Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles (ULB), 808 Route de Lennik, B-1070, Brussels, Belgium.
Molecular Pathology Research Unit, Department of Pathology, Virgen de la Salud Hospital, Toledo, Spain.
Acta Neuropathol Commun. 2020 Aug 8;8(1):128. doi: 10.1186/s40478-020-00962-1.
Intramedullary astrocytomas (IMAs) are rare tumors, and few studies specific to the molecular alterations of IMAs have been performed. Recently, KIAA1549-BRAF fusions and the H3F3A p.K27M mutation have been described in low-grade (LG) and high-grade (HG) IMAs, respectively. In the present study, we collected clinico-radiological data and performed targeted next-generation sequencing for 61 IMAs (26 grade I pilocytic, 17 grade II diffuse, 3 LG, 3 grade III and 12 grade IV) to identify KIAA1549-BRAF fusions and mutations in 33 genes commonly implicated in gliomas and the 1p/19q regions. One hundred seventeen brain astrocytomas were analyzed for comparison. While we did not observe a difference in clinico-radiological features between LG and HG IMAs, we observed significantly different overall survival (OS) and event-free survival (EFS). Multivariate analysis showed that the tumor grade was associated with better OS while EFS was strongly impacted by tumor grade and surgery, with higher rates of disease progression in cases in which only biopsy could be performed. For LG IMAs, EFS was only impacted by surgery and not by grade. The most common mutations found in IMAs involved TP53, H3F3A p.K27M and ATRX. As in the brain, grade I pilocytic IMAs frequently harbored KIAA1549-BRAF fusions but with different fusion types. Non-canonical IDH mutations were observed in only 2 grade II diffuse IMAs. No EGFR or TERT promoter alterations were found in IDH wild-type grade II diffuse IMAs. These latter tumors seem to have a good prognosis, and only 2 cases underwent anaplastic evolution. All of the HG IMAs presented at least one molecular alteration, with the most frequent one being the H3F3A p.K27M mutation. The H3F3A p.K27M mutation showed significant associations with OS and EFS after multivariate analysis. This study emphasizes that IMAs have distinct clinico-radiological, natural evolution and molecular landscapes from brain astrocytomas.
脊髓内星形细胞瘤（IMAs）较为罕见，针对其分子改变的研究较少。目前已在低级别（LG）和高级别（HG）IMAs 中分别发现了 KIAA1549-BRAF 融合和 H3F3A p.K27M 突变。本研究收集了 61 例 IMA（26 例为毛细胞型星形细胞瘤，17 例为弥漫性星形细胞瘤，3 例为 LG，3 例为 III 级，12 例为 IV 级）的临床-影像学数据，并进行了靶向下一代测序，以鉴定 KIAA1549-BRAF 融合和 33 个常见的胶质瘤相关基因以及 1p/19q 区域的突变。同时分析了 117 例脑星形细胞瘤作为对照。虽然我们没有观察到 LG 和 HG IMA 的临床-影像学特征存在差异，但观察到总生存期（OS）和无事件生存期（EFS）存在显著差异。多变量分析显示肿瘤分级与 OS 相关，而 EFS 受肿瘤分级和手术强烈影响，仅行活检的病例疾病进展率更高。对于 LG IMA，EFS 仅受手术影响，与分级无关。在 IMA 中最常见的突变涉及 TP53、H3F3A p.K27M 和 ATRX。与脑星形细胞瘤一样，I 级毛细胞型星形细胞瘤常携带 KIAA1549-BRAF 融合，但融合类型不同。仅在 2 例弥漫性星形细胞瘤 II 级中观察到非典型 IDH 突变。IDH 野生型 II 级弥漫性星形细胞瘤中未发现 EGFR 或 TERT 启动子改变。这些肿瘤似乎具有良好的预后，仅 2 例发生间变演变。所有 HG IMA 至少存在一种分子改变，最常见的是 H3F3A p.K27M 突变。多变量分析显示 H3F3A p.K27M 突变与 OS 和 EFS 显著相关。本研究强调了 IMA 与脑星形细胞瘤在临床-影像学、自然演变和分子特征方面存在明显差异。
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