Alectinib‐responsive infantile anaplastic ganglioglioma with a novel VCL–ALK gene fusion

Abstract

To the Editor: High-grade glioma (HGG) is a commonly lethal brain tumordue to its disseminated nature and lack of effective therapy.1 Pediatric HGG is an extremely aggressive brain tumor with distinct genetic differences from adult HGG. Pediatric HGG has been reported to harbor mutations in the RAS/MAPK pathway or receptor tyrosine kinase, including anaplastic lymphoma kinase (ALK).1,2 ALK is associated with a genetic abnormality in various tumors occurring in infants and children, such as neuroblastoma.3 Molecular classifications may expand the range of target therapy for brain tumors, although the response to treatmentwith newly developedALK inhibitors is unclear.We herein report a 2-year-old Japanese male who received the diagnosis of anaplastic ganglioglioma carrying a novel VCL–ALK fusion. The chemo-resistant unresectable tumor has been successfully controlled with improved development for 15 months after the administration of alectinib, a second-generation ALK inhibitor. A previously healthy 2-year-old male presented with status epilepticus following vomiting and consciousness disturbance. Magnetic resonance imaging showed a 7-cm mass on the left occipital lobe (Figure 1A,B). Hydrocephalus and extensive dissemination to the cerebral hemispheres, brain stem, and optic nerve were found. An open biopsy determined the histopathological features consisting of two distinct components: (1) densely packed, diffuse, or pseudopapillary proliferation of primitive-looking tumor cells with perivascular pseudorosettes; and (2) ganglioglioma-like component consisting of astrocytic tumor cells with well-developed cytoplasmic processes intermingled with atypical ganglion cells (Figure S1A–C). The MIB-1 staining index was 55% in (1) and 3.3% in (2). A FoundationOne CDx cancer genome profile revealed a novel VCL–ALK fusion in the tumor cells. TP53 was positive in both components of the tumor. ALK was strongly and diffusely positive in the primitive tumor cells (Figure S1D) but partially positive in the ganglioma-like component. Fluorescence in situ hybridization was performed to assess the ALK rearrangement in tumor cells (Figure S2). These findings led to the diagnosis ofmalignant evolution of ganglioglioma associated with VCL–ALK fusion. The patient underwent combination chemotherapy after control of intracranial pressure. Extracorporeal cerebrospinal fluid drainage and ventriculoperitoneal shunting controlled intracranial pressure leading to reduced frequency of vomiting (CTCAE; from grade 2 to 1), and improved consciousness levels. He came to stand and walk alone, but fully depended on intravenous fluid infusion. The tumor regrowth prompted us to start the administration of alectinib. This adjunctive therapy successfully controlled the tumor regrowth (Figure 1C–E). The patient is now eating and walking unaided without neurocognitive impairments at 15months after the diagnosis. Primary HGG occurs in pediatric population less frequently (10%– 20%) than in adults (21.7%–25.3%) with primary brain tumor.4–6 The genetic backgrounds of pediatric primary HGG are distinct from those of adult cases. HGG in the present patient had a novel VCL–ALK fusion. Among 36 reported cases of infantile glioma with ALK rearrangement, no VCL–ALK fusion had been identified in pediatric or adult patients with glioma (Table S1). An open biopsy was performed to determine the histopathological features, which consisted of two components. The gangliogliomalike component showed a lower proliferation activity than the primitive component, as indicated by MIB-1 staining indexes. Two distinct findings support the hypothesis that the ganglioglioma-like component might transform into its aggressive counterpart along with VCL–ALK fusion. The different distribution patterns of p53 and ALK fusion suggests that VCL–ALK can induce dedifferentiation of the tumor. The diffuse expression of ALK in the tumor cells suggests that ALK inhibitors are a viable treatment option. ALK fusion genes are reported in 3%–5% of adults with nonsmall-cell lung cancer (NSCLC), in which ALK is constitutively activated and leads to oncogenesis. Patients with ALK-positive NSCLC respond well to crizotinib, except for those with brain metastases. However, alectinib appears to have high intracranial efficacy.7,8 It efficiently penetrates the blood–brain barrier9 and is not transported by the P-glycoprotein efflux transporter, affecting the permeability.10 Alectinib also has a higher affinity to ALK fusions than crizotinib in vivo.11 Multiple ALK partners are associated with synapse formation and activity (CCDC88A, HIP1, SYNDIG1), neuronal cytoskeletal reorganization (CCDC88A, SPECC1L), and microtubule assembly (MAP2, PRKAR2A, EML4), as well as PI3K-MAPK signaling (PPP1CB, CCDC88A, SPECC1L) and cell-cycle progression (MAD1L). These fusions thus likely disrupt key regulatory processes in neurodevelopment. VCL is located at 10q11.2-qter and encodes vinculin, a cytoskeletal protein involved in the formation of the adhesion scaffold.12 Fifteen cases of malignant tumors harboring VCL as partner to an ALK fusion have been reported (Table S2), including renal cell carcinoma, epithelioid fibrous histiocytoma, but not glioma. The contribution of VCL to the development of malignancies remains unclear, although VCLknockout carcinomas of stratified epithelial origin showed metastatic