Somatic and mosaic HRAS mutations in pediatric malignant ectomesenchymoma

Malignant ectomesenchymoma (ME), a rare tumor of soft tissues, has a neuroectodermal component of neuroblasts and/or ganglion cells, and a mesenchymal component mostly often represented by rhabdomyoblasts. Considering the peculiar and variable morphological structure of ectomesenchymomas, establishing the correct histological diagnosis can be challenging. The investigation presents 5 cases of ME, including 3 sporadic forms and 2 tumors in patients with neurocutaneous syndrome. Morphological and genetic tumor profiles were analyzed using immunohistochemical marker panel, coupled reverse transcription PCR and customized DNA-based NGS panel. The identified somatic variants were interpreted in accordance with the AMP/ASCO/CAP Guideline recommendations. In 4 out of 5 cases, mutations in HRAS typical for ME were detected. Two patients with HRAS mutation and phenotypic features of neurocutaneous epidermal nevus syndrome and nevus sebaceous syndrome had the pathogenic HRAS variant in a spectrum of biological materials including healthy tissues with different varying allele frequency (VAF). The molecular genetic findings indicate a post-zygotic origin of the pathogenic mutation in HRAS, associated with the mosaic phenotype, in both cases. Morphological and genetic profiles were analyzed in 5 pediatric cases of ME. The investigation revealed expression of neuroblastic and mesenchymal markers in corresponding components of the tumors. The majority of cases harbored HRAS gene variants in ME samples, 2 patients with neurocutaneous syndrome had the pathogenic HRAS variant with different VAF in various biological material including healthy tissues, that exposed the driver event as postzygotic, occurring not later than the stage of migrating ectomesenchyme originating from the neural crest. These are the first descriptions of ME against a somatic mosaicism background.