Clinical, radiological and molecular characterization of intramedullary astrocytomas

Abstract

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.

Keywords: Intramedullary astrocytomas-glial tumor-spinal cord-targeted next-generation sequencing-H3F3A K27M-KIAA1549-BRAF.

Fig. 1

Representative radiological (sagittal MRI images) and histological (HE staining, 200×) features of intramedullary astrocytomas (IMAs) of grade I pilocytic (T2WI) (a), grade II diffuse (T2WI) (b), grade III (GdT1WI) (c) and grade IV (GdT1WI) (d) IMAs. HE, hematoxylin-eosin; MRI, magnetic resonance imaging; T2WI, T2 weighted image, GdT1WI, gadolinium enhanced T1 weighted images

Fig. 2

Overall survival (OS) and event-free survival (EFS) of low-grade (LG) and high-grade (HG) intramedullary astrocytomas. Kaplan-Meier curves of OS (a, c) and EFS (b, d) for all cases (a, b) and only for resected (partial and gross total resection) cases (c, d).p-values were calculated using the log-rank test

Fig. 3

Event-free survival (EFS) of grade I pilocytic and II diffuse intramedullary astrocytomas. Kaplan-Meier curves of EFS for grade I pilocytic and grade II diffuse IMAs without (a) and after (b) stratification using the extent of surgical resection: biopsy vs. (partially or totally) resected cases. p-values were calculated using the log-rank test

Fig. 4

Molecular characterization of 61 intramedullary astrocytomas (IMAs) obtained by targeted next-generation-sequencing using research, clinical and KIAA1549-BRAF fusion panels. The figure summarizes the clinico-pathological features and molecular alterations found in the 61 IMAs. EFS, event-free survival; ND, no data available; s, second surgery sample; RGP, research glioma panel; CGP, clinical glioma panel​