High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication-a comprehensive clinical, radiographic, pathologic, and genomic analysis

Abstract

High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR ex15 ITD) is a recently proposed tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. The complete spectrum of histologic features, accompanying genetic alterations, clinical outcomes, and optimal treatment for this new tumor entity are largely unknown. Here, we performed a comprehensive assessment of 10 new cases of HGNET BCOR ex15 ITD. The tumors mostly occurred in young children and were located in the cerebral or cerebellar hemispheres. On imaging all tumors were large, well-circumscribed, heterogeneous masses with variable enhancement and reduced diffusion. They were histologically characterized by predominantly solid growth, glioma-like fibrillarity, perivascular pseudorosettes, and palisading necrosis, but absence of microvascular proliferation. They demonstrated sparse to absent GFAP expression, no synaptophysin expression, variable OLIG2 and NeuN positivity, and diffuse strong BCOR nuclear positivity. While BCOR exon 15 internal tandem duplication was the solitary pathogenic alteration identified in six cases, four cases contained additional alterations including CDKN2A/B homozygous deletion, TERT amplification or promoter hotspot mutation, and damaging mutations in TP53, BCORL1, EP300, SMARCA2 and STAG2. While the limited clinical follow-up in prior reports had indicated a uniformly dismal prognosis for this tumor entity, this cohort includes multiple long-term survivors. Our study further supports inclusion of HGNET BCOR ex15 ITD as a distinct CNS tumor entity and expands the known clinicopathologic, radiographic, and genetic features.

Keywords: BCOR exon 15 internal tandem duplication; HGNET; brain tumor; high-grade neuroepithelial tumor; molecular neuro-oncology; molecular neuropathology.

Figure 1

Imaging features of the CNS high‐grade neuroepithelial tumors with BCOR exon 15 internal tandem duplication. Shown are preoperative magnetic resonance images for cases #1–9. All tumors were large, well‐circumscribed, heterogeneous masses with variable enhancement and reduced diffusion. Many of the tumors demonstrated central areas of necrosis or blood products.

Figure 2

Histologic features of the CNS high‐grade neuroepithelial tumors with BCOR exon 15 internal tandem duplication. Shown are representative hematoxylin and eosin (H&E)‐stained sections of cases #1–9.

Figure 3

Recurrent histologic features observed in CNS high‐grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication. Shown are H&E‐stained sections demonstrating the circumscribed growth, palisading necrosis, perivascular pseudorosettes, and glioma‐like fibrillarity frequently observed in this tumor entity.

Figure 4

Additional recurrent histologic features observed in a subset of CNS high‐grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication. Shown are H&E‐stained sections demonstrating the microcystic/myxoid background, hyalinized stroma, areas with dense cellularity and brisk mitotic activity, and Homer Wright‐like rosettes observed in a subset of the cases.

Figure 5

Immunohistochemical features of CNS high‐grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication. Shown are representative immunohistochemical stains demonstrating the sparse to absent GFAP positivity, variable OLIG2 positivity, consistent NeuN positivity, synaptophysin negativity, granular cytoplasmic EMA staining with absence of paranuclear dot‐like positivity, and diffuse strong nuclear BCOR expression.

Figure 6

Ultrastructural features of CNS high‐grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication. Shown are electron microscopy images demonstrating primitive cells with abundant rough endoplasmic reticulum. No tight junctions, cilia or microvilli characteristic of ependymal differentiation are seen. Additionally, no neurosecretory granules or synaptic vesicles are observed.

Figure 7

Genetic landscape of CNS high‐grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication. Oncoprint table of the clinical features, likely pathogenic genetic alterations, and quantity of chromosomal copy number alterations in the 10 cases.

Figure 8

Diagram of the amino acid sequence at the C‐terminus of the BCOR protein showing the duplicated amino acids within exon 15 for the 10 CNS high‐grade neuroepithelial tumors with BCOR exon 15 internal tandem duplication.

Figure 9

Anaplastic features in CNS HGNET BCOR ex15 ITD (case #10) in association with TP53 inactivation and marked aneuploidy. A,B. Preoperative axial and coronal T2‐weighted MR images showing a circumscribed mass in the right cerebral hemisphere. C–E. H&E‐stained sections showing a biphasic tumor composed of a lower grade appearing component with abundant fibrillar processes (C left, D), and an anaplastic component with dense cellularity, severe nuclear pleomorphism and brisk mitotic activity (C right, E). F. Genome‐wide copy number plots for the lower grade appearing component showing monosomy 13q as the solitary copy number alteration (top), and for the anaplastic component showing numerous chromosomal gains and losses (bottom).

Figure 10

Clinical features of CNS high‐grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication. Clinical data from the 10 patients in this cohort (Supplementary Table 2), as well as all previously reported cases of this tumor entity with confirmed BCOR exon 15 internal tandem duplication (Supplementary Table 9), were aggregated for analysis. A. Location of the 33 tumors with specified anatomic site in the central nervous system. B. Age at initial diagnosis stratified by location for the 32 tumors with specified age and anatomic site. C. Kaplan–Meier survival analysis for the 24 patients with available clinical outcome data.