Biology and Management of Dedifferentiated Liposarcoma: State of the Art and Perspectives

Abstract

Dedifferentiated liposarcoma (DDL) is defined as the transition from well-differentiated liposarcoma (WDL)/atypical lipomatous tumor (ALT) to non-lipogenic sarcoma, which arises mostly in the retroperitoneum and deep soft tissue of proximal extremities. It is characterized by a supernumerary ring and giant marker chromosomes, both of which contain amplified sequences of 12q13-15 including murinedouble minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) cell cycle oncogenes. Detection of MDM2 (and/or CDK4) amplification serves to distinguish DDL from other undifferentiated sarcomas. Recently, CTDSP1/2-DNM3OS fusion genes have been identified in a subset of DDL. However, the genetic events associated with dedifferentiation of WDL/ALT remain to be clarified. The standard treatment for localized DDL is surgery, with or without radiotherapy. In advanced disease, the standard first-line therapy is an anthracycline-based regimen, with either single-agent anthracycline or anthracycline in combination with the alkylating agent ifosfamide. Unfortunately, this regimen has not necessarily led to a satisfactory clinical outcome. Recent advances in the understanding of the pathogenesis of DDL may allow for the development of more-effective innovative therapeutic strategies. This review provides an overview of the current knowledge on the clinical presentation, pathogenesis, histopathology and treatment of DDL.

Keywords: atypical lipomatous tumor; dedifferentiated liposarcoma; diagnosis; pathogenesis; treatment; well-differentiated liposarcoma.

Figure 1

Magnetic resonance imaging of dedifferentiated liposarcoma in the right thigh of an 83-year-old woman. Axial T1-weighted (A) and T2-weighted spectral presaturation with inversion recovery (B) sequences display a large soft tissue mass composed of non-lipomatous (white and black asterisks) and juxtaposed lipomatous components.

Figure 2

Giant marker chromosome in dedifferentiated liposarcoma. Spectral karyotyping demonstrates that the giant marker (arrow) is mainly composed of material from the X chromosome.

Figure 3

Cut surface showing a multilobulated appearance with gray-white and yellow areas.

Figure 4

Histopathology of dedifferentiated liposarcoma. (A) Abrupt transition from well-differentiated liposarcoma (WDL)/atypical lipomatous tumor (ALT) to high-grade non-lipogenic sarcoma is seen. (B) Multivacuolated lipoblast can be seen in the WDL/ALT area. (C) The dedifferentiated component consists of atypical spindle cells, round to polygonal cells and bizarre giant cells, resembling myxofibrosarcoma. (D) MDM2 expression in the dedifferentiated area.

Figure 5

Interphase fluorescence in situ hybridization analysis using probes for MDM2 (red signals) and centromere of chromosome 12 (green signals) showing high-level amplification of MDM2.