Primary intracranial sarcomas with DICER1 mutation often contain prominent eosinophilic cytoplasmic globules and can occur in the setting of neurofibromatosis type 1

Excerpt

A broad spectrum of primary sarcoma subtypes are now recognized to occur intracranially, presumably arising from mesenchymal progenitor cells within the meningeal covering of the brain and along perivascular Virchow–Robin spaces. Here we report the clinical, radiologic, histologic, and molecular features of three patients with intracranial sarcomas that are unified by the presence of primary intracranial location with meningeal involvement, pleomorphic morphology, high proliferation index, prominent eosinophilic cytoplasmic globules, focal immunophenotypic evidence of myogenic differentiation, and the combination of DICER1 and TP53 mutations, along with ATRX inactivation and genetic alterations causing activation of the MAP kinase signaling pathway. One patient has neurofibromatosis type 1 (NF1) with multiple cutaneous neurofibromas, café-au-lait macules, an optic pathway glioma, and other brain parenchymal lesions characteristic of NF1. This patient was found to have a heterozygous germline nonsense mutation in the NF1 tumor suppressor gene, along with a second somatic mutation of NF1 in the primary intracranial sarcoma, indicating that this tumor arose due to biallelic NF1 gene inactivation. Genome-wide methylation profiling performed on two of the cases revealed that they clustered with the recently described group of tumors termed “primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features, DICER1 mutant” [7]. However, while the three tumors in our cohort demonstrate myogenic differentiation as evidenced by focal desmin immunopositivity, none contain identifiable rhabdomyoblasts, they uniformly lack myogenin expression, and are all morphologically best characterized as pleomorphic rather than predominantly spindled or round cell. Thus, this patient cohort expands the histologic spectrum and association with familial tumor predisposition syndromes of the primary intracranial sarcomas that cluster with this new methylation subgroup. As such, we suggest a broader designation for this new proposed entity: “Primary intracranial sarcoma, DICER1-mutant”. …