Pediatric mesenchymal chondrosarcoma with archetypal histology in the absence of HEY1::NCOA2 gene fusion: a molecular-morphological paradox.
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Mesenchymal chondrosarcoma (MC) is a rare, aggressive malignancy characterized by a distinctive biphasic histological pattern and frequently associated with the HEY1::NCOA2 fusion gene. We report a case of a 17-year-old male presenting with a mandibular mass initially suspected to be a benign chondro-osseous lesion. Following segmental mandibulectomy, histopathological examination revealed classical features of MC, including undifferentiated small round to spindle cells arranged around staghorn vasculature and islands of mature hyaline cartilage. Immunohistochemistry showed strong S100 positivity in the cartilaginous component and diffuse NKX3.1 expression in the undifferentiated areas. However, molecular analysis via next-generation sequencing did not detect HEY1::NCOA2 fusion, raising the possibility of a fusion-negative variant. This case highlights the potential for molecular heterogeneity in MC and emphasizes that, in the presence of unequivocal morphology, absence of canonical gene fusions should not preclude the diagnosis. It reinforces the enduring role of histopathology and the need for expanded molecular profiling in such diagnostically challenging cases.