Rare Oncogenic Fusions in Pediatric Central Nervous System Tumors: A Case Series and Literature Review

Abstract

Background and Objectives: Central Nervous System (CNS) pediatric tumors represent the most common solid tumors in children with a wide variability in terms of survival and therapeutic response. By contrast to their adult counterpart, the mutational landscape of pediatric CNS tumors is characterized by oncogenic fusions rather than multiple mutated genes. CNS pediatric tumors associated with oncogenic fusions represent a complex landscape of tumors with wide radiological, morphological and clinical heterogeneity. In the fifth CNS WHO classification, there are few pediatric CNS tumors for which diagnosis is based on a single oncogenic fusion. This work aims to provide an overview of the impact of rare oncogenic fusions (NTRK, ROS, ALK, MET, FGFR, RAF, MN1, BCOR and CIC genes) on pathogenesis, histological phenotype, diagnostics and theranostics in pediatric CNS tumors. We report four cases of pediatric CNS tumors associated with NTRK (n = 2), ROS (n = 1) and FGFR3 (n = 1) oncogenic fusion genes as a proof of concept. Cases presentation and literature review: The literature review and the cohort that we described here underline that most of these rare oncogenic fusions are not specific to a single morpho-molecular entity. Even within tumors harboring the same oncogenic fusions, a wide range of morphological, molecular and epigenetic entities can be observed. Conclusions: These findings highlight the need for caution when applying the fifth CNS WHO classification, as the vast majority of these fusions are not yet incorporated in the diagnosis, including grade evaluation and DNA methylation classification.

Keywords: CNS WHO classification; DNA methylation; RNA sequencing; oncogenic fusions; pediatric CNS tumors.

Figure 1

NTRK-fused cases (A–J); MRI and 20× magnified histological images. Case 1 (A–E): (A) Axial T1-weighted MRI showed a lesion in the left mesial temporal lobe, (B,C). HE: A pleomorphic tumor with spindle-shaped and multinucleated giant cells, and calcifications were observed. (D) The tumor was GFAP-positive. (E) Diffuse cytoplasmic and membranous positivity for CD34. Case 2 (F–J): (F) Axial T2-weighted MRI showed a large tumoral mass in the right frontal lobe. (G,H) The tumor was composed of spindle-shaped and focally gemistocytic cells with high mitotic activity; no necrosis was observed. (I,J) GFAP and olig2 were focally positive.

Figure 2

ROS1-fused (A–E) and FGFR3-fused (F–J) cases; MRI and 20× magnified histological images. Case 3: (A–E): Axial T2-weighted MRI showed two hyperintense lesions in the pineal region and in the wall of the lateral ventricle. (B,C): HE showed a biphasic tumor with piloid features, eosinophilic granular bodies and calcifications. (D,E): GFAP and olig2 were at least partially positive. Case 4 (F–J): (F). Axial T2-weighted MRI showed a hyperintense tumoral mass in the left temporal lobe. (G,H): HE showed microvascular proliferation; no necrosis was seen. The tumor cells were ‘oligodendroglial-like’ and neurons were observed in mucoïd pools. (I): GFAP showed sporadically staining cells. (J): Some rare NeuN-positive cells were seen.