Dedifferentiated liposarcoma exhibiting myxoid liposarcoma-like morphology with DDIT3 co-amplifcation and STAT6 nuclear expression.

Dedifferentiated liposarcoma (DDLPS) arises from atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLPS) through progression into non-lipogenic sarcomas of varying histological grades, driven by amplification of the chromosome 12q13-15 region containing MDM2, CDK4, DDIT3, STAT6, GLI1, HMGA2, etc. DDLPS demonstrates marked morphological heterogeneity in its dedifferentiated components. We describe two DDLPS cases featuring a prominent arborizing vascular network, myxoid stroma, and STAT6 nuclear expression-features that complicate differentiation from solitary fibrous tumors (SFT), myxoid liposarcoma (MLPS), myxofibrosarcoma (MFS), GLI1-altered tumors, low-grade fibromyxoid sarcoma (LGFMS), soft tissue angiofibroma (STA), etc. Immunohistochemistry (IHC) confirmed STAT6 overexpression, while fluorescence in situ hybridization (FISH) revealed co-amplification of MDM2 and DDIT3. STAT6 amplification in DDLPS leads to detectable protein expression by IHC. DDIT3 amplification in select WDLPS/DDLPS cases correlates with such unique MLPS-like morphology. These observations imply that analogous mechanisms may involve other genes within the 12q13-15 region, underscoring the genomic and phenotypic heterogeneity of DDLPS. Tumor diagnosis requires integrating morphological assessment, immunohistochemistry, molecular testing, clinical context, and imaging findings rather than relying on isolated genetic or immunohistochemical markers. This represents the first reported instance of DDLPS with MLPS-like morphology accompanied by MDM2 and DDIT3 co-amplification and concurrent STAT6 nuclear expression.