Bone & Soft Tissue Pathology
Case 5 -
Dedifferentiated Liposarcoma with Divergent Rhabdomyosarcomatous Differentiation
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A 62-year-old man presented with a 15 cm tumor developed in
the retroperitoneum with involvement of the small intestine
This tumor had been resected in 1992 with a portion of the small intestine.
Case 5 - Slide 1
Case 5 - Figure 1 - The tumor seemed to be well demarcated but with adhesion to the deep part of the small intestine.
Case 5 - Figure 2 - The adjacent tissue was composed of mature adipocytes arranged in lobules separated by thick fibrous septa.
Case 5 - Figure 3 - The tumor was composed of spindle and pleomorphic eosinophilic cells arranged in fascicles.
Case 5 - Figure 4 - The tumor cells tended to have an abundant eosinophilic cytoplasm with racket-like contours.
Case 5 - Figure 5 - These tumor cells showed a wide range of cell shapes from globular to tadpole-like, with atypical nuclei and mitoses.
Case 5 - Figure 6 - These tumor cells showed a wide range of cell shapes from globular to tadpole-like, with atypical nuclei and mitoses.
Case 5 - Figure 7 - A few atypical, hyperchromatic cells were visible in the fibrous septa separating adjacent adipocytic tissue.
Case 5 - Figure 8 - A few atypical, hyperchromatic cells were visible in the fibrous septa separating adjacent adipocytic tissue.
Case 5 - Figure 9 - The tumor cells were diffusely and strongly positive for desmin. At that time, the diagnosis was pleomorphic rhabdomyosarcoma.
Clinical Follow-up and Complementary Techniques
A local recurrence occurred 6 years later with multiple nodules involving the retroperitoneum, small
and large bowels, the bladder and abdominal wall. The tumor was partly resected but the patient died 5
The resected tumor was similar to the primary and showed areas of poorly differentiated spindle cell
sarcoma, pleomorphic rhabdomyosarcoma and large areas of sclerosing liposarcoma.
Immunohistochemistry showed positivity of tumor cells for desmin, myogenin, MDM2 and CDK4 on both
primary and recurrent tumors. MDM2 and CDK4 were also positive on some atypical cells seen in the
sclerosing liposarcomatous component.
FISH and Q-PCR showed a large amplification of MDM2 and CDK4.
CGH-array showed a rather simple DNA profile with amplifications of 12q13-14 including MDM2, CDK4 and MYF genes
and 1p32 including JUN gene.
Dedifferentiated liposarcoma with divergent rhabdomyosarcomatous differentiation.
Dedifferentiated liposarcoma is a term first introduced by Evans in 1979  to describe liposarcomas
containing a mixture of well differentiated and poorly differentiated areas either within the same
primary tumor or in the recurrence or metastasis. It is considered as a malignant adipocytic tumor
showing progression from atypical lipomatous tumor/well differentiated liposarcoma to non-lipogenic
sarcoma of variable grade. About 90% of dedifferentiated liposarcomas arise de novo while 10% occur in
recurrences. The risk of dedifferentiation is higher in deep seated tumors, particularly in the
retroperitoneum, and is probably a time-dependent phenomenon . Numerous reports have supported the
concept of dedifferentiated liposarcomas with two series of 32 and 155 cases
It represented 18%
of liposarcomas in a recent large series .
Tumors occurred in late adult life with no sex predilection, most commonly in the retroperitoneum (2/3
of cases), extremities, spermatic cord and trunk. Occurrence in head and neck and in subcutaneous tissue
is rare. In our experience, 60% of retroperitoneal sarcomas are liposarcomas, half of which are
Dedifferentiated liposarcoma usually presents as a large painless mass, with a median size of 20 cm in
the retroperitoneum. Radiological imaging may suggest the diagnosis by showing the coexistence of a
fatty component with a non-fatty solid one. Prognosis of dedifferentiated liposarcoma is mainly
dominated by local recurrences (40 to 60%), particularly in the retroperitoneum, with a quite low
metastatic potential (15 to 20%). The most important prognostic factor is location with a poor prognosis
for retroperitoneal tumors. Neither histological grade nor extent of dedifferentiation is of prognostic
The gross appearance of dedifferentiated liposarcoma is often helpful for the diagnosis. It usually
consists of multinodular yellow (fatty) masses containing firm tan-gray areas corresponding to
dedifferentiated foci. Necrosis is often observed.
Histologically, dedifferentiated liposarcoma is defined by the association of atypical lipomatous
tumor/well-differentiated liposarcoma areas and a non-lipogenic sarcoma, usually with an abrupt
transition between the two components. Dedifferentiated areas exhibit a wide morphological spectrum.
Most cases show areas of high grade sarcoma resembling pleomorphic MFH, myxofibrosarcoma, fibrosarcoma or
malignant hemangiopericytoma. Low grade dedifferentiation resembling low grade myxofibrosarcoma,
well-differentiated fibrosarcoma or fibromatosis is the only dedifferentiated component in about 10% of
cases . A "meningothelial-like" whorling pattern of dedifferentiation often associated with
ossification has been described
In about 5 to 10% cases, the dedifferentiated component is a
divergent differentiation with myogenic or osteo-chondrosarcomatous elements. An angiosarcomatous
component has also been reported. Myosarcomatous differentiation is the most frequent
but must be
established with both morphological features and immunohistochemical profile, and specific muscle markers
such as h-caldesmon and myogenic should be used. We recently reviewed a series of sarcomas with a
myogenic differentiation developed in the internal trunk for which initial diagnoses were leiomyosarcoma,
pleomorphic rhabdomyosarcoma, malignant mesenchymoma and dedifferentiated liposarcoma with divergent
myosarcomatous differentiation, and showed that most pleomorphic rhabdomyosarcomas and malignant
mesenchymomas were actually dedifferentiated liposarcomas with a myogenic differentiation. Moreover,
dedifferentiated liposarcomas with a myogenic component had a low metastatic potential, similar to
conventional dedifferentiated liposarcomas and significantly lower than the metastatic potential of
Contrary to this histological complexity, the genomic profile of dedifferentiated liposarcoma is
relatively simple and uniform. Cytogenetics shows ring and giant chromosomes with a normal karyotype in
As shown by CGH techniques, these ring and giant markers are composed of
amplified sequences of the 12q13-14 chromosome region. This amplicon is mainly composed of MDM2 and CDK4 genes . This basic profile is
similar to that observed in atypical lipomatous tumor/well differentiated
liposarcoma. MDM2 inhibits P53 and therefore decreases apoptosis and tends to increase cell
survival. CDK4 phosphorylates Rb gene product, which no longer interacts
with E2F transcription factors, and the cell cycle proceeds through the G1-S checkpoint. In summary, the
biological consequence of the 12q13-14 amplicon is both to decrease apoptosis and to increase cell
proliferation. In addition to this amplicon, dedifferentiated liposarcomas also usually show
coamplification of chromosomes 1 or 6. The two most frequent coamplifications are located on 1p32 and
6q23 chromosome regions. These amplifications are exclusive and never seen together in the same tumor.
Characterization by CGH-array of the minimal region of amplification shows that the target genes are
JUN in the 1p32 band and ASK1 in the 6q23 band.
ASK1 is a MAP3 kinase involved in the JNK signaling pathway .
Amplification and overexpression of ASK1 activates JNK, which phosphorylates
different target proteins, leading to the activation of some proteins including JUN and inactivation of
other proteins, in particular PPAR gamma. It has been demonstrated that PPAR gamma plays a key role in
adipocytic differentiation, and therefore, amplification of ASK1 gene
inhibits adipocytic differentiation. JUN is an oncogene which also inhibits
PPAR gamma via C/EBP beta. Therefore, dedifferentiation in liposarcoma may be explained by amplification
and overexpression of ASK1 or JUN genes. In
summary, amplification of MDM2 and CDK4, which
are seen in both atypical lipomatous tumor/well differentiated liposarcoma and dedifferentiated
liposarcoma, may be responsible for the malignant tumor process, whereas amplification of other genes
such as ASK1 and JUN may explain inhibition of
adipocytic differentiation in dedifferentiated liposarcomas.
Re-evaluation of retroperitoneal sarcomas in adults as well as these molecular data make it possible
to formulate criteria for the diagnosis of dedifferentiated liposarcomas: 1- any poorly differentiated
sarcomas including so-called pleomorphic MFH, fibrosarcomas, malignant hemangiopericytomas,
and inflammatory MFH  as well as pleomorphic rhabdomyosarcomas and malignant
mesenchymomas  developed in the retroperitoneal or in paratesticular areas are most likely
dedifferentiated liposarcomas; 2- the best criterion for the diagnosis is the presence of an atypical
lipomatous tumor/well differentiated liposarcoma area, so the clue is to sample and carefully examine the
surrounding adipocytic tissues; 3- in some cases, this well differentiated component is missing and
molecular abnormalities may be useful. CGH-array, which shows a simple DNA profile with MDM2 and CDK4 amplifications in association with one
or a few coamplifications, is the most specific technique, and could be the gold standard in the next
years; 4- at present, immunohistochemistry is a useful tool for daily practice, provided one uses the
proper antibodies: IF2 clone for MDM2 and DCS-31 for CDK4 .
For problematic cases, Q-PCR  and
especially FISH are reproducible and can be used on formalin fixed paraffin-embedded tissues. In our
experience, MDM2 amplification is constant in dedifferentiated liposarcomas
and CDK4 amplification is present in 90% of cases. These amplifications are
not seen in benign lipomatous tumors and are rare in other sarcomas.
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