3 K27M-mutant histological grade IV cases (n = 7). We also directly compared H3 K27M-mutant astrocytomas to H3-wildtype astrocytomas of the same histological grade. In histological grade II astrocytomas, compared to H3-wildtype cases (n = 37), H3 K27M-mutant patients (n = 14) had showed a significantly higher Ki-67-positive rate and poorer survival rate. However, no significant differences in these parameters were observed in histological grade III and IV astrocytoma patients. In conclusion, these findings indicate that spinal cord astrocytomas are considerably different from hemispheric and brainstem astrocytomas in terms of their molecular profiles, and that the histological grade cannot be ignored when assessing the prognosis of H3 K27M-mutant spinal cord astrocytomas.

BACKGROUND “Diffuse midline glioma, H3 K27M-mutant” (DMG) mainly arises within the pontine, thalamic, and spinal cord regions. Because of the rarity of spinal cord gliomas, the general knowledge surrounding DMGs is mainly based on pontine and thalamic gliomas, whereas tumor location tends to influence the clinicopathological features and prognosis. OBJECTIVE To determine the clinicopathological characteristics and molecular profiles of DMGs located in the spinal cord. METHODS The clinical and molecular pathologic features and prognosis were comprehensively analyzed in a series of 44 patients with spinal cord DMGs. RESULTS The median age was 36 yr, and 88.7% of patients (39/44) were adults (≥18 yr). Histopathologically, malignant grades included grade II (16 cases), grade III (20 cases), and grade IV (8 cases). Compared with patients with histological grade IV, patients with lower histological grade (grade II/III) were older (37 vs 24 yr, P = .020) and were associated with longer overall survival (24.1 vs 8.6 mo, P = .007). All 30 tested tumors were isocitrate dehydrogenase (IDH) wild type, and 96% of cases (22/23) presented with unmethylated O6-methylguanine-DNA methyltransferase. Univariate and multivariate analyses showed that histological grade and presurgery McCormick Scale scores were independent prognostic factors for overall survival, whereas extensive surgical resection and chemoradiotherapy were not significantly associated with improved survival. The most frequent anatomic locations were the cervical enlargement (C4-T1, n = 16) and conus medullaris (T12-L1, n = 13), which exhibited distinctive clinical characteristics and molecular features. CONCLUSION The findings provide guidelines for the evidence-based practice of the specialized management of spinal cord DMGs.

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