From pathogenesis to the patient’s bedside: a comprehensive review of extraskeletal myxoid chondrosarcoma

Extraskeletal myxoid chondrosarcoma (EMC) is characterised by recurrent NR4A3 gene rearrangements, most commonly EWSR1::NR4A3, and accounts for approximately 1–3% of soft-tissue sarcomas (STS). It typically arises in the deep soft tissues of the proximal lower limb, particularly the thigh. Diagnosis is best established by integrating morphology and immunophenotype with molecular confirmation; in particular, NR4A3 break-apart fluorescence in situ hybridisation (FISH) provides a practical single-assay solution. For localised disease, complete surgical excision remains the cornerstone of treatment. Radiotherapy (RT) improves local control when margins are close or tumours are large. Recurrence-free survival (RFS) varies: local recurrence (LR) rates range from 13 to 42% across studies, and distant metastases develop in around 35–45% of patients, primarily in the lungs. The median time to metastasis is approximately 28 months. Overall survival (OS) reflects the typically indolent yet metastatic course: 5-year OS 66–88%, and 10-year disease-specific survival approximately 85%. In advanced disease, anthracycline-based chemotherapy yields a low objective response rate (ORR), although occasional partial responses occur. By contrast, the anti-angiogenic tyrosine kinase inhibitor pazopanib produced an ORR of 18% and a median progression-free survival (PFS) of 19 months in a multicentre phase 2 study (NCT02066285). No clinically validated agents directly target NR4A3. This review summarises contemporary diagnostics and treatment, emphasising high-quality surgery, selective RT, and consideration of anti-angiogenic tyrosine kinase inhibitors in advanced disease. Graphical summary of a review article on Extraskeletal myxoid chondrosarcoma (EMC). Diagnosis involves integrating morphology with immunohistochemistry (INSM1, S100 and synaptophysin) and NR4A3 fusion testing, particularly break-apart fluorescence in situ hybridisation (FISH). Common fusions include EWSR1::NR4A3, TAF15::NR4A3 and FUS::NR4A3. Localised management involves wide local excision with selective radiotherapy to enhance local control, and chemotherapy plays a limited role, mainly in advanced disease. The prognosis is indolent yet metastasising. 5-year overall survival (OS) is 66–88%, ten-year disease-specific survival (DSS) is approximately 85%, local recurrence (LR) is 30–50%, and the rate of distant metastasis is 30–50%, predominantly to the lungs.