Bone & Soft Tissue Pathology
Case 1 -
Myxoid Liposarcoma with Hypercellular (Transitional) Areas
John R. Goldblum, Cleveland Clinic, Cleveland, OH
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49-year-old female with a 7-cm posterior thigh mass
Case 1 - Slide 1
Case 1 - Slide 2
This is a well-circumscribed neoplasm with a distinctly nodular growth pattern. At very low power,
one can appreciate less cellular, lighter staining myxoid zones alternating with more cellular darker
staining zones. The latter areas comprise the minority of the neoplasm, however. The less cellular
myxoid zones are comprised of spindled cells with minimal cytologic atypia deposited in an abundant
myxoid stroma. Many of the cells have eccentrically located scalloped nuclei with large cytoplasmic
vacuoles resembling lipoblasts. In some areas, a prominent plexiform "chicken wire" vascular pattern can
be appreciated. The darker staining areas show a proliferation of cells with an ovoid to round cell
morphology and higher-grade nuclear atypia. Myxoid stroma can still be seen between these cells, and in
some areas, the arborizing vascular pattern can still be appreciated, although it is less conspicuous.
Scattered mitotic figures can be identified and are generally more prominent in the more cellular zones.
The differential diagnosis includes a variety of myxoid sarcomas, including myxofibrosarcoma,
extraskeletal myxoid chondrosarcoma and myxoid liposarcoma. Another consideration might include a
well-differentiated liposarcoma with areas of dedifferentiation resembling myxofibrosarcoma.
Myxoid Liposarcoma with Hypercellular (Transitional) Areas
The pathologist need not panic when one encounters a myxoid soft tissue lesion. In general, these
entities can be separated from one another when one pays close attention to certain morphologic features
when evaluating such lesions. Immunohistochemical stains (aside from S100 protein) generally play little
role in this differential diagnosis, but more recently, molecular analyses using FISH probes to specific
genes (e.g. DDIT3, FUS, EWSR1) have become useful in the evaluation of myxoid sarcomas.
There are several benign myxoid soft tissue lesions which one might consider in this case (or in many
other myxoid soft tissue lesions). Intramuscular myxoma typically occurs in middle-aged to elderly
patients and usually presents as a painless, palpable, fluctuant mass within the deep soft tissue of the
thigh, shoulder, buttocks or upper arm, although virtually any site may be involved.  In
addition, lesions with similar histology can occur in a cutaneous and juxta-articular location. Although
usually solitary, multiple intramuscular myxomas have been found to be associated with fibrous dysplasia,
and generally occur in the same anatomic region as the bony abnormalities.  Rare patients
also display melanotic pigmentation of the skin and endocrine abnormalities (Albright syndrome). Myxomas
occurring in a cutaneous location may be sporadic or associated with Carney's complex, characterized by
an association with endocrine abnormalities, spotting pigmentation, cardiac myxomas and psammomatous
melanotic schwannoma (among other lesions), inherited in a autosomal-dominant manner.  The
juxta-articular myxoma is another variant of myxoma most commonly found in the area of the knee. 
Grossly, the intramuscular myxoma appears to be well circumscribed,
although a true fibrous capsule is not present. Histologically, these lesions characteristically are of
low cellularity, composed of bland spindled or stellate cells with cytoplasmic processes. The cells tend
not to touch one another, but rather are separated by abundant myxoid stroma composed of a hyaluronic
acid. Although some cells with vacuolated cytoplasm may be present and can resemble lipoblasts, these
are actually macrophages that have imbibed products of the myxoid stroma resulting in cytoplasmic
vacuolization. In addition, although grossly well circumscribed, there is often some infiltration into
the surrounding skeletal muscle with entrapment of atrophic skeletal muscle fibers. Although scattered
blood vessels may be present, there is relatively little vascularity, and the vascularity lacks the
organization of many myxoid sarcoma (described below). These lesions are essentially cured by local
excision and have little tendency to recur, even if incompletely excised.
Aggressive angiomyxoma typically occurs as a large, ill-defined mass
within the pelvis, perineum or genital tract in women,  although rare cases have also been
reported in men.  Histologically, aggressive angiomyxoma is composed of spindled or
stellate-shaped cells that generally do not touch one another and are separated by an abundant myxoid
stroma composed primarily of hyaluronic acid. The cells lack nuclear atypia, and mitotic figures are
difficult to identify. Mast cells are frequently prominent. In addition, these lesions are
characterized by a prominent vascularity with vessels of different caliber, including thin-walled vessels
and thick hyalinized blood vessels. Immunohistochemically, the cells often stain for desmin and estrogen
receptor. Although histologically bland, these lesions are characterized by a high rate of local
Myxofibrosarcoma (formerly referred to as myxoid MFH) is a low-grade
myxoid sarcoma that usually arises in a more superficial location, often on the upper or lower
extremities. The tumor has a nodular growth pattern and is comprised of hyperchromatic spindled or
stellate-shaped tumor cells deposited in a uniformly myxoid stroma. A characteristic vascular pattern is
typically found, with thicker-walled curvilinear blood vessels, often showing perivascular
hypercellularity. This lesion has no specific immunophenotype, nor does it show a characteristic
Also included in the differential diagnosis is low-grade fibromyxoid
sarcoma, often referred to as an Evans tumor. This lesion is deceptively bland and is composed of
spindled cells of low to moderate cellularity deposited in an alternating fibrous and myxoid stroma. The
cells often have a swirling growth pattern and occasional condense in a perivascular location.
Cytologically, there is little nuclear atypia, and mitotic figures are extremely difficult to identify.
Similar to other myxoid sarcomas, low-grade fibromyxoid sarcoma often has a rich, regular vascular
network that is useful in its distinction from a benign lesion.
cells in this neoplasm often stain for epithelial membrane antigen,  although more recently,
Doyle and colleagues described consistent expression of MUC4. 
This tumor (and the related
hyalinizing spindle cell tumor with giant rosettes) is characterized by a t(7;16) with fusion of the
CREB3L2 gene on chromosome 7 with the FUS gene
on chromosome 16. 
Mertens and colleagues reported the presence of CREB3L2-FUS fusions in 22 of 23 (96%) cases of this tumor,
they also noted rare cases of a t(11;16) involving CREB3L1-FUS fusion. We
utilize paraffin-embedded tissue for FISH, probing with a FUS breakapart
probe to confirm this difficult diagnosis.
Similar to myxoid liposarcoma, extraskeletal myxoid chondrosarcoma also
occurs primarily in the deep soft tissues of the extremities. Macroscopically, the neoplasm occurs as a
multinodular well-circumscribed mass which frequently shows large areas of hemorrhage. Histologically,
this is a lesion of moderate cellularity in which the cells tend to touch one another and are arranged in
small cords or strands. The cells show little nuclear atypia, low mitotic activity and have a moderate
amount of eosinophilic cytoplasm. The vascularity is not prominent, in contrast to that seen in myxoid
liposarcoma and myxofibrosarcoma. Immunohistochemically, these cells rarely stain for S100 protein, and
they do not express epithelial markers, unlike soft tissue myoepitheliomas, which typically co-express
both of these antigens. In addition, this tumor has been found to harbor a characteristic translocation,
t(9;22)(q22;q12) which involves a rearrangement of the EWSR1 gene on 22q12
with the NR4A3 gene on 9q22. 
Less commonly, a t(9;17) can be
detected. Unfortunately, a commercially available probe for NR4A3 is not
available and, as such, we currently use FISH to detect aberrations of EWSR1, which is only found in approximately 60-70% of such cases.
The diagnosis in the current case is myxoid liposarcoma, the second most
common subtype of liposarcoma. This is a tumor of adult life and typically occurs in the deep soft
tissues of the extremities, especially the thigh and popliteal fossa. At low magnification, the most
striking feature is the very characteristic delicate plexiform capillary pattern that is found throughout
the neoplasm. The spindled cells between the capillaries are primitive mesenchymal cells and vary little
from one another without significant nuclear atypia. The cells are evenly distributed and typically do
not touch one another. Interspersed between the primitive mesenchymal cells are the diagnostic
lipoblasts, which occur in varying numbers.
Round cell liposarcoma is considered to be the poorly differentiated form
of myxoid liposarcoma. It is not uncommon to see mixtures of both myxoid and round liposarcoma within
the same tumor. Furthermore, the characteristic translocation found in myxoid liposarcoma,
t(12;16)(q13;p11), is also found in round cell liposarcoma.
 At the molecular level, this
translocation results in fusion of the DDIT3 (formerly known as the CHOP gene) on 12q13 with the FUS gene on 6p11. Less
often, the DDIT3 gene is fused to the N-terminal portion of the EWSR1 gene [t(12;22)(q13;q12)].
A number of studies have found that round cell progression results in a tumor which is much more
likely to pursue a more aggressive clinical course.
For example, Smith et al studied 29
cases of myxoid/round cell liposarcoma of the extremities and found that those patients whose tumors had
>5% round cell component were more likely to develop metastases or died from their disease. 
Similarly, Antonescu and colleagues found a 5% cut off to be of prognostic significance. 
This is in contrast to that found by Kilpatrick et al, who found a cut off point of 25% round
cell component to be prognostically significant by multivariate analysis. 
Part of the problem in the current case is where to establish the cut off for round cell liposarcoma.
In many of the aforementioned studies, a precise definition of round cell liposarcoma was not provided.
In the study by Smith et al, round cell areas were strictly defined as those areas with a marked increase
in cellularity in which the cells were round and separated by little or no myxoid stroma. 
In these areas, the mitotic index was increased, and the plexiform vascular pattern was difficult to
recognize secondary to the overgrowth of primitive round cells. Interestingly, in that study, the
authors made a point of defining "transitional zones," defined as areas of increased cellularity compared
to typical myxoid liposarcoma, but lacking all of the necessary diagnostic features of round cell
liposarcoma mentioned above. Although they had few cases of this type, these hypercellular zones were
not found to significantly worsen clinical outcome in the absence of a round cell component. We are
currently engaged in a study which is attempting to assess these transitional and round cell zones in a
semiquantitative manner in order to more precisely define diagnostic criteria and the impact of such
areas on prognosis. In the absence of more definitive data, however, we refer to a case such as the
current case as myxoid liposarcoma with hypercellular (transitional) zones, and we typically upgrade such
lesions to grade 2/3.
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