Dedifferentiated Liposarcoma

The American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) TNM staging systems can be applied.

DDLPS shares genetic similarities with ALT/WDLPS, both characterized by amplification of the MDM2 and CDK4 genes. Similar to ALT/WDLPS, other genes from the 12q13-q21 region and other chromosomal regions are variably co-amplified with MDM2. These amplicons are situated on supernumerary ring or giant marker chromosomes with neocentromeres. Certain genomic features seem to be more frequently associated with DDLPS histology, though not exclusive to it: amplification of JUN, TERT, CPM, MAP3K5, and other genes from the 6q21-q24 region. The karyotypes (chromosome arrangements) and quantitative genomic profiles of DDLPS tend to be more complex than those of ALT/WDLPS. DDLPS shows ATRX deletion in 30% of cases. In DDLPS, loss of 11q22-q24 (carrying several genes, e.g., ATM, CHEK1, ZBTB16, PPP2R1B, and EI24) is linked to genomic complexity. In contrast to their high copy-number variations, DDLPSs have a low rate of mutations.

DDLPS typically appears as large, multinodular, yellow masses containing distinct, solid, often tan-gray non-fatty (dedifferentiated) areas. These dedifferentiated areas may show necrosis (tissue death). The transition between the fatty and dedifferentiated areas can sometimes be gradual.

The key characteristic of DDLPS is the transition from ALT/WDLPS to a non-fatty sarcoma, usually high-grade. The extent of dedifferentiation varies. The transition is typically abrupt, but in some cases, it can be more gradual, and rarely, low- and high-grade areas may appear intermingled. Sometimes, a well-differentiated fatty component is difficult to identify. Dedifferentiated areas display diverse histological patterns, most often resembling undifferentiated pleomorphic sarcoma or intermediate- to high-grade myxofibrosarcoma. Although dedifferentiation was initially defined by high-grade morphology, cases with low-grade dedifferentiation are increasingly recognized. Low-grade dedifferentiation is characterized by the presence of uniform spindle-shaped cells with mild nuclear atypia, often arranged in a fascicular pattern and exhibiting cellularity between well-differentiated sclerosing liposarcoma and usual high-grade areas. Low-grade DDLPS should not be confused with atypical spindle cell lipomatous tumors, as the latter contain atypical fat cells or lipoblasts, whereas dedifferentiated areas, both low- and high-grade, are generally non-fatty. Low-grade DDLPS is virtually indistinguishable from cellular WDLPS. DDLPS may exhibit heterologous differentiation (differentiation into tissues not normally found in that location) in about 5-10% of cases. The most common line of heterologous differentiation is muscle or bone/cartilage, but blood vessel (angiosarcomatous) elements have also been reported. A unique neural-like or meningothelial-like whorling pattern of dedifferentiation has been described, often associated with bone formation. Local recurrences of DDLPS may be entirely well-differentiated.

Occasionally, the high-grade component may show overt fat cell differentiation, either as scattered lipoblasts or as sheets of atypical pleomorphic fat cells, making these areas indistinguishable from pleomorphic liposarcoma. This phenomenon is called homologous lipoblastic differentiation or pleomorphic liposarcoma-like features. Solitary fibrous tumor-like and inflammatory myofibroblastic tumor-like morphology can rarely be observed. The primary role of immunohistochemistry (using antibodies to detect specific proteins) is to confirm divergent differentiation and rule out other tumor types. Diffuse nuclear expression of MDM2 and/or CDK4 is almost always seen and helps differentiate homologous DDLPS from pleomorphic liposarcoma.

There are few reports, but cytology (examination of cells under a microscope) is likely challenging.

DDLPS is characterized by local recurrence in at least 40% of cases. However, almost all retroperitoneal cases seem to recur locally if patients are followed for 10-20 years. Distant metastases (spread to other parts of the body) are observed in 15-20% of cases, with an overall mortality rate of 28-30% at 5-year follow-up, although this figure is likely much higher at 10-20 years. The most important prognostic factor is anatomical location, with retroperitoneal lesions having the worst clinical behavior. The extent of dedifferentiated areas does not appear to predict outcome. Despite its high-grade morphology, DDLPS has a less aggressive clinical course than other types of high-grade pleomorphic sarcoma, and an accelerated clinical course is seen in only a minority of patients. Recent data suggest a prognostic difference based on grading when the French Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system is used. Moreover, contrary to previous observations, muscle differentiation (particularly rhabdomyoblastic differentiation) appears to be associated with a worse outcome. Multivisceral resections (removal of multiple organs) seem to improve relapse-free survival.

Detecting MDM2 amplification by FISH (fluorescence in situ hybridization), multiplex ligation-dependent probe amplification, and array comparative genomic hybridization helps distinguish DDLPS from other undifferentiated sarcomas in the appropriate clinical context.

Essential: Transition (abrupt or gradual) from WDLPS (of any type) to a spindle cell and pleomorphic non-fatty (rarely fatty) tumor (of low or high grade).

Desirable (in selected cases): Expression of MDM2 or demonstration of MDM2 gene amplification.