Clinical and Molecular Spectrum of Liposarcoma

Abstract

Liposarcomas are rare malignant tumors of adipocytic differentiation. The classification of liposarcomas into four principal subtypes reflects the distinct clinical behavior, treatment sensitivity, and underlying biology encompassed by these diseases. Increasingly, clinical management decisions and the development of investigational therapeutics are informed by an improved understanding of subtype-specific molecular pathology. Well-differentiated liposarcoma is the most common subtype and is associated with indolent behavior, local recurrence, and insensitivity to radiotherapy and chemotherapy. Dedifferentiated liposarcoma represents focal progression of well-differentiated disease into a more aggressive, metastasizing, and fatal malignancy. Both of these subtypes are characterized by recurrent amplifications within chromosome 12, resulting in the overexpression of disease-driving genes that have been the focus of therapeutic targeting. Myxoid liposarcoma is characterized by a pathognomonic chromosomal translocation that results in an oncogenic fusion protein, whereas pleomorphic liposarcoma is a karyotypically complex and especially poor-prognosis subtype that accounts for less than 10% of liposarcoma diagnoses. A range of novel pharmaceutical agents that aim to target liposarcoma-specific biology are under active investigation and offer hope of adding to the limited available treatment options for recurrent or inoperable disease.

Fig 1.

Radiologic appearance of retroperitoneal well-differentiated/dedifferentiated liposarcoma. Sagittal and coronal precontrast computed tomography images of a large liposarcoma expanding the retroperitoneum and encasing and displacing the left kidney. The blue arrow denotes a well-differentiated tumor, which shares a similar appearance to normal fat, extending inferiorly to the pelvic brim. The red arrow denotes a complex, ill-defined solid component of mixed attenuation, representing an area of dedifferentiated disease superior to left kidney.

Fig 2.

Histologic appearance of liposarcoma subtypes. (A) Hematoxylin and eosin stain of well-differentiated liposarcoma (× 40). Tumor is composed of mature adipocytes in normal adipose tissue prominently intersected by sparsely cellular fibrous septa containing atypical, enlarged spindle cells with hyperchromatic nuclei. (B) Dedifferentiated liposarcoma (× 200). Hematoxylin and eosin stain illustrates typical appearance of dedifferentiated component as a high-grade spindle or pleomorphic sarcoma, with sheets of moderately atypical spindle cells with scattered mitotic figures and no apparent adipocytic differentiation. (C) Immunohistochemistry staining of dedifferentiated liposarcoma (× 40) shows diffuse and strong expression of CDK4, frequently coamplified with MDM2 in well-differentiated and dedifferentiated liposarcoma. (D) Myxoid liposarcoma (× 200). Relatively bland and uniform appearance, with small ovoid or spindle cells dispersed in prominent myxoid stroma alongside plexiform network of curvilinear, thin-walled blood vessels. In many areas, small lipoblasts with nuclear indentation and vacuolated cytoplasm are identifiable (arrows). (E) Round cell variant of myxoid liposarcoma (× 40). Markedly cellular distribution of round and ovoid cells containing rounded, hyperchromatic nuclei and minimal, largely amphophilic cytoplasm. As in this example, the absence of discernible myxoid stroma can lead to round cell myxoid liposarcoma being mistaken for other round cell neoplasms such as Ewing sarcoma. (F) Pleomorphic liposarcoma (× 200). Large, atypical multivacuolated lipoblasts with indented hyperchromatic nuclei are dispersed in a background of atypical spindle cells.

Fig 3.

Radiologic appearance of myxoid liposarcoma of the proximal thigh. (A) Coronal T2-weighted magnetic resonance image of 80-mm tumor (arrow) with characteristic high signal intensity. T1-weighted fat-suppressed axial magnetic resonance images of (B) pregadolinium and (C) postgadolinium contrast show avid and heterogeneous enhancement of tumor (arrow).