MDM4 Amplification in Liposarcoma: A Rare Finding or an Underrecognized Pathway?

Atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLPS) is typically characterized by MDM2 and/or CDK4 amplification. However, a subset lacks these alterations, suggesting alternative oncogenic drivers. We report a patient with recurrent retroperitoneal WDLPS who developed multiple relapses over more than 25 years. Histology demonstrated a well-differentiated morphology with extensive myxoid change, without evidence of dedifferentiation. Molecular profiling using next-generation sequencing (NGS) identified MDM4 amplification, together with mutations in PIK3CA and TERT. This finding supports MDM4 as a potential alternative driver in liposarcomagenesis, possibly correlating with a more indolent clinical course. Recognition of this rare alteration is important for accurate diagnosis and may have future therapeutic implications.