Rare Pediatric Cerebellar High-Grade Gliomas Mimic Medulloblastomas Histologically and Transcriptomically and Show p53 Mutations

Abstract

Pediatric high-grade gliomas (HGG) of the cerebellum are rare, and only a few cases have been documented in detail in the literature. A major differential diagnosis for poorly differentiated tumors in the cerebellum in children is medulloblastoma. In this study, we described the histological and molecular features of a series of five pediatric high-grade gliomas of the cerebellum. They actually showed histological and immunohistochemical features that overlapped with those of medulloblastomas and achieved high scores in NanoString-based medulloblastoma diagnostic assay. Methylation profiling demonstrated these tumors were heterogeneous epigenetically, clustering to GBM_MID, DMG_K27, and GBM_RTKIII methylation classes. MYCN amplification was present in one case, and PDGFRA amplification in another two cases. Interestingly, target sequencing showed that all tumors carried TP53 mutations. Our results highlight that pediatric high-grade gliomas of the cerebellum can mimic medulloblastomas at histological and transcriptomic levels. Our report adds to the rare number of cases in the literature of cerebellar HGGs in children. We recommend the use of both methylation array and TP53 screening in the differential diagnoses of poorly differentiated embryonal-like tumors of the cerebellum.

Keywords: MYCN; PDGFRA; children; high-grade gliomas; p53.

Figure 1

Histological and immunohistochemical features of tumor samples. (A–E) Case 1. (A) T2 MRI showing large fourth ventricular tumor. (B) H&E showing monomorphic sheets of small hyperchromatic embryonal-looking cells with no cytoplasm (×200). Tumor cells were positive for (C) synaptophysin (×400), (D) Olig2 (×200), and (E) p53 (×200). Tumor cells were negative for GFAP and NeuN, positive for INI-1, and showed high Ki67 labeling (not shown). (F–J) Case 2. (F) T2 MRI showing large tumor involving cerebellar peduncle and fourth ventricle. (G) H&E showing features similar to case 1 with sheets of primitive-looking cells (×200). Immunostaining for (H) synaptophysin (×400), (I) Olig2 (×200), and (J) p53 (×200). Tumor cells were negative for NeuN and focally positive for GFAP, positive for INI-1, and showed high Ki67 labeling (not shown). (K–O) Case 3. (K) T2 MRI shows tumor at cerebellar peduncle. Histology shows (L) groups of hyperchromatic cells with no cytoplasm packed together (×200) with small foci of necrosis and microvascular proliferation (not shown). Immunostaining for (N) synaptophysin (×200) and (M) GFAP (×400). Tumor cells were focally positive for Olig2, negative for NeuN, positive for INI-1, positive for p53, and showed high labeling for Ki67 (not shown). (O) FISH demonstrates PDGFRA amplification consistent with CNV findings. (P–T) Case 4. (P) T2 MRI showing large cerebellar tumor. (Q) H&E shows sheets of hyperchromatic embryonal cells with small foci of microvascular proliferation (×400). Expression of (R) synaptophysin (×400) and (S) Olig2 (×200). Tumor cells were focally positive for p53 and GFAP, negative for NeuN, positive for INI-1, and showed high labeling for Ki67. (T) FISH shows MYCN gains consistent with CNV findings.

Figure 2

Oncoprint summary of clinical and molecular profiles of this cohort. ^ Nanostring transcriptome array as was done according to previous studies [26,27]. # Methylation class was assigned by DKFZ [21].

Figure 3

tSNE clustering of DNA methylation profiles of the five tumors (red triangles) alongside 2801 reference samples from Capper et al. [21].