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Clinicopathologic evaluation of dedifferentiated liposarcoma lacking MDM2 amplification
Charlotte I Wang1, Soma Jobbagy1, Anne B Giersch2
1Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Histopathology
|May 8, 2026
Summary
Dedifferentiated liposarcoma (DDLPS) lacking MDM2 amplification is rare but driven by cell-cycle alterations like CDK4 gain. Recognizing this variant is crucial for accurate diagnosis and treatment of retroperitoneal sarcomas.
Area of Science:
- Oncology
- Genetics
- Pathology
Background:
- Dedifferentiated liposarcoma (DDLPS) is typically characterized by MDM2 amplification.
- MDM2 amplification detection is key for diagnosing DDLPS, especially in retroperitoneal biopsies.
- The spectrum of MDM2 non-amplified DDLPS is not well understood.
Purpose of the Study:
- To characterize the diagnostic features, genomic alterations, and clinical behavior of MDM2 non-amplified DDLPS.
- To identify alternative molecular drivers in DDLPS lacking MDM2 amplification.
Main Methods:
- Retrospective review of DDLPS cases from pathology archives (2010-2025).
- Inclusion criteria: high-grade sarcoma with WDLPS background, absence of MDM2 overexpression (IHC) and amplification (FISH/SNP array).
- Clinicopathologic features, immunophenotype, treatment, and outcomes were analyzed.
Main Results:
- Four cases (1.6%) of MDM2-negative DDLPS were identified, all in the retroperitoneum/intra-abdominal soft tissues.
- All cases showed high-grade sarcoma morphology with a WDLPS component and strong CDK4 expression despite lacking MDM2 amplification.
- Molecular analysis revealed CDK4 copy number gain in all cases, CDKN2A loss in three, and TP53 alterations in two. Outcomes were heterogeneous.
Conclusions:
- MDM2 non-amplified DDLPS is a rare subset driven by alternative cell-cycle dysregulation, primarily CDK4 gain and CDKN2A loss.
- Accurate diagnosis requires integrating morphology, IHC, and genomic profiling to avoid misclassification.
- Awareness of this variant is critical for managing challenging retroperitoneal sarcomas.
