Myxoid Variant of Well-Differentiated Liposarcoma
University of California
San Francisco, CA
A 65 year old woman with vague abdominal discomfort was found to have a 10 cm tumor of the
retroperitoneum. The tumor was resected.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The specimen consisted of an approximately 10 cm relatively well-defined mass with fatty, myxoid and
cystic components. Areas of hemorrhage and possible necrosis were noted grossly (Figure 1).
At low magnification, the tumor consisted of abundant myxoid stroma and a moderately cellular
spindle-cell proliferation. In some areas (Figure 2) the stroma formed pools reminiscent of a so-called
"pulmonary edema" pattern.
At higher magnification, immature adipocytes (lipoblasts) were admixed with more primitive appearing
spindle cells. Some of the lipoblasts showed a small lipid vacuole with an eccentric, scalloped
hyperchromatic nucleus suggesting a signet-ring type of morphology (Figure 3).
However, further inspection showed transitional areas (Figure 4) where the small signet ring-like
lipoblasts contrasted with more cellular pleomorphism. At higher magnification, the latter areas (Figure
5) consisted of pleomorphic spindle cells and lipoblasts with large, bizarre and hyperchromatic nuclei.
The tumor cells showed nuclear staining with CDK4 and MDM2 in all areas (Figure 6) as well as
amplification of 12q13-15 (Figure 7)
Gross examination demonstrates a fatty and myxoid neoplasm with areas of hemorrhage.
Low magnification shows myxoid matrix and areas of cyst formation reminiscent of a so-called "pulmonary edema" pattern.
Some areas of tumor demonstrate immature fat cells (lipoblasts), a subset of which are reminiscent of signet ring cells.
A transitional area of the tumor shows juxtaposition of myxoid areas with small lipoblasts to cells with higher grade cytomorphology.
Higher grade areas have more fibrous stroma and striking nuclear pleomorphism, yet retain adipocytic differentiation
Tumor cells show nuclear positivity with antibodies to CDK4 and MDM2
The tumor shows high level amplification of chromosome region 12q13-15 by array comparative genomic hybridization
The differential diagnosis includes:
- Myxoid / round cell liposarcoma
- Myxoid / round
cell liposarcoma with dedifferentiation
- Myxoid variant of
- Mixed type liposarcoma (collision
Myxoid variant of well-differentiated liposarcoma
Summary of adipocyte differentiation
Our understanding of adipocyte differentiation from mesenchymal progenitor cells derives
from culture data using 3T3-L1 cells.  In a markedly simplified paradigm, increased p53
and Rb activity cause cell cycle arrest followed by increased levels of CCAAT/enhancer-binding protein
beta (CEBPβ) and CEBPγ . These transcription factors, in turn, induce increased levels of CEBPα and
peroxisome proliferator gamma (PPARγ) triggering a feedback loop between the latter two transcription
factors. PPARγ , especially, is a master regulator of adipocyte genes such as lipoprotein lipase (LPL),
leptin, adipsin and fatty acid synthase.
Differential diagnosis and workup of liposarcomas
Liposarcomas are classified into three major clinicopathologic families:
|Liposarcoma group ||Genetics|
|Well-differentiated / dedifferentiated ||Amp 12q13-15|
|Myxoid / round cell ||t(12;16) FUS;DDIT3 |
The above families of tumors not only differ in clinically and histologically, but also in
genetically. Our growing understanding of the genetic abnormalities conserved between liposarcoma
subtypes has lead to insights into the pathogenesis of these tumors. Although no established targeted
therapy yet exists for liposarcomas, continued efforts to dissect the molecular pathogenesis of these
tumors may ultimately lead to effective anticancer drugs. The discussion below focuses on the
well-differentiated and myxoid families of liposarcomas because these have been best characterized at the
molecular and genetic level.
The accurate diagnosis of liposarcoma subtype is clinically
important. Whereas well-differentiated liposarcomas essentially never metastasize, their
dedifferentiated counterparts as well as myxoid and pleomorphic liposarcomas carry substantial metastatic
risk. Consequently, systemic chemotherapy has little role in the treatment of well-differentiated
In most cases, H&E findings are adequate to distinguish between liposarcoma types. In
classic examples, well-differentiated liposarcoma consist of adipose tissue with variability of adipocyte
size, prominent fibrous septae containing fine, almost powdery, collagen and cytologically atypical
spindle cells and atypical adipocytes. The atypia is characterized by nuclear hyperchromasia and in some
cases, larger cells with multilobed nuclei. Mitotic activity, necrosis and most importantly, lipoblasts,
are not required for the diagnosis. De-differentiated liposarcoma is defined by the presence of two
components: well-differentiated liposarcoma and a second, macroscopic, mesenchymal component that lackslipogenic differentiation. Most commonly, both
components are present at the time of initial diagnosis, but in about 10% of cases the non-lipogenic
component presents years after the diagnosis of well-differentiated liposarcoma. The non-lipogenic
component may be a high grade undifferentiated sarcoma (so-called "MFH"), or have heterologous areas
including osteosarcoma, chondrosarcoma or rhabdomyosarcoma.
The hallmark of myxoid liposarcoma is a reticular pattern of delicate capillaries
(so-called chicken wire pattern) in a myxoid matrix. The cellular component consists of variable
amounts of short spindle cells with bland nuclei and small, immature adipocytes (so-called signet-ring
lipoblasts). The atypical spindle cells and large adipocytes of
well-differentiated liposarcoma are notably absent. Round cell areas, typically at the edges of
tumor lobules, are sufficiently dense to have cell-cell contact or even overlap. The cells are round to
oval, epithelioid, have amphophilic cytoplasm, central round nuclei sometimes with obvious nucleoli, lack
lipid vacuoles but retain the chicken wire vasculature. The metastatic potential of this family of
tumors ranges from 20% (Grade I) to 75% (Grade III) based on the proportion of round-cell component.
Recent data indicates that any round cell area (even 1%)
may confer a worse prognosis. 
Genetic abnormalities and molecular pathogenesis
As previously mentioned, the well-differentiated - dedifferentiated liposarcoma family of
tumors share high level amplification of chromosome subregion 12q13-15. Furthermore, this amplification
is highly sensitive and specific for well-differentiated and dedifferentiated liposarcoma.
The 12q13-15 region is ~10Mb long and encompasses important cell cycle regulatory
genes (CDK4 and MDM2) and a gene involved in
adipocyte differentiation (HMGA2). In most cases, the region actually
encompasses two discontinuous amplicons, one incorporating CDK4 and the
The amplification of 12q13-15 can be
detected by cytogenetics, fluorescence in-situ hybridization (FISH) or comparative genomic
hybridization. Immunohistochemical detection of CDK4 and MDM2 protein overexpression is a highly
sensitive and specific surrogate to molecular methods.
Though these regulatory
proteins have diverse functions, at the simplest level, increased levels of CDK4 and MDMD2 cause
down-regulation of Rb and p53, respectively. Therefore, increased CDK4 and MDM2 promote cell
proliferation and survival.
Dedifferentiated liposarcomas show 12q13-15 amplification but, in addition, have more
total amplifications than their well-differentiated counterparts. However,
no genetic changes uniformly distinguish between these entities.  Through diverse
mechanisms, a general increase of AP-1 signaling pathways (through increased C-JUN, ASK-1 and FOS-B)
is more common in dedifferentiated tumors.
Elevated AP-1 transcription factor
activity, in turn, may have an inhibitory effect on adipocyte differentiation by inhibiting both CEBP and
In contrast, myxoid / round cell liposarcomas uniformly lack 12q13-15 amplification.
Rather, these tumors demonstrate t(12;16) or t(12;22) translocations in most cases, resulting in the
FUS:DDIT3 or EWS:DDIT3 gene fusions,
respectively (in earlier reports, FUS is also known as TLS while DDIT3 is also known as CHOP). In the more common translocation, the N-terminal transactivation domain of
FUS is joined to DDIT3, the latter is also a member of the CEBP family of transcription factors. The
FUS:DDIT3 fusion product may inhibit adipogenesis by interfering with CEBPβ
and PPAR-γ activity based on in vitro and transgenic mouse studies.
Of course, this is probably an oversimplified mechanism and other signaling pathways,
(e.g. NF kB)
may be involved. 
What about mixed type liposarcoma?
As mentioned above, conventional well-differentiated liposarcoma may have myxoid areas,
particularly in the retroperitoneum. Further complicating the diagnosis, myxoid areas of
well-differentiated liposarcoma may also demonstrate a branching vascular pattern although the vessels
tend to be of larger caliber than in true myxoid / round cell liposarcoma.
In the past, such retroperitoneal tumors may have been classified as so-called "mixed type liposarcoma"
(implying both well-differentiated and myxoid / round cell differentiation) but amplification of 12q13-15
and FUS:DDIT3 translocations appear to be mutually exclusive arguing against this possibility.
Furthermore, genetic and clinicopathologic data suggests that true myxoid liposarcoma is
exceedingly rare, possibly nonexistent, in the retroperitoneum.  The distinction between
well-differentiated and myxoid liposarcoma is very significant because the latter has metastatic
potential but is also more chemo- and radiosensitive.
Review of the Literature/Treatment Options:
From biology to Treatments
The mainstay of therapy for localized liposarcoma is surgery alone or in combination with radiation
therapy. In patients with unresectable, recurrent or metastatic disease, conventional cytotoxic
chemotherapy with Adriamycin and ifosphamide based regimens may be used. However, two additional
"targeted" modalities, nuclear receptor ligands and Trabectedin, deserve mention.
Nuclear receptor ligands
As discussed above, PPAR-γ is a transcription factor in the nuclear receptor family that
promotes transcription of multiple adipocyte-specific genes. PPAR-γ binds to DNA as a heterodimer with
the retinoid X receptor (RXR) and activates transcription. PPAR-γ is expressed in benign adipose tissue
and all liposarcoma subtypes.  PPAR-γ binds to the thiazolidinedione class of
antidiabetic drugs and terminal adipocyte differentiation can be induced in myxoid/round cell and
well-differentiated liposarcomas by thiazolidenediones.
An initial phase II study of
3 patients with liposarcoma treated with troglitazone showed morphologic and gene expression changes
suggesting tumor differentiation.  Unfortunately, a second phase II study of nine patients
with advanced liposarcoma treated with rosiglitazone did not demonstrate morphologic or gene expression
evidence of differentiation.  It is important to recognize that such therapies may not be
expected to shrink tumors, since differentiation and accumulation of intracellular lipid may actually
cause tumors to grow clinically and a decrease in proliferation rate may be difficult to measure in
liposarcomas that often have a low proliferative fraction at baseline. Nevertheless, the reasons for the
discrepancy between the two studies is unknown but may be related to the tumors, agent used or patients.
Stimulation of RXRα with the specific ligand LG268 can also trigger terminal
differentiation in vitro
 but, to date, no clinical trials have
investigated the utility of combined RXRα -PPARγ therapy in liposarcoma.
Trabectedin (Yondelis, ET-743) is a relatively novel agent derived from the sea squirt Ecteinascidia turbinata and preclinical studies have shown antitumor effects
against a number of solid tumors including sarcomas.  The suggested mechanisms of action
include site specific DNA damage and transcriptional interference. In vitro evidence suggests that
Trabectedin promotes differentiation in myxoid liposarcomas by blocking the effects of the FUS:DDIT3
chimeric protein and allowing activation of the CEBPs. Myxoid/ round cell liposarcomas show particular
sensitivity to Trabectedin and long term efficacy in a retrospective study. 
Interestingly, both the clinical and in vitro effects are selective for a
subset of FUS:DDIT3 fusions (the shorter, type 1 and 2 fusions).
 The efficacy of this
novel agent in other liposarcoma types remains to be established.
- Understanding of adipocyte differentiation
has given insight into the mechanisms of tumorigenesis in liposarcoma.
- The mainstay of liposarcoma therapy is
surgery, but the decision to use adjuvant therapy requires accurate tumor classification.
- Novel agents targeting nuclear receptors
(PPAR-γ, RXR) or FUS:DDIT3 show some promise for future study.
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