ORIGINAL ARTICLE

Cutaneous and Subcutaneous Pleomorphic Liposarcoma

A Clinicopathologic Study of 29 Cases With Evaluation of MDM2 Gene
Amplification in 26
Jerad M. Gardner, MD,* Monisha Dandekar, MD,w Dafydd Thomas, MD, PhD,w
John R. Goldblum, MD,z Sharon W. Weiss, MD,* Steven D. Billings, MD,zy David R. Lucas, MD,w
Jonathan B. McHugh, MD,w and Rajiv M. Patel, MDw8

favorable outcome compared with their deep-seated counterparts,

Abstract: Pleomorphic liposarcoma (PL) is an uncommon form
of liposarcoma that rarely occurs in the skin and subcutis. As its
behavior in this setting is incompletely characterized, we un-
dertook a study of a series of superficial PLs, defined as those
arising or based primarily in the dermis and/or subcutis without
involvement of deep structures. In addition, MDM2 gene am-
plification, a diagnostic signature of well-differentiated/dedif-
ferentiated liposarcoma (WDL/DL), was evaluated to address
the recent observation that this gene is amplified within PL-like
areas in DL. PLs were obtained from institutional and con-
sultation files (n = 29). Cases were evaluated with respect to age,
sex, location (dermis, dermis and subcutis, subcutis), size, pre-
dominant pattern (pleomorphic spindled or epithelioid), extent
of lipogenic differentiation, and tumor necrosis. MDM2 ampli-
fication was analyzed using FISH on formalin-fixed, paraffin-
embedded material in 26 cases. Patients ranged in age from 5 to
93 years (M:F = 1.4:1). Tumors were located on the extremity
(n = 15), trunk (n = 7), and head and neck (n = 7) and involved
the dermis (n = 4), dermis and subcutis (n = 10), and subcutis
(n = 15). Tumor size ranged from 0.8 to 15 cm (median = 2 cm).
All were mitotically active high-grade sarcomas [FNCLCC
grade 2 (n = 23) or 3 (n = 6)] with either a pleomorphic spindled
(n = 24) or an epithelioid pattern (n = 5) with variable extent of
lipogenic differentiation [ < 25% (n = 15), 25% to 50% (n = 9),
>50% (n = 5)]. Necrosis was present in 3 cases. MDM2 gene
amplification was present in 3 of 26 cases. Follow-up in-
formation in 24 cases (range = 1 to 192 mo; median = 48 mo;
mean = 59 mo) revealed local recurrences (4/24) but no meta-
stasis or death from disease. We conclude that cutaneous and
subcutaneous PLs, despite their high grade, have a much more
From the *Department of Pathology and Laboratory Medicine, Emory
University, Atlanta, GA; Departments of wPathology; 8Dermato-
logy, University of Michigan, Ann Arbor, MI; Departments of
zPathology; and yDermatology, Cleveland Clinic, Cleveland, OH.
J.M.G. and M.D. are co-first authors.
Conflicts of Interest and Source of Funding: The authors have disclosed
that they have no significant relationships with, or financial interest
in, any commercial companies pertaining to this article.
Correspondence: Rajiv M. Patel, MD, Departments of Pathology
and Dermatology, Section of Dermatopathology, University of
Michigan, 1301 Catherine Road, M3261-Med Sci I, Ann Arbor, MI
48109-0602 (e-mail: rajivpat@med.umich.edu).
Copyright r 2012 by Lippincott Williams & Wilkins
most likely attributed to their small size and superficial location.
The low incidence of MDM2 gene amplification in our series
indicates that most superficial PLs are unrelated to WDL/DL. PL
likely evolves by way of more than 1 molecular pathway.
Key Words: liposarcoma, pleomorphic liposarcoma, MDM2
gene amplification, dedifferentiated liposarcoma, cutaneous
sarcoma
(Am J Surg Pathol 2012;36:1047–1051)
L iposarcoma, the most common soft tissue sarcoma,
includes a number of subtypes that differ in their his-
tologic, biological, and molecular features. Pleomorphic
liposarcoma (PL) is the rarest subtype. It occurs princi-
pally in deep soft tissue and, unlike other subtypes of
liposarcoma, does not display a consistently recurring
cytogenetic abnormality; rather, it shows a complex kar-
yotype. Recently, MDM2 gene amplification, a charac-
teristic molecular signature of WDL/DL, has been
reported in PL-like areas in DL, suggesting that some
sarcomas that resemble PL are actually DL.7 Another
interpretation is that PL may be more closely related to
DL than previously thought. To better understand the
behavior of PL when it occurs in a superficial location
and to assess the frequency of MDM2 amplification, we
analyzed our experience with cutaneous PL.
MATERIALS AND METHODS
After receiving Institutional Review Board appro-
val, 36 cases of superficial PL were retrieved from the
institutional files of the University of Michigan Depart-
ment of Pathology, Emory University Department of
Pathology and Laboratory Medicine, Cleveland Clinic
Department of Pathology, and from the personal con-
sultation files of 3 of the authors (S.D.B., J.R.G., and
S.W.W.) from 1990 to 2010. A diagnosis of PL had been
rendered previously on the basis of World Health
Organization criteria, which define this entity as a
“pleomorphic, high grade sarcoma containing a variable
number of pleomorphic lipoblasts.”3 The current World
Health Organization classification defines pleomorphic

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Gardner et al
lipoblasts as “pleomorphic, multivacuolated lipoblasts,
with bizarre, hyperchromatic and scalloped nuclei.”3
Lesions were considered cutaneous and subcutaneous if
they were located in the dermis and/or subcutis without
involvement of deeper structures. Seven cases were ex-
cluded because of extension beyond the subcutis.
Hematoxylin and eosin-stained sections were re-
viewed and evaluated for the following features: pre-
dominant histologic pattern [epithelioid or pleomorphic
spindled/malignant fibrous histiocytoma (MFH)-like],
percentage of necrosis, percentage of lipogenic compo-
nent as defined by areas containing lipoblasts (< 25%;
25% to 50%; >50%), mitotic rate [mitoses/10 high-
power fields (HPF)], and histologic grade [according
to the French Federation of Cancer Centers (FNCLCC)
system].11
MDM2 gene amplification was analyzed by fluo-
rescence in situ hybridization (FISH) carried out ac-
cording to the manufacturer’s instructions. Briefly,
sections were dewaxed and rehydrated. After digestion
with pepsin (5 min at 371C) and microwave epitope re-
trieval in 1 mM EDTA buffer at pH 8, the slides were
incubated with 10 mL of prediluted probes [MDM2
(Chr12q15): red; Chr12 centromere: green; Poseidon
Probes, Veridex, Raritan, NY, cat. (sharp) KI-10717].
After overnight incubation, the slides were washed twice
in 0.4  saline-sodium citrate containing 0.3% Igepal for
2 minutes at 371C and then at 721C. The final stringency
wash was in 2  saline-sodium citrate containing 0.1%
Igepal at ambient temperature. Slides were stained with
DNA staining dye 40 ,6-diamidino-2-phenylindole in a
nonfading mounting medium (ProLong Gold, Molecular
probes, Carpinteria, CA). The slides were allowed to dry
overnight in a dark dry chamber, and the edges were
sealed. Images were captured separately on an Olympus
BX51 microscope at 3 different extinction/emission
wavelengths and combined using Olympus Microsuite
Software (Olympus MicroSuite Biological Suite v5.0,
2004, Olympus, Center Valley, PA). A cutoff of >2x
MDM2 probe/centromere probe was used to determine
a positive test result.
Clinical data from 24 cases of superficial PL, in-
cluding patient age, sex, site of involvement, tumor size
and depth, treatment modality, and follow-up informa-
tion, were obtained from the referring pathologists.
RESULTS
Clinical Features
A total of 29 cases of superficial PL were available
for review (Table 1). The patients ranged in age from 5 to
93 years (median = 55 y) with a male:female ratio of
1.4:1. Tumors were located on the extremities (n = 15),
trunk (n = 7), or head and neck (n = 7). Tumor depth
was characterized as dermis only (n = 4), as dermis
and subcutis (n = 10), or as subcutis only (n = 15). By
definition, none of the cases involved the underlying
musculature. Tumor sizes ranged from 0.8 to 15 cm
(median = 2 cm).
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Am J Surg Pathol  Volume 36, Number 7, July 2012
TABLE 1. Results—Clinical Findings
Age, y (median) 5-93 (55)
Sex, Male:female 1.4:1
Location
Extremity, n 15
Trunk, n 7
Head and neck, n 7
Depth
Dermis only, n 4
Dermis and subcutis, n 10
Subcutis only, n 15
Size, cm (median) 0.8-15 (2)
Clinical diagnoses included lipoma (n = 5), benign
cyst (n = 3), fibroma (n = 1), neurofibroma (n = 1), and
fibroepithelial polyp (n = 1). In 1 patient with a remote
history of retinoblastoma as a child (case 8), the possi-
bility of recurrent retinoblastoma was considered clin-
ically. The referring diagnoses included “liposarcoma” or
“PL” in 9 cases, “MFH” in 6, “myxoid liposarcoma” in 3,
and “pleomorphic lipoma” in 2 cases. Other diagnoses
included pleomorphic rhabdomyosarcoma, nodular fas-
ciitis, lipoblastoma, atypical fibroxanthoma, atypical
nerve sheath tumor, DL, signet ring cell carcinoma,
melanoma, and inflammatory myxohyaline tumor of the
distal extremities.
Histologic Features
Dermal PL often appeared circumscribed (Fig. 1),
whereas those in the subcutis were often infiltrative. Twenty-
four cases had a pleomorphic spindled pattern (Fig. 2), and 5
had an epithelioid pattern (Fig. 3). The pleomorphic spin-
dled pattern resembled undifferentiated pleomorphic sarco-
ma/MFH. The epithelioid pattern consisted of round tumor
cells that occasionally had a vacuolated cytoplasm, a feature
reminiscent of adrenal cortical carcinoma. By definition, all
cases had pleomorphic lipoblasts (Fig. 4) and were inter-
mediate to high grade [FNCLCC grade 2 (n = 23) or 3
(n = 6)—that is, high grade in a 2-tiered system].10 Of
FIGURE 1. Low-power view of dermal PL showing a relatively
circumscribed appearance.
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Am J Surg Pathol  Volume 36, Number 7, July 2012
FIGURE 2. Pleomorphic spindled pattern of PL with scattered
pleomorphic lipoblasts.
the pleomorphic spindled cases, 5 had variable degrees of
myxoid change, and 1 had a prominent mononuclear
inflammatory infiltrate (case 25). The percentage of lipogenic
differentiation, defined by areas of lipoblasts and/or adipo-
cytic cells, varied widely. The majority of cases had <25%
(n = 15) differentiation, whereas only a minority (n = 5) had
>50% differentiation. Necrosis was identified in 3 of 30
cases. Mitotic rate ranged from <1 to up to 48 per 10 HPF
(median = 5). Ten cases (34%) had 2 or fewer mitoses per
10 HPF. MDM2 gene amplification (Fig. 5) was identified in
3 of the 26 cases available for FISH analysis; none of these 3
cases had any identifiable areas of WDL (Table 2).
Clinical follow-up information was available for 24
cases. The follow-up period ranged from 1 to 192 months
(median = 48 mo). Four patients (17%) developed a local
recurrence, and 3 of these 4 patients had multiple local
recurrences (3 recurrences for case 12, 2 recurrences for
case 26, and at least 8 recurrences for case 16). The tumor
in case 16 eventually involved deeper structures and re-
FIGURE 3. Epithelioid pattern of PL with pleomorphic lipo-
blasts.
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Cutaneous and Subcutaneous Pleomorphic Liposarcoma
FIGURE 4. Pleomorphic lipoblast within PL. Note the bizarre,
hyperchromatic nucleus scalloped by multiple vacuoles.
quired amputation. Time to first recurrence ranged from
4 to 80 months (median = 26 mo). The longest interval to
recurrence was 125 months. Of the 4 patients with local
recurrence, 2 had narrowly clear margins at the time of
initial resection, 1 had positive margins, and 1 had un-
known or questionable margin status. No patient had
regional or distant metastasis, and no patient died of
disease. The most recent follow-up status was as follows:
alive with no evidence of disease (n = 19), alive with
disease (n = 2), died of disease (n = 0), died of unrelated
cause (n = 3), lost to follow-up (n = 5) (Table 3).
DISCUSSION
The current study represents the largest series to
date of superficial PL and also adds 4 cases of purely
dermal PL to the literature, bringing the total to 10 cas-
es.2,6,12 As is commonly the case for superficially located
sarcomas, the treating physicians usually suggested be-
FIGURE 5. MDM2 gene amplification by FISH. Green signals:
centromeric probe. Red signals: MDM2. Note numerous red
signals within the nuclei of tumor cells.
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Gardner et al Am J Surg Pathol  Volume 36, Number 7, July 2012

in a small number of PLs analyzed by Southern blot

TABLE 2. Results—Histologic Findings
analysis. Schneider-Stock et al8 found MDM2 amplifica-
Histologic pattern tion in 3 of 9 cases and Nilbert et al9 in 1 of 2 cases of PL
Pleomorphic spindled, n 24
Epithelioid, n 5 “amplified.” It is difficult to know whether the MDM2
Lipogenic differentiation, n “amplification” detected by Southern blotting in earlier
< 25% 15 studies was true amplification of 12q13-15 or merely an
25%-50% 9 increased number of MDM2 genes because of polysomy
> 50% 5
Necrosis, n
of chromosome 12 as a result of the aneuploidy/complex
Present 3 karyotype.13 However, quite recently 2 studies described
Absent 26 MDM2 gene amplification by FISH in PL-like areas as-
Mitoses (per 10 HPF) < 1-48 (median = 5) sociated with WDL. Boland and colleagues reported 12
MDM2 amplification, n such cases with both PL and WDL components, 11 of
Present 3
Absent 23 which (91%) were positive for MDM2 amplification in
Not tested 3 the PL-like areas. They interpreted these tumors as pos-
sibly representing a “transitional” stage between WDL
and DL or as a “partially differentiated” form of DL.
They also suggested that perhaps a subset of PLs arises by
nign preoperative clinical diagnoses such as lipoma or way of the WDL/DL pathway.1 Mariño-Enrı́quez and
epidermal inclusion cyst. One of our cases (case 8) was colleagues also reported a series of 11 similar cases
unusual in that the tumor arose on the forehead of a showing WDL and PL components. They interpreted
52-year-old woman with a history of retinoblastoma as a them as DL with “homologous” lipoblastic differ-
child that was treated with radiation therapy, raising the entiation, noting that the cases were also positive for
possibility of either a radiation-induced or RB-1-asso- MDM2 amplification both by immunohistochemistry and
ciated tumor. Although displaying the usual range of by FISH. A recent study by Ghadimi et al5 evaluated
features from pleomorphic spindled to epithelioid areas, MDM2 overexpression by immunohistochemistry in a
lipogenic differentiation was present in only a minor part series of PLs and found all cases to be negative. We only
of the tumor, probably accounting for the referring di- identified 1 case of pure PL in the literature that was
agnosis of “MFH” (undifferentiated pleomorphic sarco- tested for MDM2 amplification by FISH, and that case
ma), as is often suggested. was negative.10 Our study afforded an opportunity to
Cutaneous and subcutaneous PLs have a behavior evaluate MDM2 gene amplification within a significant
quite different from that of their deep counterparts. Local number of pure PLs. The majority of our cases displayed
recurrence was relatively uncommon (17%), and none no amplification of MDM2, providing support for the
developed distant metastasis, although rare cases of cu- prevailing view that PL is unrelated to WDL/DL. This is
taneous PL have metastasized.”5 This contrasts with the further supported by the finding of Ghadimi and col-
40% to 50% rate of metastasis associated with deep leagues that states that the majority of their PLs harbored
PL.4,6,7 The case of the one patient whose tumor pro- p53 mutations, an aberration that is thought to be mu-
gressed to involve deep soft tissue necessitating amputa- tually exclusive of MDM2 amplification in liposarcomas.5
tion for local control highlights the fact that superficial However, 3 of 26 cases tested displayed amplification.
forms of cutaneous PL do have the capacity for more This could be interpreted as supporting either the view
aggressive behavior. that PL may evolve by more than 1 molecular pathway
Unlike other forms of liposarcoma, PL has not been or, alternatively, that such cases are in actuality DL in
associated with a recurring and consistent cytogenetic which partial lipoblastic differentiation occurs.
abnormality. MDM2 gene amplification, long considered In summary, superficial PLs confined to the dermis
the molecular hallmark of WDL/DL, has been reported and subcutis have a much more favorable prognosis,
compared with their deep-seated counterparts, despite
their high grade. We attribute this to their small size,
TABLE 3. Results—Follow-up Information superficial location, and surgical resectability, factors that
Follow-up available, n 24 have been imputed for the excellent course of other sar-
Length of follow-up 1-192 mo (median = 48) comas confined to the skin, such as leiomyosarcoma and
Local recurrence
Single recurrence, n 1 atypical fibroxanthoma. Furthermore, the presence of
Multiple recurrences, n 3 MDM2 gene amplification in a small subset of histolog-
No recurrence, n 20 ically defined PL indicates greater heterogeneity in this
Time to first recurrence 4-80 mo (median = 26) group of lesions than is generally recognized. Whether
Distant metastasis None
Survival status
MDM2 amplification should be used as evidence to
Alive, no evidence of disease, n 19 classify such lesions within the spectrum of WDL/DL or
Alive with disease, n 2 should be accepted as PL evolving by way of an alternate
Died of disease, n 0 pathway is not clear. Tumors with MDM2 gene amplifi-
Died of unrelated cause, n 3 cation, however, did not appear to segregate into any
Lost to follow-up, n 5
unique histologic or biological group.

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Am J Surg Pathol  Volume 36, Number 7, July 2012
ACKNOWLEDGMENTS
The authors thank the following pathologists and
treating physicians for their gracious contribution of case
material, clinical history, and clinical follow-up:
Dr P. Bellaire, Albany, NY; Dr S. Brown, Salem, VA;
Dr I. Cossette, Spokane, WA; Dr T. Cudahy, Indianapolis,
IN; Dr N. Damera, Danville, IN; Dr M. Dhar, Naperville,
IL; Dr J. Felgenhauer, Spokane, WA; Dr L. Flores, St
Louis, MO; Dr C. Heaton, Manassas, VA; Dr C. Helm-
stedter, Baldwin Park, CA; Dr J. Hoffman, Atlanta, GA; Dr
R. Hurwitz, Indianapolis, IN; Dr L. Hutchins, Little Rock,
AR; Dr C. Hunter, Broken Arrow, OK; Dr T. Johnson,
Picayune, MS; Dr B. Kamen, New Brunswick, NJ; Dr A.
Marshall, Lexington, KY; Dr B. McKenna, Ann Arbor, MI;
Dr M. McMullen, Spring Hill, FL; Dr T. Mervak, South-
field, MI; Dr D. Miller, Charlotte, NC; Dr R. Nicholas,
Little Rock, AR; Dr S. Oskouei, Atlanta, GA; Dr T.
Puckett, Hattiesburg, MS; Dr R. Rao, Brooksville, FL; Dr
C. Rich, Charlotte, NC; Dr P. Roddey, Charlotte, NC; Dr
B. Rougraff, Indianapolis, IN; Dr G. Segall, Youngstown,
OH; Dr F.M. Sexton, Charlotte, NC; Dr J. Skovronsky,
Manassas, VA; Dr K. Smith, Oklahoma City, OK; Dr R.
Thomas, Little Rock, AR; Dr T. Tong, New York, NY; Dr
D. Weissmann, New Brunswick, NJ; Dr K. Westphal, Santa
Cruz, CA; and Dr R. Zuch, Baldwin Park, CA.
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