Clinicopathologic evaluation of dedifferentiated liposarcoma lacking MDM2 amplification

Introduction Dedifferentiated liposarcoma (DDLPS) is a typically non‐lipogenic malignant neoplasm that arises from progression of an underlying atypical lipomatous tumour/well‐differentiated liposarcoma (ALT/WDLPS) and is classically defined by amplification of chromosome 12q15, including MDM2 and frequently cyclin‐dependent kinase 4 ( CDK4 ). Detection of MDM2 amplification by fluorescence in situ hybridization (FISH) and/or MDM2 protein expression immunohistochemistry (IHC) has, therefore, become central to the diagnosis of DDLPS, particularly in small biopsies from the retroperitoneum. Rare exceptions to this paradigm have been described, but the clinicopathologic and molecular spectrum of MDM2 non‐amplified DDLPS remains poorly characterized. We report a series of MDM2 non‐amplified DDLPS to better define their diagnostic features, genomic alterations and clinical behaviour. Methods Pathology archives from 2010 to 2025 were queried for cases diagnosed as DDLPS. Inclusion criteria required a high‐grade sarcoma arising in a histologically confirmed ALT/WDLPS background, absence of MDM2 overexpression by IHC and lack of MDM2 amplification by FISH and/or single nucleotide polymorphism array. Clinicopathologic features, immunophenotype, treatment and outcomes were reviewed. Results Among 253 cases of DDLPS identified during the study period, four (1.6%) fulfilled criteria for MDM2 ‐negative DDLPS. All tumours arose in the retroperitoneum or intra‐abdominal soft tissues and demonstrated high‐grade sarcoma morphology with an associated WDLPS component on resection. Despite the absence of MDM2 amplification, all cases showed strong CDK4 expression by IHC. Molecular analysis revealed recurrent alterations involving cell‐cycle regulation, including CDK4 copy number gain in all cases and loss of CDKN2A in three. Two cases harboured TP53 alterations. Clinically, outcomes were heterogeneous, ranging from aggressive disease with rapid recurrence and death within months to prolonged disease‐free survival exceeding 5 years. Conclusion MDM2 non‐amplified DDLPS represents a rare subset of DDLPS that appear to be driven by alternative mechanisms of cell‐cycle dysregulation, most commonly involving CDK4 gain and CDKN2A loss, with occasional TP53 alterations. Awareness of this variant is critical to avoid misclassification as other high‐grade sarcomas, particularly on limited biopsies, and underscores the importance of integrating morphology, IHC and broad genomic profiling in diagnostically challenging retroperitoneal sarcomas.