Abstract
BACKGROUND: Astrocytoma, IDH-mutant, is the most common primary brain tumor in young adults, with peak incidence between 30 and 40 years of age. It is defined by mutations in the IDH1 or IDH2 genes and the absence of 1p/19q codeletion, and it frequently harbors alterations in ATRX and TP53. Rarely, astrocytoma, IDH-mutant, amay exhibit primitive neuronal differentiation, morphologically resembling “small round blue cell” tumors or large anaplastic embryonal-like cells. METHODS: We analyzed 18 cases of astrocytoma, IDH-mutant, with primitive neuronal differentiation. In 11 cases where both the primitive neuronal and glial components were available, macrodissection was performed by a pathologist. Each component was subjected to separate genetic (next-generation sequencing) and epigenetic (DNA methylation profiling) analyses. Morphological and immunophenotypic features were also evaluated. RESULTS: The primitive neuronal component was characterized by absent or markedly reduced GFAP expression, positivity for neuronal markers, a high Ki-67 proliferation index, and frequent TTF1 expression. This component also exhibited distinct epigenetic signatures and copy number alterations compared to the glial component. All tumors were high-grade, with extensive copy number variations, frequent MYCN amplification, and RB1 loss. DISCUSSION: Astrocytoma, IDH-mutant, with a primitive neuronal component expands the morphological spectrum of IDH-mutant astrocytomas and presents a significant diagnostic challenge. Recognition of this rare subtype is critical due to its aggressive biological behavior. This work was supported by Masaryk University in Brno, Czech Republic, under Grant MUNI/A/1621/2024, the Ministry of Health, Czech Republic, grant project no. NU23-03-00100 and by the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102) - Funded by the European Union - Next Generation EU.