Novel HSPA8-NR4A2 rearrangement in extraskeletal myxoid chondrosarcoma: a sarcoma mimicker of neuroendocrine neoplasia

Extraskeletal myxoid chondrosarcoma (EMC) is a rare mesenchymal neoplasm of uncertain differentiation associating with diagnostic NR4A3 gene rearrangements. An unusual case of EMC harboring the novel HSPA8::NR4A2 gene fusion and neuroendocrine phenotype is described. The tumor exhibited a lobular architecture, myxoid stroma, and epithelioid tumor cells with a complete neuroendocrine phenotype by specific immunohistochemistry and transmission electron microscopy. The lesions showed a low tumor mutational burden (1.9 muts/Mb), a microsatellite stable status, no cancer driver gene mutations, no canonical NR4A3 fusion and low copy number variation. A novel in-frame fusion between HSPA8 (exon 2) and NR4A2 (exon 3) was identified by RNA-sequencing and methylation analysis placed the lesion into the EMC class (0.99 score). Transcriptome cluster comparative analysis placed its expression profile close to pancreas neuroendocrine tumors. This case suggests NR4A2 as a functionally substitute for NR4A3 in tumorigenesis and a neuroendocrine lineage differentiation for a subset of EMC.