Primary CNS Neuroblastoma, FOXR2-Activated: Clinicopathological Study of Two Cases With Immunohistochemical Characterization and Literature Review.

Abstract

Primary central nervous system (CNS) neuroblastoma, FOXR2-activated (CNS-NB-FOXR2), is a rare embryonal tumor characterized by neuroblastic differentiation and structural rearrangement of the FOXR2 gene. Previously grouped under CNS primitive neuroectodermal tumors (PNET), this entity has been reclassified based on genome-wide DNA methylation profiling. In this study, we present the detailed clinicopathological and immunohistochemical features of two pediatric cases diagnosed at our center. The first case involved a six-year-old with a left frontal mass; the second was a one-year-old with a large bifrontal lesion. Radiologically, both cases mimicked other embryonal tumors or high-grade gliomas. Histologically, tumors displayed small round blue cell morphology with neuroblastic features, including Homer-Wright rosettes and ganglionic differentiation. Immunohistochemistry demonstrated diffuse positivity for OLIG2, synaptophysin, and L1CAM, with negative expression for GFAP, EMA, and IDH1 R132H. FOXR2 showed nuclear positivity in both cases, supporting the diagnosis. Both cases exhibited diffuse L1CAM positivity-a rare finding with limited evidence in the existing literature. Although DNA methylation profiling could not be performed, the diagnosis was supported by characteristic morphology and immunohistochemistry profile. This report highlights key diagnostic features and potential mimics of CNS neuroblastoma, FOXR2-activated, and underscores the utility of immunohistochemistry in low-resource settings. Recognizing this entity is essential for accurate classification and appropriate therapeutic planning. Further studies are warranted to explore targeted therapies, including MEK inhibitors, which may hold promise based on emerging molecular data.