Congenital glioblastoma: a clinicopathologic and genetic analysis

Abstract

Congenital central nervous system (CNS) tumors are uncommon, accounting for 1% of all childhood brain tumors. They present clinically either at birth or within the first 3 months. Glioblastoma (GBM) only rarely occurs congenitally and has not been fully characterized. We examined clinicopathologic features and genetic alterations of six congenital GBMs. Tumors were seen by neuroimaging as large, complex cerebral hemispheric masses. All showed classic GBM histopathology, including diffuse infiltration, dense cellularity, GFAP-positivity, high mitotic activity, endothelial proliferation and pseudopalisading necrosis. Neurosurgical procedures and adjuvant therapies varied. Survivals ranged from 4 days to 7.5 years; two of the three long-term survivors received chemotherapy, whereas the three short-term survivors did not. Paraffin-embedded tissue sections were used for FISH analysis of EGFR, chromosomes 9p21 (p16/CDKN2A) and 10q ( PTEN/DMBT1); sequencing of PTEN and TP53; and immunohistochemistry for EGFR and p53. We uncovered 10q deletions in two cases. No EGFR amplifications, 9p21 deletions, or mutations of TP53 or PTEN were noted; however, nuclear p53 immunoreactivity was strong in 5/6 cases. Tumors were either minimally immunoreactive (n = 3) or negative (n = 3) for EGFR. We conclude that congenital GBMs show highly variable survivals. They are genetically distinct from their adult counterparts and show a low frequency of known genetic alterations. Nonetheless, the strong nuclear expression of p53 in these and other pediatric GBMs could indicate that p53 dysregulation is important to tumorigenesis.

Figures

Figure 1

Neuroimaging and macroscopic features of congenital glioblastoma.A. Axial, post‐contrast MRI demonstrates a large, heterogeneous, contrast‐enhancing mass centered in the parietal lobe of the right cerebral hemisphere and extending across the midline (Case 3). The skull and head are asymmetrically enlarged on the right and there is moderate ventricular enlargement on the left. B. H&E‐stained coronal section of postmortem brain with large, congenital glioblastoma involving the left cerebral hemisphere, centered in the basal ganglia and parietal lobe (Case 6). The tumor showed extensive regions of necrosis and caused significant midline shift and hydrocephalus.

Figure 2

Pathologic features of congenital glioblastoma. A. All tumors showed marked hypercellularity and consisted of monotonous sheets of tumor cells with astrocytic morphology that displayed only modest amounts of cytoplasm or fibrillarity. B. “Pseudopalisading” necrosis was present in all tumors. C. All tumors were strongly and diffusely positive for glial fibrillary acidic protein (GFAP) by immunohistochemistry.

Figure 3

Representative FISH results from congenital glioblastoma. A. Glioblastoma (GBM) with a normal disomic complement of 9p21. Most cells have two red (9p21) and two green (CEP9) signals. Some nuclei have less than two copies because of the truncation artifact encountered in thin tissue sections. B. Pattern of chromosome 10 deletion in a congenital GBM (case 4). Only one green (PTEN) signal and one red (DMBT1) signal are detected in each nucleus, most likely representing either a large 10q deletion or the loss of an entire chromosome 10.

Figure 4

p53 and EGFR expression in congenital glioblastoma. A. Immunohistochemistry for p53 showing strong (3+) nuclear immunoreactivity (Case 5). B. Immunostains for EGFR of (case 4) demonstrated mild (1+) reactivity focally.