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Intimal Sarcoma Is the Most Frequent
Primary Cardiac Sarcoma
Clinicopathologic and Molecular Retrospective Analysis
of 100 Primary Cardiac Sarcomas
Agnès Neuville, MD, PhD,*wz Françoise Collin, MD,y Patrick Bruneval, MD,8
Marie Parrens, MD,*z Françoise Thivolet, MD,# Anne Gomez-Brouchet, MD, PhD,**
Philippe Terrier, MD,ww Vincent Thomas de Montpreville, MD,zz François Le Gall, MD,yy
Isabelle Hostein, PhD,z Pauline Lagarde, MsC,*wz Frédéric Chibon, PhD,wz
and Jean-Michel Coindre, MD*wz
Abstract: We report novel molecular and pathologic features of
sarcomas involving the heart. Intimal sarcoma appears as the
most frequent primary cardiac sarcoma within the largest described
series of 100 primary cardiac sarcomas. Immunohistochemical
analysis, fluorescence in situ hybridization, real-time polymerase
chain reaction, and array-comparative genomic hybridization
were performed on materials from 65 women and 35 men, aged
18 to 82 years (mean 50 y), retrieved from the French Depart-
ments of Pathology, between 1977 and early 2013. Right and left
heart was involved in 44 and 56 cases, respectively. There were
42 intimal sarcomas, 26 angiosarcomas, 22 undifferentiated
sarcomas, 7 synovial sarcomas, 2 leiomyosarcomas, and 1 pe-
ripheral neuroectodermal tumor. All but 1 angiosarcomas or-
iginated from the right heart, whereas 83% of the intimal
sarcomas and 72% of the undifferentiated sarcomas were from
the left heart. MDM2 overexpression was immunohistochemi-
cally observed in all intimal sarcomas, as well as in 10 of the 22
undifferentiated sarcomas and in 5 of the 26 angiosarcomas.
MDM2 amplification was only demonstrated in intimal sarco-
mas. Genomic analysis showed a complex profile, with recurrent
12q13-14 amplicon involving MDM2, 4q12 amplicon involving
KIT and PDGFRA, 7p12 gain involving EGFR, and 9p21 de-
letion targeting CDKN2A. Immunohistochemical detection of
MDM2 overexpression can easily detect intimal sarcoma, pro-
vided that molecular aberration is proved. As resections are
limited to the left atrium, this histologic subtype could benefit
from therapies targeting PDGFRA or MDM2.
Key Words: cardiac sarcoma, intimal sarcoma, MDM2 ampli-
fication
(Am J Surg Pathol 2014;38:461–469)
Primary cardiac sarcomas are rare but represent the
majority of primary malignant cardiac tumors. There
are few series describing sarcomas of the heart,1–8 and the
majority of publications refers to case reports. Among the
reported sarcomas, angiosarcomas appear to be the most
prominent type9,10; however, many other histologic types
are described, such as leiomyosarcoma, rhabdomyosarco-
ma, undifferentiated sarcoma, or myxofibrosarcoma. Tu-
mor location within the heart chambers correlates with
histologic types of angiosarcomas in the right heart and of
other sarcomas in the left heart.10 The prognosis of these
tumors is poor and is more influenced by the surgical
possibilities rather than by the histologic subtype.11 Intimal
sarcoma has not yet been reported in the heart. Among
major sarcomas of large vessels, intimal sarcoma is char-
acterized as an undifferentiated and aggressive sarcoma, for
which overexpression and amplification of MDM2 has
been described.12 Genomic and functional studies showed
an amplification and activation of PDGFRA, opening
therapeutic opportunities using receptor tyrosine kinase
inhibitors.13 In this study, we report the characterization of
the largest series of 100 primary cardiac sarcomas for their
clinicopathologic and molecular features. We performed
immunohistochemical analyses with a large panel of anti-
bodies as well as molecular analyses with a specific focus on
MDM2, with the aim of identifying histologic and molec-
ular diagnostic tools and laying the molecular foundations
for novel targeted therapies.
From the *University of Bordeaux; wINSERM U916; zDepartment of
Biopathology, Institut Bergonié, Bordeaux; yDepartment of Patho-
logy, Centre Georges-François Leclerc, Dijon; 8Department of
Pathology, Hôpital Européen Georges Pompidou, Paris; zDepart-
ment of Pathology, Hôpital du Haut-Lévèque, Pessac; #Department
of Pathology, Hôpital Universitaire, Lyon; **Department of Patho-
logy, Hôpital Rangueil, Toulouse; wwDepartment of Pathology, In-
stitut Gustave Roussy, Villejuif; zzDepartment of Pathology, Centre
Chirurgical Marie Lannelongue, Le Plessis Robinson; and yyDe-
partment of Pathology, Hôpital Universitaire, Rennes, France.
Presented in abstract form at the 101st Annual Meeting of the United
States and Canadian Academy of Pathology, Vancouver, BC,
Canada, March 2012.
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: Agnès Neuville, MD, PhD, Department of Bio-
pathology, 229 cours de l’Argonne, 33076 Bordeaux Cedex, France
(e-mail: a.neuville@bordeaux.unicancer.fr).
Copyright r 2014 by Lippincott Williams & Wilkins
ORIGINAL ARTICLE
Am J Surg Pathol � Volume 38, Number 4, April 2014 www.ajsp.com | 461
MATERIALS AND METHODS
A total of 122 cases of primary cardiac sarcomas were
retrieved from the consult files of the Department of Path-
ology of Institut Bergonié, University hospital, Bordeaux;
Centre Georges-François Leclerc, Dijon; University hospi-
tal, Lyon; University hospital, Nantes; University hospital,
Paris; Marie Lannelongue Surgical Center, Paris; University
hospital, Rennes; University hospital, Toulouse and Gustave
Roussy Institute, Villejuif, from a period ranging from 1977
to early 2013. Clinical information on patient age and sex
and on tumor location and size was retrieved from hospital
records. Representative hematoxylin and eosin–stained slides
were reviewed by the first 2 authors (A.N. and F.C.) and
the last author (J-M.C.). The final diagnosis was collegially
accepted, taking into account the results of immuno-
histochemical analysis and molecular biology. The tumors
were classified according to the grade of the Fédération
Nationale des Centres de Lutte Contre le Cancer, taking into
account the tumor differentiation, the presence of necrosis,
and the mitosis count.14 Twenty-two cases were discarded
from the study because of vessel origin, metastatic location,
benign tumor, or lack of sufficient material. Finally, fixed
and paraffin-embedded tissues for 100 cases and frozen
samples for 7 cases were retrieved. Samples were fixed in
formalin (n=83) or Bouin fixative (n=17).
Ethical approval from the scientific advisory board
of Institut Bergonié was obtained. The samples were
centralized in the Biological Resources Center of Institut
Bergonié (http://www.bergonie.org/fr/la-recherche/centrederes
sourcesbiologiques.html), which received the agreement
from the French authorities to deliver samples for scien-
tific research (number AC-2008-812), approved by the
Committee of Protection of Individuals.
For each case, immunohistochemical staining anal-
yses were performed with the following monoclonal (mc)
and polyclonal (pc) antibodies: pankeratin AE1/AE3 (mc,
PCK26, prediluted; Ventana), EMA (mc, E29, 1/60;
Dako), a-smooth muscle actin (mc, 1A4, 1/12,000;
Sigma), desmin (mc, D33, 1/100; Dako), h-caldesmon
(mc, h-CD, 1/50; Dako), myogenin (mc, LO26, 1/20;
Novocastra), CD31 (mc, JC/70 A, 1/50; Dako), CD34
(mc, QBEnd10, 1/100; Beckman Coulter), S100 protein
(pc, Z311, 1/500; Dako), MDM2 (mc, 1F2, 1/100; In-
vitrogen), CDK4 (mc, DCS-31, 1/100; Invitrogen),
HMGA2 (pc, 1/500; Biocheck INC). The preparations
were entirely processed on automate Ventana-Bench-
mark-XT (avidin-biotin-peroxidase complex method).
For all the cases positive with MDM2 and/or
CDK4 and/or HMGA2 antibodies and fixed in formalin,
fluorescence in situ hybridization (FISH) was carried out
on 5-mm-thick paraffin-embedded tissue sections.15 Slides
were deparaffinized for 3�10 minutes in xylene, washed
in 100% ethanol, air-dried, incubated in 2� sodium sal-
ine citrate(SSC) at 721C for 40 minutes, incubated in a
proteinase K solution (500 mg/mL in 2� SSC; Roche,
Meylan, France) at 451C for 5 to 80 minutes, washed in
2� SSC for 2�3 minutes at room temperature, and
stored in 70% ethanol at 41C. Two hundred nanograms
of the SpectrumGreen-labeled BAC clone RP11-775J10
containing the MDM2 gene and the SpectrumOrange-
labeled BAC clone RP11-571M6 containing the CDK4
gene (Roswell Park Cancer Institute, Buffalo, NY) were
hybridized according to the standard procedures. A
minimum of 100 nuclei per slide was visualized.
For all the cases positive with MDM2 and/or CDK4
and/or HMGA2 antibodies and fixed in Bouin fixative, and
for cases in which FISH results were uninterpretable,MDM2
and CDK4 gene amplification was analyzed by real-time
polymerase chain reaction (qPCR) on paraffin-embedded
material, as previously described.16 PCR amplification was
performed using a 96-well plate (Applied Biosystems, Foster
City, CA) with a 50mL final reaction mixture containing
300nM of each primer and 200nM probe in a 1� qPCR
buffer containing a passive reference (Rox fluorochrome)
(Eurogentec, Seraing, Belgium). The PCR was preheated at
501C for 2 minutes and then at 951C for 10 minutes, followed
by 40 cycles at 951C for 15 seconds and 601C for 1 minute.
All reactions were performed in the ABI Prism 5700
Sequence Detection System (Applied Biosystems).
Detection of SYT-SSX transcripts was performed
using qPCR from 50mg of fixed, embedded tumor tissue,
removed by scraping the block with a sterile disposable
scalpel. Protocols for RNA extraction and reverse tran-
scription PCR were described in detail by Bijwaard et al.17
Array-comparative genomic hybridization (aCGH)
analysis was performed on frozen samples, as previously
described.18 DNA was hybridized to 8�60k whole-genome
Agilent arrays (G4450A) according to the manufacturer’s
protocol. The ADM-2 algorithm of comparative genomic
hybridization Analytics v4.0.76 software (Agilent) was used
to identify DNA anomalies at the probe level.
RESULTS
Clinicopathologic Findings
The 100 cases originated from 65 women and 35 men
(female/male, 1.8:1). The mean age of the patients was 50
years (range, 18 to 82 y); 53 years for women (range, 19 to
82 y) and 45 years for men (range, 18 to 82 y).
The mean tumor size was 57mm (range, 7 to 150mm).
The histologic samples comprised 30 biopsies and 70 sur-
gical specimens. The most common origin of the tumors was
TABLE 1. Histologic Types of Primary Cardiac Sarcoma
Histology Before Review (n) After Review (n)
Intimal sarcoma 6 42
Angiosarcoma 29 26
UDS 34 22
Synovial sarcoma 6 7
Leiomyosarcoma 12 2
PNET 3 1
Myxofibrosarcoma 4 0
Rhabdomyosarcoma 3 0
PLPS 1 0
DDLPS 2 0
DDLPS indicates dedifferentiated sarcoma; n, number of cases out of 100
cases; PLPS, pleomorphic liposarcoma; PNET, peripheral neuroectodermal
tumor; UDS, undifferentiated sarcoma.
Neuville et al Am J Surg Pathol � Volume 38, Number 4, April 2014
462 | www.ajsp.com r 2014 Lippincott Williams & Wilkins
the left atrium, seen in 47 cases. Twenty-nine cases were in
the right atrium, 8 in the right ventricle, 8 in the left ven-
tricle, 7 in the 2 right cavities, and 1 in the 2 left cavities.
The most common histologic types were intimal sar-
coma (42%), angiosarcoma (26%), and undifferentiated
sarcoma (22%). The diagnoses are detailed in Table 1 with
FIGURE 1. Histologic aspects of cardiac intimal sarcomas: spindle cells sarcoma (A, HES), spindle and pleomorphic cells sarcoma
(B, HES), pleomorphic cells sarcoma (C, HES), with myxoid area (D). E and F, Atypical nuclei with mitosis (HES). HES indicates
hematoxylin and eosin stain.
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initial and post–present study diagnoses. All tumors were
classified as grade II or III according to the grade of the
Fédération Nationale des Centres de Lutte Contre le Cancer,
irrespective of their histologic type. Intimal sarcoma was
usually undifferentiated sarcoma, composed of spindle and
pleomorphic cells (Fig. 1). In 25% of cases, it could mimic
FIGURE 2. Histologic variants of cardiac intimal sarcomas (HES): spindle cells sarcoma with a storiform pattern (A); sarcoma with
rhabdomyosarcomatous differentiation (B); myxofibrosarcoma-like (C); hemangioendothelioma-like (D); epithelioid cells sarcoma
(E); synovial sarcoma-like (F).
Neuville et al Am J Surg Pathol � Volume 38, Number 4, April 2014
464 | www.ajsp.com r 2014 Lippincott Williams & Wilkins
another type of sarcoma, such as myxofibrosarcoma, syno-
vial sarcoma, or epithelioid leiomyosarcoma, or show
rhabdoid differentiation (Fig. 2). Thirty intimal sarcomas
were grade III, and 11 were grade II. Among the 26 angio-
sarcomas, 23 cases were poorly differentiated and of grade
III, and 3 cases were well differentiated and of grade II. They
were constituted of spindle cells (n=17), epithelioid cells
(n=4), pleomorphic cells (n=3), and round cells (n=2).
Undifferentiated sarcoma showed variable patterns: spindle
and pleomorphic cells in 20 cases and epithelioid cells and
round cells in 1 case each. Grade III was predominant (20
cases), with only 2 undifferentiated sarcoma classified as
grade II. In the cases of synovial sarcoma, a spindle mono-
phasic pattern was observed in 4 cases. One case had a bi-
phasic pattern, and 2 cases were composed of round cells. All
cases were high grade.
Angiosarcoma was almost equally distributed
among women with regard to age. Intimal sarcoma was,
however, predominant in women 40 years of age or older,
and undifferentiated sarcoma was mostly observed in
40- to 60-year-old men (Fig. 3).
Side origin was associated with histologic type.
Angiosarcoma was right-sided. Intimal sarcoma and un-
differentiated sarcoma were left-sided (Fig. 4).
Immunohistochemistry
All intimal sarcomas were positive for MDM2
(Fig. 5). More than two thirds were also positive for
CDK4 and HMGA2. Positivity for SMA or desmin was
observed in one third of cases, but none showed positivity
for h-caldesmon. Positivity for other antibodies was weak
(Table 2), and 5 positive cases for myogenin were noted.
All angiosarcomas were positive for CD31, and 88% of
them were positive for CD34. Moreover, 19% and 15% of
them, representing 8 cases, were also positive for MDM2
and HMGA2, respectively. The immunohistochemical
profile of undifferentiated sarcoma was not specific. Pos-
itivity for MDM2 and HMGA2 was noted in 27% and
40% of cases, respectively. The 2 leiomyosarcomas coex-
pressed SMA, desmin, h-caldesmon, and MDM2. Among
the cases of synovial sarcoma, 4 were positive for both
cytokeratin and EMA, 2 were positive only for cytoker-
atin, and 1 was positive only for EMA. The positivity for
epithelial markers was always focal, but none of the
synovial sarcomas expressed MDM2 or HMGA2.
Molecular Features
Molecular analysis, using FISH, qPCR, or aCGH,
was performed in 70 cases, and results were obtained for 67
cases (Table 3). MDM2 amplification was detected in 42
sarcomas. In the majority of cases, it could be confirmed by
FISH. The aspect of the FISH was different from that
usually observed in MDM2 amplification of dediffer-
entiated liposarcoma. The numerous copies were organized
in small clusters scattered throughout the cell, instead of
large clusters (Fig. 6). All cases of angiosarcoma and un-
differentiated sarcoma that expressed MDM2 and/or
HMGA2 protein were negative for MDM2 amplification.
The fusion transcript of synovial sarcoma was detected in 7
sarcomas, with 4 cases of SSX1 and 3 cases of SSX2. On
the 3 initial cases of suspected peripheral neuroectodermal
tumor, only 1 was rearranged for EWS in FISH, and 1 case
turned out to be positive for SSX1. Genomic analysis by
aCGH was performed on frozen material for 7 cases. These
cases were first studied par FISH. Three cases were am-
plified for MDM2, 2 cases were negative, and 2 cases were
uninterpretable. The 2 negativecases were undifferentiated
pleomorphic sarcomas with overexpression of MDM2.
Their genomic profiles were complex with alterations on all
chromosomes but without 12q13-14 amplicon. The 3 pos-
itive cases and the 2 uninterpretable cases in FISH, corre-
sponding to undifferentiated sarcomas with overexpression
of MDM2, showed a complex genomic profile as well, with
alterations on all chromosomes, some of which were
shared, especially amplifications in 12q13 and 4q12 regions
including MDM2, KIT, and PDFGRA, gain in 7p12 region
including EGFR, and loss of 9p21 region targeting
CDKN2A (Fig. 7).
FIGURE 3. Repartition of cardiac sarcomas among sex, his-
tologic type, and age. AS indicates angiosarcoma; IS, intimal
sarcoma; UDS, undifferentiated sarcoma.
FIGURE 4. Side origin of cardiac sarcomas. AS indicates
angiosarcoma; IS, intimal sarcoma; UDS, undifferentiated
sarcoma.
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DISCUSSION
In this study, we characterize the largest series of
primary cardiac sarcomas, using a systematic panel of im-
munohistochemical markers and modern genetic molecular
tools for a better classification. As previously reported,2,5,9
we observed a significant group of angiosarcomas arising
almost exclusively in the right atrium, as well as a few
synovial sarcomas and leiomyosarcomas.
FIGURE 5. Immunohistochemical profile of cardiac intimal sarcomas: diffuse (A) or focal (B) positivity of MDM2. C, Myogenin
positivity when a rhabdomyosarcomatous component is present. D, Positivity of cytokeratin can misdiagnose a synovial sarcoma.
TABLE 2. Results of Immunohistochemical Panel in Cardiac Sarcoma
IS (n [%]) AS (n [%]) UDS (n [%]) SS (n [%]) LMS (n [%])
MDM2 42 (100) 5 (19) 6 (27) 0 2 (100)
CDK4 30 (71) 0 0 0 1 (50)
HMGA2 37 (88) 4 (15) 9 (40) 0 1 (50)
Desmin 14 (33) 0 2 (9) 1 (14) 2 (100)
Myogenin 5 (11) 0 0 0 0
H-caldesmon 0 0 1 (4.5) 0 2 (100)
SMA 15 (35) 5 (19) 5 (22) 1 (14) 2 (100)
CD31 0 26 (100) 0 0 0
CD34 3 (7) 23 (88) 3 (13) 0 0
KAE1/AE3 6 (14) 2 (7) 6 (27) 6 (85) 0
EMA 3 (7) 0 1 (4.5) 5 (71) 0
S100 3 (7) 0 2 (9) 0 0
AS indicates angiosarcoma; IS, intimal sarcoma; LMS, leiomyosarcoma; SS, synovial sarcoma; UDS, undifferentiated sarcoma.
Neuville et al Am J Surg Pathol � Volume 38, Number 4, April 2014
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However, our approach allowed the identification
of intimal sarcoma as the most frequent cardiac sarcoma
histotype. Intimal sarcoma is a malignant mesenchymal
tumor arising in large blood vessels of the systemic and
pulmonary circulation19 and is usually a poorly differ-
entiated sarcoma composed of atypical spindle and/or
pleomorphic cells with the possibility of myxoid areas or
epithelioid morphology. Rare cases may contain areas of
rhabdomyosarcomatous differentiation. Our study re-
vealed that all cases showed overexpression and amplifi-
cation of MDM2. Beside amplification of the 12q12-15
region involving MDM2, CDK4, HMGA2, DDIT3, and
GLI, aCGH analysis showed amplification of KIT and
PDGFRA and gain of EGFR in most cases as well as loss
of CDKN2A. A systematic use of immunohistochemistry
for MDM2 in poorly differentiated heart sarcomas al-
lowed the identification of potential intimal sarcomas,
which had to be confirmed by FISH, qPCR, or aCGH
analysis. In our series, about two third (42 of 64) of
poorly differentiated sarcomas showed an MDM2 am-
plification, and, when performed, aCGH analysis showed
the typical genomic profile previously reported in intimal
sarcomas of large vessels.13 Five of 42 (12%) sarcomas
showed a rhabdomyosarcomatous component. Whether
the name intimal sarcoma should be restricted to only
poorly differentiated sarcomas with amplicons on 12q12-
15 and 4q12 or to any poorly differentiated sarcomas
arising in the large vessels and the heart is questionable,
but, in terms of molecular classification and potential
therapeutic targets, it may be important to clearly sepa-
rate typical intimal sarcomas with MDM2 and/or
PDGFRA amplification and/or EGFR gain from un-
differentiated pleomorphic sarcomas showing a complex
genomic profile without these molecular features.
True dedifferentiated liposarcoma also shows ampli-
fication of the 12q12-15 region and can arise in the thorax
with a secondary cardiac involvement.20 However, a good
tumor sampling usually identifies a well-differentiated lip-
osarcomatous component, and the whole genomic profile is
simpler with no amplification of 4q12 and gain of 7p12.21
Parosteal and central well-differentiated osteosarcomas also
bear an amplification of the 12q12-15,22 but both clinical
situations and histologic aspects are very different.
In our study, we systematically used a panel of
immunohistochemical markers to rule out a secondary
tumor such as a carcinoma and melanoma and to help
classify a sarcoma. The most useful markers were
CD31 for confirming or identifying an angiosarcoma,
MDM2 for identifying potential intimal sarcomas, h-
caldesmon for identifying leiomyosarcomas, and muscu-
lar markers for identifying a heterologous component in
intimal sarcomas. Epithelial markers were also useful for
identifying synovial sarcomas. Other markers were used
according to the suggested diagnosis by histology.
Molecular cytogenetic tools are being needed in-
creasingly more often to classify sarcomas.23 In the field
of cardiac sarcomas, identification of MDM2 amplifica-
tion mainly by FISH analysis but also by qPCR and
aCGH can now be considered as a determinant tool.
Overexpression of MDM2 identified by immunohisto-
chemistry is not specific, as about 20% of sarcomas with
no MDM2 amplification are positive as previously re-
ported,24 and was found in this series in angiosarcomas
and undifferentiated sarcoma. In contrast, CDK4 over-
expression is almost specific of a CDK4 amplification but
less sensitive than MDM2 overexpression. Molecular
cytogenetic tools also offer the possibility of synovial
sarcomas and peripheral neuroectodermal tumor diag-
noses. In this rare location, such diagnoses, even when
histologically typical, should certainly be confirmed by
molecular cytogenetics.25
Data obtained with aCGH in our series are quite
comparable to those described by Dewaele et al13 in intimal
sarcomas of large vessels. Intimal sarcoma of large blood
vessels and of the heart probably represent the same entity.
Recurrent alterations of 12q13-14, 7p12, 9p21, and 4q12
were observed with amplification of MDM2, gain of
EGFR, and deletion of CDKN2A for all the tested cases
and KIT and PDGFRA amplification in 2 of 5 cases (40%),
respectively. These genomic alterations could represent
FIGURE 6. FISH analysis in intimal sarcoma: the presence of a
large copy number of MDM2 gene organized in small clusters.
TABLE 3. Molecular Analysis of Cardiac Sarcoma
IS (n [%]) AS (n [%]) UDS (n [%]) LMS (n [%])
FISH MDM2/CDK4 29/29 (100) 0/7 (0) 0/9 (0) 0/1 (0)
qPCR MDM2/CDK4 8/8 (100) 0/1 (0) 0/4 (0) 0/1 (0)
aCGH 5/5 (100) NA 0/2 (0) NA
AS indicates angiosarcoma; IS, intimal sarcoma; LMS, leiomyosarcoma; NA, not available; UDS, undifferentiated sarcoma.
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therapeutic targets. In fact, the prognosis of primary car-
diac sarcoma is poor, with a median overall survival of 17.2
months,26 depending on location, size of the tumor, and
localized or metastatic stage. For nonmetastatic patients,
complete surgical resection, often unachievable, remains the
best therapeutic option associated with prolonged survival.
Chemotherapy and radiotherapy can improve pro-
gression-free survival, especially for incomplete resection or
nonresected patients. But the therapeutic management is
further decided regardless of the histologic type of primary
cardiac sarcoma. Molecular evidences and preliminary tests
on celllines of intimal sarcoma have shown a potential
effect of tyrosine kinase inhibitors on intimal sarcoma.13,27
However, the use of MDM2 small-molecule antagonists to
block the interaction between p53 and MDM2, restore the
p53 pathway, and inhibit tumoral cell proliferation has
already been evaluated.28,29 This new therapeutic approach
shows encouraging perspectives at both the animal phar-
macology and human clinical levels.30,31
In conclusion, our study describes the im-
munohistochemical and molecular features of the largest
series of primary cardiac sarcomas. It shows that intimal
sarcoma exists in the heart and that it represents the most
frequent sarcoma histotype. As in large vessels, this type
of sarcoma is characterized by overexpression and am-
plification of MDM2. The genomic profile reveals a sar-
coma with alterations on all chromosomes but with
recurrent alterations in genes like MDM2, PDGFRA, or
EGFR that could lay the ground for novel targeted
therapeutic approaches. Despite the presence of 12q13-14
amplicon, intimal sarcoma shares no other features with
dedifferentiated liposarcoma but could benefit from ad-
vanced clinical trials developed around MDM2.
ACKNOWLEDGMENTS
The authors thank Valérie Dapremont, Agnès Ribeiro,
Mélanie Muller, and Marlène Boucheix for technical work.
The authors also thank the following centers that partici-
pated in the study: University hospital, Besancon; University
hospital, Clermont-Ferrand; University hospital, Dijon; Uni-
versity hospital, Lille; University hospital, Limoges; University
hospital, Marseille; Institut Pauli Calmette, Marseille; Path-
ology Center, Montpellier; University hospital, Nancy; Antoine
Lacassagne Center, Nice; Institut Curie, Paris; University
hospital, Paris; Saint Joseph hospital, Paris; University hos-
pital, Poitiers; University hospital, Saint Etienne.
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FIGURE 7. Penetrance plot of aCGH analysis in intimal sarcoma: among the numerous genomic alterations, amplification of
MDM2 is consistent (A), amplification of PDGFRA is observed in 40% of cases (B), gain of EFGR in 100% of cases (C), and deletion
of CDKN2A in 100% of cases (D).
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