Morphologic characteristics and immunohistochemical profile of diffuse intrinsic pontine gliomas

Abstract

Tumors of the central nervous system are the second most common malignancy in children. In particular, diffuse intrinsic pontine gliomas (DIPGs) are aggressive tumors with poor prognosis and account for 10% to 25% of pediatric brain tumors. The majority of DIPGs are astrocytic, infiltrative, and localized to the pons. Studies have shown median survival times of less than a year, with 90% of children dying within 2 years. We built multitissue arrays with 24 postmortem DIPG samples and analyzed the morphology and expression of several proteins (p53, EGFR, GFAP, MIB1, BMI1, β-catenin, p16, Nanog, Nestin, OCT4, OLIG2, SOX2) with the goal of identifying potential treatment targets and improving our understanding of the biology of these tumors. The majority of DIPGs were high-grade gliomas (22), with 18 cases having features of glioblastoma (World Health Organization [WHO] grade IV) and 4 cases with high-grade features consistent with anaplastic astrocytoma (WHO grade III). One case was low grade (WHO grade II), and 1 case showed intermediate features between a grade II and grade III glioma (low mitotic rate but increased cellularity and cell atypia), being difficult to grade precisely. The majority of the tumors were positive for GFAP (24/24), MIB1 (23/24), OLIG2 (22/24), p16 (20/24), p53 (20/24), SOX2 (19/24), EGFR (16/24), and BMI1 (9/24). Our results suggest that dysregulation of EGFR and p53 may play an important role in the development of DIPGs. The majority of DIPGs express stem cell markers such as SOX2 and OLIG2, consistent with a role for tumor stem cells in the origin and maintenance of these tumors. Targeted therapies against these proteins could be beneficial in treatment.

Conflict of interest statement

The authors have no conflict of interest to disclose.

Figures

Fig. 1

Morphologic spectrum of DIPGs. Mitosis (A), pseudopalisading necrosis and microvascular proliferation (B), microcalcifications (C), and giant cells (D) were observed.

Fig. 2

Immunohistochemical stains showing GFAP expression (A), high MIB1 labeling (B), EGFR expression (C) and increased p53 staining (D).

Fig. 3

Immunohistochemical stains showing nuclear staining pattern with p16 (A). Staining with IDH1 (R132H) was negative (B). Nestin positive staining with a fibrillary pattern (C). SOX2 positive staining with a nuclear distribution (D).

Fig. 4

Immunohistochemical stains showing nuclear staining with OCT3/4 (A), OLIG2 (B), and BMI1 (C). Staining for β-catenin showed a submembranous/cytoplasmic pattern (D).