REVIEW ARTICLE

Liposarcoma: New Entities and Evolving Concepts

Angelo P. Dei Tos, MD

Liposarcoma is the most common soft tissue sarcoma and accounts for approxi-
mately 20% of all mesenchymal malignancies. In the last decade, the results of
several studies have led to the delineation of new variants as well as to the
introduction of new concepts, mainly as a result of the fruitful interactions
between genetics and pathology. Spindle cell liposarcoma represents an uncommon
variant of well-differentiated liposarcoma. It tends to occur in adults and often
involves the subcutaneous soft tissue. However, from the observation of a larger
number of cases, the anatomic distribution of spindle cell liposarcoma seems to be
comparable to that of the other well-differentiated liposarcoma subtypes. Spindle
cell liposarcoma tends to recur locally and may dedifferentiate. Morphologically it
is composed of a fairly bland neural-like spindle cell proliferation set in a fibrous
and/or myxoid background and is associated with an atypical lipomatous compo-
nent. Great debate has been generated by the introduction of the term atypical
lipoma to emphasize the fact that well-differentiated liposarcoma shows risk of
local recurrence but no potential for metastasis. In our opinion well-differentiated
liposarcoma and atypical lipoma should be considered synonyms that describe
lesions identical both morphologically and kayotypically. Dedifferentiated liposar-
coma is a distinct type of liposarcoma in which transition from low-grade to
high-grade nonlipogenic morphology within a well-differentiated liposarcoma is
observed. The transition usually occurs in an abrupt fashion; however, in rare
cases it can be more gradual. Recently, it also has been proposed that dedifferenti-
ated liposarcoma should be further classified into low and high grade. Dedifferen-
tiated liposarcoma rarely exhibits heterologous (most often myoid) differentia-
tion. A peculiar ‘‘neural-like whorling pattern’’ of dedifferentiation also has been
described recently. Surprisingly, the clinical outcome of dedifferentiated liposar-
coma is less aggressive that in other high-grade pleomorphic sarcomas but genetic
as well as molecular data exist that may partially justify such a discrepancy. Myxoid
and round cell liposarcoma, even if still classified by the World Health Organiza-
tion as two distinct subtypes, share both clinical and morphologic features. Lesions
combining both patterns are very frequent and wide agreement exists in consider-
ing round cell liposarcoma as the high-grade counterpart of myxoid liposarcoma.
Furthermore, myxoid and round cell liposarcoma share the same characteristic
chromosome change. Albeit rare, it has been recently shown that liposarcoma
indeed can occur as a primary skin lesion. It often presents clinically as a
dome-shaped or polypoid lesion that, histologically, most frequently shows high-
grade morphologic features but carries a comparatively good prognosis. Consider-
ing currently available data, the most logical classification of liposarcoma is into
three main groups: (1) well-differentiated liposarcoma (including adipocytic, scle-
rosing, inflammatory, spindle-cell, and dedifferentiated variants), characterized
by ring or long markers chromosomes derived from the long arm of chromosome
12; (2) myxoid and round cell (poorly differentiated myxoid) liposarcoma, charac-
terized in most cases by a reciprocal translocation t(12;16)(q13;p11); and (3)
pleomorphic liposarcoma, characterized by complex karyotypes.
Ann Diagn Pathol 4: 252-266, 2000. Copyright r 2000 by W.B. Saunders Company

Index Words: Liposarcoma, atypical lipomatous tumor, cytogenetics

From the Departments of Pathology and Oncology, Regional Hospital of

Treviso, Italy.
Address reprint requests to Angelo P. Dei Tos, MD, Department of Pathology,
L IPOSARCOMA is the most common soft tissue
sarcoma and accounts for approximately 20% of all
mesenchymal malignancies encountered by practicing
Regional Hospital, I-31100 Treviso, Italy.
Copyright r 2000 by W.B. Saunders Company
surgical pathologists. Diagnostic criteria for liposarcoma
1092-9134/00/0404-0002$10.00/0 have been well established,1,2 as reflected by the fact
doi:10.1053/adpa.2000.8133 that the current World Health Organization (WHO)

252 Annals of Diagnostic Pathology, Vol 4, No 4 (August), 2000: pp 252-266

 Liposarcoma: New Entities & Evolving Concepts 253

classification scheme for liposarcoma3 (with the notable

exception of the inclusion of dedifferentiated liposar-
coma) (Table 1) is almost identical to the one designed
by Enzinger and Winslow4 in the early 1960s.4 However,
over the last few years several studies focusing on
adipocytic tumors have led to the delineation of new
variants as well as to the introduction of new concepts,
mainly as a result of the fruitful interactions between
genetics and pathology. These studies have validated a
major part of the morphologic observations, but also
have supported proposals for significant changes in the
classification scheme.
The purpose of this review is to summarize the main
clinicopathologic features of liposarcoma while trying to
focus on the most relevant recent developments. Atten-
tion is also paid to some controversial aspects of liposar-
coma diagnosis which still represent the source of
considerable debate.

Well Differentiated Liposarcoma

Well-differentiated liposarcoma represents approxi-
mately 40% to 45% of all liposarcomas and tends to
occur equally in the retroperitoneum or the limbs.
Spermatic cord and mediastinum represent less-fre-
quent but well-known anatomic locations. Morphologi-
cally, the WHO classification recognizes three subtypes
of well-differentiated liposarcoma: adipocytic (or lipoma-
like), sclerosing, and inflammatory. Adipocytic liposar-
coma is mostly composed of mature adipocytes exhibit-
ing striking variation in cell size and at least focal
nuclear atypia and hyperchromasia (Fig 1). Scattered
hyperchromatic stromal cells may be encountered within
fibrous septa. Of course, a varying number (from many
to none) of monovacuolated or multivacuolated lipo-
blasts (defined by the presence of single or multiple
sharply marginated cytoplasmic vacuoles that indent an
enlarged hyperchromatic nucleus) may be found (Fig 2).
It is a commonly held opinion that lipoblasts represent
the hallmark for any type of malignant adipocytic lesion.
Table 1. World Health Organization Classification of
Liposarcoma (1994)
Well-differentiated liposarcoma
Adipocytic (lipoma-like)
Sclerosing
Inflammatory
Dedifferentiated liposarcoma
Myxoid liposarcoma
Round cell liposarcoma
Pleomorphic liposarcoma
Data from Weiss.3
Figure 1. The presence of striking variation in adipocyte cell
size represents an important diagnostic clue in atypical lipoma-
tous tumors.
However, it is important to emphasize that the mere
presence of lipoblasts does not make (or is required for)
a diagnosis of liposarcoma. As a matter of fact, there
exist a number of entirely benign adipocytic lesions (eg,
lipoblastoma, pleomorphic lipoma, chondroid lipoma)
that may contain numerous lipoblasts. By contrast, the
absence of lipoblasts within an adipocytic neoplasm
fulfilling all the remaining diagnostic criteria for liposar-
coma does not prevent such a diagnosis.
Sclerosing liposarcoma is characterized clinically by
the tendency to occur most frequently in the retroperito-
neum and in the paratesticular region. Microscopically,
the main histologic finding is the presence of scattered,
distinctive, bizarre stromal cells associated with rare
multivacuolated lipoblasts set in a fibrillary collagenous
background (Fig 3). Occasionally the fibrous component
represents the vast majority of the neoplasm to the
extent that lipogenic areas can be easily overlooked or
even missed in a small tissue sample (Fig 4).
Another morphologic variation that represents a
254 Angelo P. Dei Tos

In 1994, a rare variant of well-differentiated liposar-

coma was described under the term spindle cell liposar-
coma,8,9 which occurs in adults and, at least in the first
series, appeared to relatively often involve subcutaneous
soft tissue. However, through observation of a larger
number of cases, the anatomic distribution of spindle
cell liposarcoma seems to be comparable to that of the
other well-differentiated liposarcoma subtypes. Morpho-
logically, spindle cell liposarcoma is composed of a fairly
bland neural-like spindle cell proliferation set in a
fibrous and/or myxoid background (Fig 6) and is associ-
ated with an atypical lipomatous component that usu-
ally includes lipoblasts (Fig 7). Main differential diag-
noses include spindle cell lipoma (composed of bland,
sometimes palisading, CD34-positive spindle cells, ad-
mixed with eosinophilic refractile collagen bundles),
neurofibroma (characterized by a less cellular S-100–
positive spindle cell proliferation with wavy nuclei),

Figure 2. High-power view of a lipoblast exhibiting a nucleus

indented by multiple vacuoles.

potential diagnostic pitfall is the presence of a chronic

inflammatory infiltrate to the extent that the adipocytic
nature of the neoplasm can be obscured (Fig 5). The
existence of examples of liposarcoma characterized by
the presence of prominent mononuclear inflammatory
infiltrates has been acknowledged since the publication
of Stout’s5 classification of liposarcoma. Nonetheless,
reports dealing specifically with this subtype have not
been available until very recently.6,7 The inflammatory
infiltrate is usually composed of polyphenotypic lympho-
plasmacytic aggregates in which a B-cell phenotype
tends to predominate. However, cases exist in which a
T-cell population represents the main inflammatory
component. Differential diagnosis includes nonadipo-
cytic lesions such as inflammatory myofibroblastic tu-
mor and Castleman’s disease. Careful as well as exten-
sive sampling is mandatory to permit recognition of the Figure 3. The presence of scattered hyperchromatic stromal
adipocytic component that otherwise could be easily cell set in fibrillary background and associated with an atypical
lipomatous component represents the hallmark of well-differen-
missed. The presence of bizarre multinucleate stromal tiated sclerosing liposarcoma. A lipoblast is present but can be
cells represents a useful diagnostic clue. rare.
 Liposarcoma: New Entities & Evolving Concepts 255

As previously mentioned, the integration between

morphologic and cytogenetic observations has proved
extremely useful, and adipocytic neoplasms represent
one of the fields of surgical pathology wherein such a
synergy has been most fruitful (Table 2). Karyotypic
analysis of well-differentiated liposarcoma has shown
that this group of mesenchymal neoplasms is marked by
the presence of extra ring and/or giant marker chromo-
somes.10 Fluorescence in situ hybridization studies have
demonstrated that these rings and giant markers con-
tain amplified sequences derived from the 12q13-15
chromosome region.11 The 12q13-15 chromosome re-
gion is very complex and contains several important
protooncogenes, such as MDM2, CDK4, HMGI-C, SAS,
GLI, CHOP, OS1, and OS9, known to play an important
role in the molecular pathogenesis of many neoplastic
processes. Interestingly, concomitant amplification of
HMGI-C (a gene encoding for an architectural transcrip-
tion factor involved in adipocytic differentiation), MDM2,
and CDK4 (both acting as positive regulators of cell

Figure 4. Lipogenic areas can be sometimes hard to find in

sclerosing well-differentiated liposarcoma. However, the recog-
nition of bizarre hyperchromatic cells set in a fibrillary back-
ground represents a helpful diagnostic feature.

dermatofibrosarcoma protuberans (cytologically bland,

monomorphic CD34-positive spindle cell proliferation
organized in a distinctive storiform growth pattern and
characterized by tendency to infiltrate the surrounding
fat in a peculiar ‘‘honeycomb’’ pattern), malignant
peripheral nerve sheath tumor (generally highly cellular
tumors composed of tapering or wavy spindle cells
featuring perivascular accentuation and focal S-100–
positive immunoreactivity in approximately 50% of
cases), and well-differentiated sclerosing liposarcoma
(characterized by the presence of bizarre hyperchro-
matic stromal cells set in fibrillary collagen). The pres-
ence of an atypical lipomatous component also permits
distinction from low-grade fibromyxoid sarcoma (Evans’
tumor). Interestingly, spindle cell liposarcoma exhibits
chromosome changes (ring chromosomes and giant
marker chromosomes) identical to those observed in
Figure 5. In well-differentiated inflammatory liposarcoma it is
other members of the well-differentiated liposarcoma important to identify lipogenic areas that can be obscured by the
group, thus validating its classification. presence of the inflammatory infiltrate.
256 Angelo P. Dei Tos

cycle progression at the G1-S checkpoint), as well as

overexpression of the proteins thereof has been recently
demonstrated in well-differentiated liposarcomas.12 The
fact that the 12q13-15 region is also rearranged in
ordinary benign lipomas (leading to HMGI-C activa-
tion) and the observation of 12q15 duplication in adipo-
cytic neoplasms exhibiting minimal atypical changes
(C.D.M. Fletcher, unpublished observation) have led to
the postulation that ordinary lipomas may form a
morphologic and genetic continuum with well-differenti-
ated liposarcoma, with the degree of atypia being a gene
dosage effect.12

The Atypical Lipoma Controversy

The very fact that well-differentiated liposarcoma
shows a risk of local recurrence (approximately 30%),
but no potential for metastasis unless it undergoes
dedifferentiation, represents the main reason to justify

Figure 7. The presence of lipoblasts is helpful when dealing

with the differential diagnosis of spindle cell liposarcoma.

the introduction (pioneered by Evans et al13 in 1979) of

terms such as atypical lipoma or atypical lipomatous tumor.
Evans et al13 initially suggested atypical lipoma as a more
appropriate name for well-differentiated liposarcoma
occurring in the subcutis, intermuscularly and intramus-
cularly in the limbs. Other investigators suggested
adoption of the term atypical lipoma just for adipocytic
neoplasms showing variation in adipocyte size and
nuclear atypia but lacking lipoblasts. In 1988 Evans15
extended the use of the term atypical lipomatous tumor to

Table 2. Specific (Primary) Chromosome Changes

in Liposarcoma

Tumor Type Cytogenetic Change

Atypical lipoma/ ⫹ Ring or long marker

well-differentiated (sequences 12q13-q15)
liposarcoma
Myxoid and round t(12;16)(q13;p11) genes: CHOP/TLS
Figure 6. The presence of a neural-like spindle cell prolifera- cell liposarcoma t(12;22)(q13;q11) genes: CHOP/EWS
tion set in a fibrous background and associated with an atypical Pleomorphic lipo- Complex rearrangements
lipomatous component represents the typical morphologic pic- sarcoma
ture of spindle cell liposarcoma.
 Liposarcoma: New Entities & Evolving Concepts
retroperitoneal lesions lacking lipoblasts and also sug-
gested entirely abandoning the term well-differentiated
liposarcoma. More recently, Weiss and Rao16 suggested
limiting use of the term atypical lipomatous tumors to
subcutaneous lesions. The rationale for such a proposal
was the belief that liposarcoma, when occurring in the
subcutis, does not dedifferentiate.16 However, bona fide
examples of subcutaneous dedifferentiated liposarcoma
exist that make this approach less acceptable.8,17-19 The
debate around the use of this alternative term to
well-differentiated liposarcoma is still far from settle-
ment, with the result that the term atypical lipoma is
heterogeneously applied by different institutions. In our
opinion well-differentiated liposarcoma and atypical
lipoma should be considered synonyms. As a matter of
fact, both terms describe lesions identical both morpho-
logically and karyotypically. Their use therefore should
be determined by the degree of reciprocal comprehen-
sion between the surgeon and the pathologist to prevent
either inadequate or excessive treatment.20 Impor-
tantly, pleomorphic lipoma, which represents an en-
tirely benign lesion closely related to spindle cell lipoma,
should be kept separated from the atypical lipoma
category as it rarely recurs and has no potential to
dedifferentiate. The presence in spindle cell and pleomor-
phic lipomas of chromosome 16q rearrangements repre-
sents further support of this view.21
Dedifferentiated Liposarcoma
Dedifferentiated liposarcoma represents both a mor-
phologically and biologically fascinating lesion in which
Figure 8. Abrupt transition
from low-grade lipogenic areas
to high-grade MFH-like pleo-
morphic sarcoma is frequently
seen in dedifferentiated liposar-
coma.
257
transition from low-grade to high-grade nonlipogenic
morphology within a well-differentiated liposarcoma is
observed. First described in 1979 by Evans,22 who coopted
the term from Dhalin et al’s23 description of tumor
progression in chondrosarcoma, dedifferentiation in well-
differentiated liposarcoma tends to occur more fre-
quently in the primary tumor (90%) but can also be
observed in recurrences (10%). The transition usually
occurs in an abrupt fashion (Fig 8); however, in some
cases this can be more gradual and exceptionally low-
grade and high-grade areas appear to be intermingled.
Dedifferentiated areas exhibit a variable histologic pic-
ture but most frequently it overlaps with storiform and
pleomorphic malignant fibrous histiocytoma (Fig 9) as
well as myxofibrosarcoma. Recently, it also has been
proposed that dedifferentiated liposarcoma should be
further classified into low-grade and high-grade sub-
types.18,24 Low-grade dedifferentiation was defined by
the presence of bland spindle cells organized in a
fascicular pattern and exhibiting a cellularity intermedi-
ate between well-differentiated sclerosing liposarcoma
and usual high-grade areas. The very existence of
low-grade dedifferentiation raises the question of the
differential diagnosis with spindle cell liposarcoma.
However, it should be noted that spindle cell liposar-
coma represents a lipogenic lesion (eg, it contains
atypical adipocytes or lipoblasts) whereas dedifferenti-
ated areas, both low- and high-grade, are generally
nonlipogenic.
Dedifferentiated liposarcoma may exhibit heterolo-
gous differentiation in approximately 5% to 10% of
258 Angelo P. Dei Tos
cases, which apparently does not affect the clinical
outcome. Most often the line of heterologous differentia-
tion is myogenic (Figs 10-12) or osteo/chondrosarcoma-
tous, but angiosarcomatous elements also have been
reported. Recently, a peculiar ‘‘neural-like’’ or ‘‘meningo-
thelial-like whorling pattern of dedifferentiation has
been described but both immunohistochemistry and
electron microscopy failed to elucidate the line of differ-
entiation in these lesions25,26 (Fig 13). This pattern is
often associated with ossification (Fig 14).
Figure 10. Abrupt transition
from well-differentiated liposar-
coma to a hypercellular high-
grade sarcoma is seen.
Figure 9. A growth pattern
reminiscent of the so-called
‘‘storiform’’ and ‘‘pleomorphic’’
MFH is appreciable in this ex-
ample of dedifferentiated lipo-
sarcoma.
Surprisingly, the biological behavior of dedifferenti-
ated liposarcoma tends to be less aggressive than that of
other types of high-grade pleomorphic sarcomas.17,18 At
variance with well-differentiated liposarcoma, dediffer-
entiation is associated with a 15% to 20% metastatic
rate. However, long-term survival rates for retroperito-
neal dedifferentiated liposarcoma is not significantly
worse than that observed in ordinary well-differentiated
liposarcoma occurring at the same site, mortality being
more related to repeated destructive local recurrences
 Liposarcoma: New Entities & Evolving Concepts
Figure 11. The high-grade
component is characterized by
the presence of clusters of
rhabdomyoblasts featuring
large deeply eosinophilic cyto-
plasm as well as hyperchro-
matic nuclei.
than to metastatic spread. The fact that dedifferenti-
ated liposarcoma can recur as an entirely well-differenti-
ated liposarcoma also represents a morphologic indica-
tor of the unique biologic behavior of this liposarcoma
subtype.
Genetics as well as molecular pathology have recently
provided data that, at least in part, may account for the
discrepancy observed between morphology and biologic
aggressiveness. Interestingly, in stark contrast with the
complex karyotypic aberrations observed in pleomor-
phic sarcomas, dedifferentiated liposarcoma usually re-
259
tains the same basic cytogenetic anomalies as well-
differentiated liposarcoma represented by the presence
of ring and/or giant marker chromosomes,27 although
there may be superimposed additional aberrations.28 A
significant increase in the level of both MDM2 overex-
pression and amplification in the high-grade areas has
been observed that may account for the tumor progres-
sion in this subset of sarcomas.29,30 However, at variance
with high-grade pleomorphic sarcomas, in which con-
comitant MDM2 amplification and TP53 mutation are
detected31 and that are significantly related to poor
Figure 12. Strong cytoplasmatic
desmin immunopositivity within rhab-
domyoblasts is appreciable.
260 Angelo P. Dei Tos
clinical outcome, retention of TP53 integrity is almost
always observed in dedifferentiated liposarcoma.29 There-
fore, dedifferentiated liposarcoma appears to be just one
more step along the spectrum of well-differentiated
adipocytic neoplasms, showing only an increased dosage
of the same molecular targets involved in the molecular
pathogenesis of well-differentiated liposarcoma.
Myxoid and Round Cell Liposarcoma
Myxoid and round cell liposarcoma represents approxi-
mately 30% to 35% of liposarcomas. They are still
Figure 14. Areas of ossifica-
tion are frequently seen in de-
differentiated liposarcoma ex-
hibiting the neural-like whorling
growth pattern.
Figure 13. A peculiar whor-
ling growth pattern is rarely
seen in dedifferentiated liposar-
coma. Neoplastic cells exhibit
either a meningothelial-like or
neural-like morphology.
classified by WHO as two distinct subtypes. How-
ever, clinical, morphologic, and cytogenetic evidence
clearly supports the existence of a single spectrum of
lesions in which purely myxoid and round cell lipo-
sarcomas represent the well and poorly differentiated
ends, respectively. Clinically, myxoid and round cell
liposarcoma tends to occur in the limbs (especially the
thigh) of patients ranging in age between 35 and 55
years, while in contrast with the well-differentiated
group, the retroperitoneal location seems to be excep-
tional.
 Liposarcoma: New Entities & Evolving Concepts
Figure 15. A cytologically
bland spindle cell proliferation
set in a myxoid background
and associated with a distinc-
tive plexiform capillary network
represent the histologic hall-
mark of pure myxoid liposar-
coma.
Purely myxoid liposarcoma is defined by the presence
of a hypocellular spindle cell proliferation set in a
myxoid background (Fig 15), often with mucin pooling
that sometimes is so extensive to produce the so-called
‘‘pulmonary edema’’ pattern (Fig 16). Lipoblasts tend
to be small and often monovacuolated and to cluster
around vessels or at the periphery of the lesion (Fig 17).
Nuclear pleomorphism is minimal and mitoses are
rare. The presence of distinctive capillary-sized blood
vessels organized in a plexiform (eg, crow’s feet,
261
chicken wire) pattern represents one of the most useful
diagnostic clues when dealing with myxoid sarcomas
(Fig 15).
The presence of hypercellular areas sometimes featur-
ing an undifferentiated round cell morphology and
ranging in extent between 5% and 80% permits the
recognition of the myxoid/round cell liposarcoma sub-
type (Fig 18). Pure round cell liposarcoma is a rare
neoplasm in which hypercellularity or round cell differ-
entiation account for more than 80% of tumor tissue
Figure 16. The formation of
pools of mucin is relatively com-
mon in myxoid liposarcoma but
rarely can it be so extensive to
produce the so-called ‘‘pulmo-
nary edema’’ pattern.
262 Angelo P. Dei Tos
(Fig 19). Most frequently, early foci of hypercellularity
begins to form in a perivascular distribution. Adipocytic
differentiation in pure round cell liposarcoma is some-
times hard to appreciate, but it is worth noting that
approximately 80% of round liposarcomas exhibit con-
vincing S-100 immunopositivity, which represents a
useful diagnostic clue in this context.32 The fact that
transition to hypercellular/round cell areas are com-
monly observed in myxoid liposarcoma provides strong
evidence in favor of the concept that myxoid and round
Figure 18. In myxoid and
round cell liposarcoma pure
myxoid liposarcoma merges
with hypercellular areas some-
times exhibiting an undifferenti-
ated round cell morphology.
Usually hypercellular foci be-
gin to form around blood ves-
sels.
Figure 17. Myxoid liposar-
coma lipoblasts more often
cluster at the periphery of the
neoplasm and tend to be of the
monovacuolated type.
cell liposarcoma represents a morphologic continuum of
myxoid adipocytic neoplasia. Evans22 was the first to
suggest abandoning the distinction between these sub-
types. Recently, these morphologic observations have
gained the conclusive support of genetic analysis. Myx-
oid and round cell liposarcoma share exactly the same
characteristic chromosome translocation that, at the
molecular level, fuses the CHOP gene on 12q13 with the
FUS (or TLS) gene on 16p11 or with EWS on 22q12.33,34
When dealing with poorly differentiated lesions as well
 Liposarcoma: New Entities & Evolving Concepts
Figure 19. Round cell liposar-
coma neoplastic cells may ex-
hibit a predominant undifferen-
tiated round cell morphology
with minimal lipogenic differen-
tiation.
as with those rare examples of myxoid liposarcoma
featuring a predominantly spindle cell morphology that
closely mimics myxofibrosarcoma,35 cytogenetics may
play a key role in arriving at a correct diagnosis.
Molecular analysis of myxoid liposarcoma has shown
that TP53 gene mutations occur in approximately one
third of cases but these are independent from tumor
grade. Overexpression of mdm2 protein represented
the only parameter that correlated in a statistically
significant way with tumor progression in this subset of
sarcomas.36
It has been repeatedly observed that the presence of
hypercellularity or round cell differentiation is associ-
ated with worsening of prognosis. The 70% 5-year
survival rate of myxoid liposarcoma decreases to 20%
when dealing with round cell liposarcomas. Yet, accu-
rate prognostication is everything but easy in this subset
of adipocytic malignancies. While it seems to be clear
that hypercellularity or round cell differentiation indi-
cates a more aggressive clinical behavior, different
cutoff values, ranging between 5% and 25%, have been
set by independent studies.37,38 Considering the intrinsic
difficulty as well as the subjectivity of establishing the
percentage of hypercellularity in a given tumor, it
appears reasonably safe to consider any amount of
hypercellularity as prognostically relevant. Future appli-
cation of more rigorous tools, such as image analysis, is
encouraged to make prognostication in myxoid liposar-
coma more reliable.39
263
Pleomorphic Liposarcoma
Pleomorphic liposarcoma represents the rarest of all
liposarcoma subtypes. Clinically it represents an aggres-
sive neoplasm that tends to occur in the limbs of older
adults. The trunk and retroperitoneum also represent
less-frequently affected anatomic locations. It may pre-
sent with either of two main morphologic pictures: a
high-grade pleomorphic MFH-like sarcoma containing
scattered multivacuolated lipoblasts (Fig 20) or a cellu-
lar pleomorphic or spindle cell neoplasm containing
sheets of bizarre pleomorphic monovacuolated as well as
multivacuolated lipoblasts (Fig 21). An acute inflamma-
tory infiltrate may be rarely present that should not be
confused with the lymphoplasmacytic infiltrate ob-
served in well-differentiated inflammatory liposarcoma.
In a recent series, pleomorphic liposarcoma proved to be
an aggressive neoplasm with a 30% metastatic rate and
an overall mortality rate of at least 40%.40 Karyotypi-
cally, pleomorphic liposarcoma exhibits complex aberra-
tions similar to those observed in other high-grade
pleomorphic sarcomas.
Cutaneous Liposarcoma
Although any liposarcoma subtype occasionally arises
in the subcutis, the dermis seems to represent a rare site
of occurrence to the extent that the very existence of
primary cutaneous liposarcoma has been questioned.
Nonetheless, we recently have shown that liposarcoma
can indeed occur as a primary skin lesion, with an
264 Angelo P. Dei Tos

classification of soft tissue neoplasms in general and of

lipomatous tumors in particular. Considering currently
available data, the most logical classification of liposar-
coma is divided into three main groups: (1) well-
differentiated liposarcoma (including adipocytic, scleros-
ing, inflammatory, spindle-cell, and dedifferentiated
variants), characterized by ring or long markers chromo-
somes derived from the long arm of chromosome 12; (2)
myxoid and round cell (poorly differentiated myxoid)
liposarcoma, characterized in most cases by a reciprocal
translocation t(12;16)(q13;p11); (3) pleomorphic liposar-
coma, characterized by complex karyotypes. It also has
to be noted that, rarely, liposarcoma may elude any
classification scheme and may combine features of
different histologic subtypes.
Cytogenetics as well as molecular genetics and molecu-
lar pathology have not only greatly contributed to a
better elucidation of some of the mechanism involved in
the pathogenesis of adipocytic tumors, but also repre-
sent valuable adjuncts that are increasingly used in the

Figure 20. A high-grade spindle cell and pleomorphic cell

proliferation is seen at the bottom. Lipogenic differentiation
represented by clusters of lipoblasts is appreciable at the top
and permits the recognition of this example of pleomorphic
liposarcoma.

apparent predilection for the scalp.41 Interestingly, it

often presents clinically as a dome-shaped or polypoid
lesion that, histologically, most frequently shows high-
grade morphologic features. As frequently occurs with
superficially located soft tissue sarcomas, primary cuta-
neous liposarcoma carries a comparatively good progno-
sis, although this needs to be confirmed by larger series.
It may be that the tendency for superficial sarcomas to
exhibit a less-aggressive clinical course is mainly due to
earlier detection as well as easier resectability. Nonethe-
less, albeit difficult to prove, the existence of an ‘‘environ-
mental’’ advantage for superficial lesions cannot be
ruled out with certainty.

Conclusion
Figure 21. Pleomorphic liposarcoma can be entirely repre-
During the last decade, the integration of morphology sented by a proliferation of pleomorphic monovacuolated as
and genetics has greatly contributed to a more accurate well as multivacuolated lipoblasts.
 Liposarcoma: New Entities & Evolving Concepts
diagnosis of liposarcoma. Certainly, 135 years after
Virchow’s42 first detailed description of liposarcoma,
there remain many unsolved problems. The need for
identification of less-subjective prognostic parameters
in myxoid liposarcoma represents only one example of
such problematic areas. Nonetheless, while waiting for
further diagnostic advances, it is important to remem-
ber that a better knowledge of the mechanisms involved
in the pathogenesis of adipocytic tumors also may have a
significant impact over the delineation of innovative
therapeutic approaches. This concept is exemplified by
recent studies that have shown the induction of terminal
differentiation on human liposarcoma cells, both in
vitro43 and in vivo,44 by ligands for peroxisome prolifera-
tor-activated receptor and the retinoid X receptor.
However, while looking with enthusiasm to the valu-
able information provided by these new methodologic
approaches, it has to be underlined that a consistent as
well as accurate morphologic classification still repre-
sents the key step in the clinical management of
liposarcoma patients. Any effort to confer reproducibil-
ity to liposarcoma diagnosis, as well as to reduce at
minimum the existence of terminologic disagreements,
will prove beneficial to achieve the most effective thera-
peutic approach.
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