High-grade glioma in infants and young children is histologically, molecularly, and clinically diverse: Results from the SJYC07 trial and institutional experience

Abstract

Background: High-grade gliomas (HGG) in young children pose a challenge due to favorable but unpredictable outcomes. While retrospective studies broadened our understanding of tumor biology, prospective data is lacking.

Methods: A cohort of children with histologically diagnosed HGG from the SJYC07 trial was augmented with nonprotocol patients with HGG treated at St. Jude Children's Research Hospital from November 2007 to December 2020. DNA methylome profiling and whole genome, whole exome, and RNA sequencing were performed. These data were integrated with histopathology to yield an integrated diagnosis. Clinical characteristics and preoperative imaging were analyzed.

Results: Fifty-six children (0.0-4.4 years) were identified. Integrated analysis split the cohort into four categories: infant-type hemispheric glioma (IHG), HGG, low-grade glioma (LGG), and other-central nervous system (CNS) tumors. IHG was the most prevalent (n = 22), occurred in the youngest patients (median age = 0.4 years), and commonly harbored receptor tyrosine kinase gene fusions (7 ALK, 2 ROS1, 3 NTRK1/2/3, 4 MET). The 5-year event-free (EFS) and overall survival (OS) for IHG was 53.13% (95%CI: 35.52-79.47) and 90.91% (95%CI: 79.66-100.00) vs. 0.0% and 16.67% (95%CI: 2.78-99.74%) for HGG (p = 0.0043, p = 0.00013). EFS and OS were not different between IHG and LGG (p = 0.95, p = 0.43). Imaging review showed IHGs are associated with circumscribed margins (p = 0.0047), hemispheric location (p = 0.0010), and intratumoral hemorrhage (p = 0.0149).

Conclusions: HGG in young children is heterogeneous and best defined by integrating histopathological and molecular features. Patients with IHG have relatively good outcomes, yet they endure significant deficits, making them good candidates for therapy de-escalation and trials of molecular targeted therapy.

Keywords: high-grade glioma; infant-type hemispheric glioma; outcomes; prospective; young children.

Figure 1.

Cohort composition and key clinical outcome. (A) The cohort was assembled from a multicenter study, SJYC07 and an NPTP cohort. Patients were included based on histology at diagnosis or treatment initiation. Treatment was divided into low and high-risk categories for SJYC07 and low-like, high-like, and other categories for NPTP patients. (B) EFS and OS of the whole study cohort (N = 56). (C) EFS and OS based on treatment categories for SJYC07 patients (N = 41). (D) EFS and OS based on treatment categories for the whole cohort (N = 56).

Figure 2.

Molecular analysis and integrated diagnosis. (A) Sankey’s plot demonstrates the integration of histology at diagnosis, methylation class (MNP version 12.5), and molecular characteristics to formulate the integrated diagnosis. Abbreviations: Anaplastic astrocytoma, AA; Anaplastic pilocytic astrocytoma, APA; CNS embryonal tumor with PLAG-family amplification, ET PLAG; CNS tumor with BCOR internal tandem duplication, CNS BCOR ITD; CIC -rearranged CNS sarcoma SARC CIC; FOXR2-activated CNS neuroblastoma, CNS NB FOXR2; Embryonal tumor with multilayered rosettes, ETMR; Infant-type hemispheric glioma, IHG; Glioblastoma; Ganglioglioma, GG; High-Grade Glioma, HGG; H3K27M-mutant diffuse midline glioma, DMG H3K27M; High-grade neuroepithelial tumor, HGNET; Low-Grade Glioma, LGG; MYB/MYBL1-altered diffuse astrocytoma, DA MYB/MYBL1; Neuroepithelial tumor with PATZ1 fusion, NET PATZ; neuroepithelial tumor, PLAGL1-fused, NET PLAGL1; Non-classifiable, NC; Not done, ND; Pediatric diffuse high-grade glioma subtype MYCN, pHGGMYCN; Pilocytic astrocytoma, PA; Pilomyxoid glioma, PMG; Pleomorphic xanthoastrocytoma, PXA; Polymorphous low-grade neuroepithelial tumor of the young, PLNTY;

Figure 3.

Molecular and Clinical Features by Integrated Diagnosis: (A) Oncoplot depicting molecular (Methylation Class, Structural Variants, Copy Number Variants, Somatic Mutations, and Cytogenetics) and clinical characteristics of tumors by newly defined integrated diagnosis. (B) Scatter Plot of the integrated diagnosis of the tumors (N = 51) against 2482 reference cases from Capper et al. and Clarke et al. The cohort samples appear as solid-colored circles over reference samples shown in faded grey color. Abbreviations: Anaplastic astrocytoma, AA; Anaplastic pilocytic astrocytoma, APA; CNS embryonal tumor with PLAG-family amplification, ET PLAG; CNS tumor with BCOR internal tandem duplication, CNS BCOR ITD; CIC -rearranged CNS sarcoma SARC CIC; FOXR2-activated CNS neuroblastoma, CNS NB FOXR2; Embryonal tumor with multilayered rosettes, ETMR; Ependymoma, EPN; Ewing’s Sarcoma, EWS; Infant-type hemispheric glioma, IHG; Glioblastoma, GB; Glioblastoma Multiforme, GBM; Ganglioglioma, GG; High-Grade Glioma, HGG; H3K27M-mutant diffuse midline glioma, DMG H3K27M; High-grade neuroepithelial tumor, HGNET; Low-Grade Glioma, LGG; meningioma, MNG; MYB/MYBL1-altered diffuse astrocytoma, DA MYB/MYBL1; Neuroepithelial tumor with PATZ1 fusion, NET PATZ; Neuroepithelial tumor, PLAGL1-fused, NET PLAGL1; Non-classifiable, NC; Not done, ND; Pediatric diffuse high-grade glioma subtype MYCN, pHGGMYCN; Pilocytic astrocytoma, PA; Pilomyxoid glioma, PMG; Pleomorphic xanthoastrocytoma, PXA; Polymorphous low-grade neuroepithelial tumor of the young, PLNTY.

Figure 4.

Event Free (EFS) and Overall Survival (OS) based on Integrated Diagnosis (A) EFS and OS by integrated diagnosis Tier 3 (IHG vs. LGG vs. HGG vs. Other-CNS Tumors). (B) EFS and OS in IHG based on the presence of RTK fusions (Fusion-positive vs. fusion-negative cases). (C) EFS and OS of the fusion-positive IHG patients based on the fusion type.

Figure 5.

Neurocognitive and radiographic features of HGG in young children: (A) Change in IQ in 22 patients enrolled on SJYC07. (B) Comparison of Imaging features (anatomical location, tumor margin, and hemorrhagic changes within the tumor) in IHG vs. HGG. (C-F) Representative images of IHG.