Epithelioid Soft Tissue Tumors

A. Paolo Dei Tos,a,1 Andrew J. Wagner,b,1 Piergiorgio Modena,c,1

Alessandro Comandone,d,2 and Serge Leyvraze,2

Epithelioid neoplasms are generally carcinomas. As confirmation that every rule is meant to be
broken, some sarcomas demonstrate epithelioid morphology, and can even express cytokeratins.
These sarcomas have unique behavior, for example, a much higher rate of lymph node metastasis
than other sarcomas. This group of sarcomas also presents diagnostic and therapeutic challenges to
those clinicians who help patients contend with these difficult tumors. In this review, some of the
major categories of epithelioid soft tissue tumors are described, with clinical data reported as
available. Some of these tumors provide excellent opportunities to examine newer protein-targeted
agents in investigational settings.
Semin Oncol 36:347-357 2009 Elsevier Inc. All rights reserved.

S ome mesenchymal neoplasms characteristically

exhibit an epithelioid morphology, often accom-
panied by expression of epithelial differentiation
markers. This phenomenon makes the differential diag-
nosis of this group of neoplasms particularly challeng-
ing. This brief review will focus mostly on malignant
epithelioid mesenchymal tumors.
EPITHELIOID SARCOMA
First described by Enzinger in 1970,1 epithelioid
sarcoma (ES) represents the prototypical example of
epithelioid mesenchymal malignancy. It generally oc-
curs in the distal extremities of adolescents and young
adults. It may be found rarely in children.2 About 25%
of cases arise superficially, and males outnumber fe-
males 2:1. The original paper1 and the 1985 follow-up
report3 identified the tumor to be indolent but progres-
sive. Despite its relatively bland histology, ES is charac-
terized by multiple recurrences and high metastatic
aDepartment of Anatomic Pathology, General Hospital of Treviso, Tre-
viso, Italy.
bCenter for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute,
Boston, MA.
cUnit of Molecular CytogeneticsUO5, Fondazione IRCCS, Istituto Na-
zionale dei Tumori, Milano, Italy.
dSC Oncologia Ospedale Gradenigo, Torino, Italy.
eCentre Pluridisciplinaire dOncologie, University Hospital, Lausanne,
Switzerland.
1,2These authors contributed equally to this work.
Address correspondence to Angelo Paolo Dei Tos, MD, Director of
Anatomic Pathology, General Hospital of Treviso, Piazza Ospedale 1,
31100 Treviso, Italy. E-mail: apdeitos@ulss.tv.it
0270-9295/09/$ - see front matter
2009 Elsevier Inc. All rights reserved.
doi:10.1053/j.seminoncol.2009.06.005
rates. Typically ES shows a slow progression character-
ized by numerous recurrences almost always in the
proximal direction, eventually followed by distant me-
tastasis (most often to the lungs). Characteristically, ES
propagates along fascial planes, tendons, and nerve
sheaths. The overall recurrence rate reaches 90%,
whereas the metastatic rate ranges in different series
between 35% 40%.4 7 Ten-year survival rates vary from
25%50%, with recurrence, metastasis, and death being
documented even 20 years or more following the initial
diagnosis.
Histologically, ES exhibits a relatively variable mor-
phology that makes this diagnosis one of the greatest
challenges of surgical pathology. In addition, classic ES
often shows a fairly bland appearance to the extent that
its real biological potential may be overlooked. As a
consequence, ES also represents a cause of medical
litigation. Different growth patterns are recognized in
ES that also sometimes can be observed in the same
lesion.
The classic necrobiotic (granulomatous) growth
pattern consists of coalescent cystic nodules lined by
festoons composed of polygonal and spindled cells.
The spaces are filled with a mixture of necrotic debris
and hyalinized collagen (Figure 1). The epithelial-ap-
pearing cells are mostly centrally located with the spin-
dled elements pushed at the periphery of the nodules.
The transition between the two cell types is usually
gradual. Nuclei are rounded and vesicular, and contain
small nucleoli. Pleomorphism is usually minimal. In
rare cases necrosis can be minimal or totally absent
(so-called solid nodular variant). Immunohistochemi-
cally, all variants of ES are characteristically positive for
vimentin, low and high molecular weight cytokeratins,
and epithelial membrane antigen (EMA).8 CD34 immu-

Seminars in Oncology, Vol 36, No 4, August 2009, pp 347-357 347

348
Figure 1. The classic variant of epithelioid sarcoma con-
sists of coalescent cystic nodules lined by festoons com-
posed of polygonal and spindled cells. The spaces are filled
with a mixture of necrotic debris and hyalinized collagen.
(Courtesy of A.P. Dei Tos.)
nopositivity is present in half of cases.9 Granuloma
anulare and rheumatoid nodule represents the main
differential diagnoses for the classic ES subtype10; how-
ever, immunonegativity for keratins and positivity for
CD68/CD163 will permit separation.
The fibroma-like variant consists predominantly of
spindle cells, with an inconspicuous epithelioid com-
ponent.11 Neoplastic cells show minima atypia and are
set in an abundant collagen-rich stroma. Cytokeratin
positivity is extremely helpful in this context.
The angiomatoid variant is perhaps the rarest of
the ES variants. Histologically, the tumors show cys-
tic, blood-filled spaces bordered by epithelioid and
spindled cells. Endothelial differentiation markers
are negative, therefore allowing separation from ep-
ithelioid angiosarcoma.
The proximal type represents the most important
variant of ES. It tends to arise in deep tissues of limb
girdles or buttocks, vulva, and perineum, and is com-
posed of polygonal cells exhibiting higher cytologic
atypia than the other variants of ES.12 Mitotic activity is
usually high and often a rhabdoid phenotype is ob-
served, characterized by the presence of eosinophilic
cytoplasm, and eccentric vesicular nuclei with large
nucleoli (Figure 2). Smooth muscle actin expression
can be detected; however, desmin is most often nega-
tive. It should be emphasized that a rhabdoid pheno-
type is more commonly found in the proximal type
but is not unique to this subtype. Moreover, since the
rhabdoid phenotype can be found in a broad variety of
malignancies wherein it is associated with poor prog-
nosis, it has been postulated that it simply represents a
pattern of dedifferentiation.1315 The proximal variant
of ES seems to be associated with increased risk of
recurrence and metastasis.12,16
A.P. Dei Tos et al
The differential diagnosis of ES includes carcinoma,
melanoma, and synovial sarcoma, as well as epithelioid
variants of mesenchymal neoplasm, particularly vascu-
lar tumors. Carcinoma, either adnexal or metastatic, is
generally negative for CD34, while about half of ES are
positive. When occurring in the skin, carcinoma also
may have associated epithelial dysplasia or carcinoma
in situ.
Amelanotic melanoma could be confused with prox-
imal type ES as it also can exhibit a rhabdoid pheno-
type.13 The presence of epidermal tropism along with
expression of S100 and/or other melanoma markers
such as HMB45, Melan-A, and tyrosinase, which are not
present in ES, represent helpful diagnostic clues.
Synovial sarcoma and ES both express cytokeratins
and EMA; however, there are sufficient clinical and
morphological differences. ES more often involves dis-
tal structures including skin, while synovial sarcoma is
usually more proximal, and is rarely superficial. Classic
synovial sarcoma, both monophasic and biphasic, does
not overlap morphologically with ES. However, a large
cell undifferentiated variant of synovial sarcoma has
been described that may cause diagnostic difficulties.
In such cases genetic analysis may prove extremely
helpful by demonstrating the synovial sarcomaspecific
translocation t(X;18).
As mentioned, extra-renal rhabdoid tumor (ERT)
represents the main differential diagnosis for the prox-
imal type of ES. If rhabdoid features predominate, sep-
aration may be virtually impossible. Clinically, ERT
tends to occur in infants and young children and to
pursue an extremely aggressive behavior. Loss of INI1
immunoreactivity is observed in both ES and ERT,17,18
raising the possibility of the existence of a morpho-
logic continuum between the two entities. However,
it seems likely that different molecular mechanisms
may lead to INI1 abnormalities in several unrelated
Figure 2. Epithelioid sarcoma proximal type composed of
polygonal cells exhibiting higher cytologic atypia than the
other variants of ES. (Courtesy of A.P. Dei Tos.)
Epithelioid soft tissue tumors
subsets of mesenchymal tumors.19 It appears that
INI1 expression is not related to clinical outcome, by
multivariate analysis of one of the larger studies of
patients with ES.20
Irrespective of subtype, ES is a unique tumor. ES
shows a tendency to metastasize to regional nodes (at
variance with most other sarcomas), although lung is
the most common site, like most sarcomas. Aggressive
surgery still represents the primary treatment option
despite an 85% local-regional recurrence rate. The fre-
quency of regional lymph node metastasis is typically
between 22% 45%. Distant metastatic disease has been
reported in up to 45% of patients with ES. The metas-
tasis is usually to the lung and pleura. Lymphatic and
pulmonary metastases occur particularly when there is
vascular invasion. Unlike other sarcomas that are cur-
rently treated with limb-sparing surgery associated
with chemotherapy and/or radiotherapy, when ES
arises in the distal extremity, consideration should be
given to amputation, thereby preventing relentless
proximal tumor progression.21 Patients must be moni-
tored with yearly lung x-rays since recurrence or me-
tastasis may occur many years after the initial diagnosis
and treatment.22
Callister et al reviewed the records of 24 patients
with localized ES treated at M.D. Anderson Cancer
Center.22 All patients were treated with conservative
surgery and radiotherapy. At a median follow-up of 131
months, 14 patients had relapsed and 13 patients had
died. The actuarial overall and disease-free survival
rates at 10 years were 50% and 37%, respectively. Local,
nodal, and metastatic failures occurred in 7, 4, and 10
patients, respectively, yielding 10-year actuarial local,
nodal, and metastatic control rates of 63%, 81%, and
56%, respectively. Univariate analysis indicated that
size 5 cm and extremity location were favorable
prognostic factors for overall, disease-free, and metas-
tasis-free survival. The actuarial 5-year overall, disease-
free, and metastasis-free survival rates were 79% versus
25% (P .002), 51% versus 13% (P .03), and 79%
versus 13% (P .001), respectively, for lesion size 5
cm versus 5 cm. The actuarial 5-year overall, disease-
free, and metastasis-free survival rates were 77% versus
39% (P .002), 56% versus 0% (P .01), and 78%
versus 17% (P .01), respectively, for extremity versus
non-extremity location. Multivariate analysis of the fac-
tors correlating with the overall, disease-free, and me-
tastasis-free survivals confirmed the favorable prognos-
tic significance of small lesion size.22
The largest study of ES reported to date reinforces
many of these findings. In the 441 patients identified
with ES in the Surveillance, Epidemiology and End
Results (SEER) database, disease-specific survival de-
clined until approximately 8 years after diagnosis, after
which survival was unrelated to ES. The overall inci-
dence of ES during 2005 was 0.041 per 100,000, an
increase of about 5% per year since 1973. By multivar-
349
iate analysis, age under 16 years, negative nodes, local-
ized disease, and operability of primary disease inde-
pendently predicted survival.23
ES can respond to systemic agents such as doxoru-
bicin, ifosfamide, or cisplatin, but responses are gener-
ally transient and did not affect disease-free survival in
one series.24 Prospective studies are needed to identify
novel therapeutics for metastatic disease.
ALVEOLAR SOFT PART SARCOMA
Alveolar soft part sarcoma (ASPS) represents a mes-
enchymal malignancy first described by Christopher-
son in 1952.25 Its name accurately describes the proto-
typical histological picture, represented by a proliferation
of an epithelioid, polygonal cell population organized in
an alveolar growth pattern (Figure 3). Periodic acid-
Schiffpositive intracytoplasmic inclusion bodies can
be observed in approximately 70% of cases. Clinically,
ASPS occurs most frequently in the lower limbs of
young adults, between 15 and 35 years of age. In
pediatric patients, it involves mostly the head and
neck region orbit and tongue. ASPS also has been
described occasionally in a number of other sites,
such as female genital tract, mediastinum, lung, stomach,
and bone.26,27
ASPS exhibits an invariable tendency to metastatic
spread to the lungs, bones, and brain. The clinical
course is prolonged; however, long-term follow-up in-
dicates that the vast majority of patients die of meta-
static disease within 15 years from diagnosis. Lieber-
man et al reported a 5-year survival rate of 60% and only
15% of patients demonstrated long-term disease-free
survival.26 The line of differentiation and cell of origin
of ASPS remain elusive. Early reports of MyoD1 (a
striated muscle differentiation marker) cytoplasmic im-
munopositivity most probably represent technical arti-
Figure 3. Alveolar soft part sarcoma is composed of a
proliferation of an epithelioid cell population organized in
an alveolar growth pattern. (Courtesy of A.P. Dei Tos.)
350
fact. ASPS is characterized by a specific chromosome
translocation t(X;17)(p11;q25) leading to the fusion of
the ASPL and TFE3 genes.28 Interestingly, the same
translocation can be observed in a subset of pediatric
renal cell carcinoma.29 Nuclear expression of TFE3 has
been proposed as a confirmatory diagnostic finding,30
as is the demonstration of the associated chromosome
aberration.31 The relationships between TFE3 and the
MET signaling pathway may represent a potential ratio-
nale for molecularly targeted therapy,32 as discussed by
Mertens et al in this issue of Seminars in Oncology.
Although slow-growing, ASPS has a fatal prognosis if
complete surgical resection is not possible. Reichardt
et al reviewed 757 sarcomas cases: eight had ASPS; 60
other cases from the literature with chemotherapy data
also were reviewed. Seven of eight patients developed
brain metastases with a median interval of 51 months
from primary diagnosis. All patients were still alive after
12 months of surgical procedure under curative intent
or palliation. Seven of the eight patients received an-
thracyclines or ifosfamide-containing first-line chemo-
therapy. There were no objective responses.33 Of 33
publications related to chemotherapy in ASPS, an an-
thracycline regimen was used in 29 of 47 patients. Six
of 47 patients received second- and third-line chemo-
therapy. Best response to first-line chemotherapy was
as follows: three complete responses (CRs; one after
thiotepa and two after an anthracycline regimen), no
partial responses (PRs), 17 stable disease (SD), and 27
progressive disease (PD). Two of six patients treated
with second- and third-line therapies achieved a CR
(one with anthracycline and other with interferon-al-
pha). Data from the Charit University in Berlin in 68
patients, including 13 children were as follows: CR 4%,
PR 3%, SD 41%, and PD 51%, resulting in an overall
response rate of approximately 7%.The response rate
did not seem to be significantly higher for the subgroup
treated with an anthracycline-based regimen, com-
pared to other regimens (consisting of ifosfamide, thio-
tepa, methotrexate or others; CR PR 4/40 [10%] v
1/28 [3.6%]). Ifosfamide-containing regimens did not
lead to increased efficacy in the subgroup of 15 pa-
tients: PR 7%, SD 60%, PD 33%.33 Current discussions
suggest that progression-free survival might be a better
primary endpoint to assess treatment efficacy in sarco-
mas. However, given the indolent nature of ASPS, the
clinical significance of 41% of ASPS patients with SD as
best outcome following chemotherapy must be consid-
ered when examining the overall disease course.33
For example, Ogose et al reported 57 patients with
ASPS who were monitored for 20 years.34 Seven pa-
tients underwent marginal excision without radiother-
apy, and four of them had local recurrence, at a mean
of 14 months. Three patients underwent marginal ex-
cision with preoperative or postoperative radiation
therapy. None of them had local recurrence. Thirty-six
patients had wide local excision and two patients had
A.P. Dei Tos et al
amputation with wide surgical margins. None had local
recurrence. Chemotherapy was given for metastatic
tumor and included cisplatin, ifosfamide, doxorubicin,
carboplatin, methotrexate, interferon, and interleu-
kin-2 regimens, with no responses reported. Despite
the lack of radiological responses, the overall survival
rates at 5, 10, and 15 years were 56%, 23%, and 15%,
respectively. Metastasis at presentation, tumor size, and
bone involvement at the primary site were factors in-
dicating a significantly (P .05) poorer survival.34
Newly diagnosed patients with unresectable or meta-
static ASPS should be enrolled in phase I and II clinical
trials in an attempt to identify novel active agents. The
striking finding of activity of a vascular endothelial
growth factor (VEGF) receptor-directed oral kinase in-
hibitor gives hope that even this chemotherapy-insen-
sitive sarcoma will have an Achilles heel.35
SCLEROSING EPITHELIOID FIBROSARCOMA
Sclerosing epithelioid fibrosarcoma (SEF) is a dis-
tinctive variant of fibrosarcoma that morphologically
closely mimics infiltrating carcinoma.36,37 SEF tends to
occur in the lower extremities, limb girdles, trunk, and
head and neck of adults with a peak incidence in the
fourth decade.
Histologically, SEF is generally well circumscribed
and is composed of nests and cords of eosinophilic to
clear cell epithelioid neoplastic cells, set in a densely
sclerotic stroma (Figure 4). Mitotic count is generally
low. Immunohistochemically, vimentin is consistently
positive. Rare cases may show focal EMA or even ker-
atin positivity.
Local recurrences are observed in approximately
half of patients with an overall metastatic rate of 40%.
SEF remains both a clinically and morphologically elu-
sive neoplasm, at risk to represent a heterogeneous
Figure 4. Epithelioid sclerosing fibrosarcoma is composed
of cords of eosinophilic to clear cell epithelioid neoplastic
cells, set in a densely sclerotic stroma. (Courtesy of A.P. Dei
Tos.)
Epithelioid soft tissue tumors
collection of unrelated entities if strict diagnostic crite-
ria are not met. The potential relationships to low-
grade fibromyxoid sarcoma remain to be elucidated
further,38 as noted by Mertens et al in this issue.
Ossendorf et al reviewed 90 cases in the literature
and found that the clinical behavior of this tumor was
somewhat aggressive, with recurrence after resection
in 27 of 90 patients (30%).39 Twenty-seven percent of
patients had metastases at the primary diagnosis and
the most common site were lungs (70%), bones (41%),
and pleura/chest wall (11%). A total of 38% of patients
had metastases at multiple sites. Postoperative radia-
tion was administered to 37% of patients and to one
patient preoperatively. Chemotherapy was given to
18% of patients and three patients underwent com-
bined chemotherapy and radiation therapy. Twenty-
seven patients recurred after a of mean 36 months.
Patients with tumors larger than 10 cm more com-
monly had metastasis at diagnosis. Patients with head
and neck tumors had the worse prognosis.39 Antonescu
et al analyzed 16 patients and found 50% with local
recurrence and 86% with distant metastasis at 1 year of
follow-up. SEF may be treated with wide resection, and
preoperative or postoperative radiation therapy should
be considered.36
Patients with metastatic disease should be consid-
ered for investigational trials as the response to chemo-
therapy is low.
EPITHELIOID VASCULAR TUMORS
An epithelioid morphology can be shared by vascu-
lar neoplasm exhibiting a totally different clinical be-
havior. It is possible that a spectrum of lesions exists
that includes benign lesions such as epithelioid (histio-
cytoid) hemangioma,40,41 and malignant neoplasms
such as epithelioid hemangioendothelioma (EHE)42 and
the highly aggressive epithelioid angiosarcoma of soft
tissue.43 It is common experience that transitional le-
sions exist to the extent that separation between atyp-
ical forms of EHE and angiosarcoma appears to be
challenging and sometimes somewhat arbitrary.44 The
term hemangioendothelioma should actually identify
lesions belonging to the group of low-grade malig-
nancy. This is certainly true for the retiform, kaposi-
form, and composite types of EHE. In the case of
epithelioid EHE, the metastatic rate is high enough to
justify inclusion in the malignant category.
Epithelioid Hemangioendothelioma
EHE usually presents as a painful, deep soft tissue
mass, most often located in the extremities of adult
patients.42,44 The entity formerly known as intravascu-
lar bronchioloalveolar tumor (IVBAT) is currently re-
garded as a form of primary pulmonary EHE. Bone and
liver also can be involved as primary sites. In a 23-year
351
Figure 5. EHE is composed of rounded eosinophilic cells,
organized in strands, cords or solid nests, sometimes har-
boring intracytoplasmic vacuoles. (Courtesy of A.P. Dei
Tos.)
case series, EHE represented 10 of 30 primary liver
sarcomas.45 In general, a visceral location is frequently
associated with multicentricity. Approximately half of
the cases appear to originate from a blood vessel. His-
tologically, EHE is composed of rounded eosinophilic
cells, organized in strands, cords, or solid nests, some-
times harboring intracytoplasmic vacuoles (Figure 5).
Neoplastic cells are usually cytologically bland and are
set in a myxochondroid background. Low mitotic ac-
tivity is generally observed. Immunohistochemically,
EHE express consistently factor VIII (FVIII)-related an-
tigen, CD31, CD34, and the nuclear transcription factor
FLI1.46
Approximately 30% of cases feature marked cytolog-
ical atypia, foci of necrosis, and higher mitotic activity,
which is associated with aggressive behavior.44 EHE
tends to recur locally in about 20% of cases and, in its
classic form, the metastatic rate is less than 20% and
mortality around 3%. The presence of atypical histology
raises mortality rates up to 20%. In consideration of this
clinical behavior, EHE can no longer be included in the
low-grade or borderline category. According to the
definition provided by the most recent World Health
Organization classification of soft tissue tumors, EHE
should be regarded as a fully malignant neoplasm.
Recently, an ES-like variant of EHE has been re-
ported, which makes differential diagnosis even more
challenging.47 Interestingly, these lesions were consis-
tently positive for cytokeratin, CD31, and FLI1 but
negative for CD34, making immunohistochemistry cru-
cial in the differential diagnosis with ES.
Liver EHE is a very rare vascular neoplasm with an
estimated incidence of one in 1,000,000, and a mean
age of presentation of 32 years. Mosoia et al found that
surgical treatment offers good long-term results in pa-
tients submitted to liver resection for monolobar intra-
352
hepatic disease and liver transplantation is a good op-
tion for patients with bilobar disease.48 Nudo et al
found a 36% of recurrence rate and a 5-year survival
rate of 82% for patients undergoing liver transplant for
bilobar EHE.49
Pulmonary EHE affects younger patients and more
commonly women. The patients can be divided into
twogroups: asymptomatic patients with nodules, who
have a median survival of 180 months, and patients
with symptoms of vascular endothelial cell prolifera-
tion (alveolar hemorrhage, hemoptysis, hemorrhagic
pleural effusion, anemia), who have significantly worse
survival. There is no standard treatment. In patients
with unilateral nodule, wedge resection offers the same
survival as that observed after anatomic resection (P
.15). Hilar lymph node resection has been proposed as
a standard practice, but the prognostic value of lymph
node invasion remains statistically unclear because of
the low number of patients. In patients with bilateral
nodules, PR or CR response has been reported with
interferon-alfa, and three spontaneous partial regres-
sions also have been reported. Other proposed sys-
temic therapies include corticosteroids, azathioprine,
multiple wedge resections, or simple follow-up. In pa-
tients with hemorrhagic symptoms only one report
described a complete response to carboplatin and eto-
poside chemotherapy; other treatments, including ma-
jor pulmonary resection, were unsuccessful. The me-
dian 5-year survival is 60% and patients with anemia
and hemorrhagic pleural effusion survive less than 1
year.50 A variety of chemotherapy agents have been
used anecdotally against EHE with limited success (li-
posomal doxorubicin, other anthracyclines, taxanes,
interferon).
Epithelioid Angiosarcoma
Epithelioid angiosarcoma is a highly malignant vascular
neoplasm, predominantly composed of large, epithelioid
endothelial cells.43,51 Typically, neoplastic cells exhibit a
large eosinophilic cytoplasm along with vesicular, macro-
nucleolated nuclei (Figure 6). Although it was originally
recognized in the skin and in the thyroid gland,52,53
typical presentation is that of a deep-seated soft tissue
mass located in the lower extremities. A significant
number of patients are diagnosed with a primary ab-
dominal location or in other visceral sites. Lung and
adrenal also represent relatively frequently affected
sites. Rare cases may feature a predominantly solid
growth pattern mimicking an undifferentiated carci-
noma. In addition to the expression of usual endothe-
lial markers, epithelioid angiosarcoma frequently ex-
presses epithelial markers such EMA and keratins that
represents a potential diagnostic pitfall.
Epithelioid angiosarcoma may mimic the angioma-
tous variant of ES, both in morphology and by expres-
sion of cytokeratin. However, it usually shows more
A.P. Dei Tos et al
Figure 6. Neoplastic cells in epithelioid angiosarcoma ex-
hibit a large eosinophilic cytoplasm along with vesicular,
macronucleolated nuclei. (Courtesy of A.P. Dei Tos.)
pleomorphism and expresses CD31 and FVIII. Drawing
the line between so-called malignant EHE and epithe-
lioid angiosarcoma is sometimes difficult. However, the
presence of solid growth generally should be regarded
as a diagnostic clue in favor of epithelioid angiosar-
coma.
Epithelioid angiosarcoma is a very aggressive mes-
enchymal malignancy to the extent that half of the
patients are expected to die within 1 year from diag-
nosis. Distant metastasis is most often detected in the
lungs, lymph node, bone, and soft tissue. Nagano et al
reviewed nine cases of cutaneous angiosarcoma treated
with docetaxel. Six patients had a major response (two
CRs and four PRs).The two patients who achieved a CR
had angiosarcoma of the scalp.54 Fata et al evaluated
nine patients at Memorial Hospital with cutaneous an-
giosarcoma of the head and neck treated with pacli-
taxel 250 mg/m2 every 3 weeks or 90 mg/m2 weekly.
Of the nine patients, eight had major responses (four
PRs and four CRs), for a major response rate 89%. The
duration of response was 213 months (median, 5
months). Responses were seen with both regimens.55
Anthracycline-based therapy appeared slightly more ac-
tive than taxanes in one case series.56 A phase II study
from France confirmed the activity of taxanes in angio-
sarcoma, with five PRs after two cycles of therapy in 27
evaluable patients, a median time to progression of 4
months, and median overall survival of 8 months.57
Pasquier et al characterized two distinct effects of
paclitaxel on human endothelial cells: cytostatic effects
of paclitaxel at low concentrations and cytotoxic at
high concentrations.58 The cytostatic effect of pacli-
taxel is associated with increases in mitochondrial
membrane potential, p53 expression, and modification
of the Bax/Bcl-2 ratio, whereas the cytotoxic effect
involves an inhibition of endothelial cell proliferation
Epithelioid soft tissue tumors
without apoptosis induction and without any structural
modification of the microtubule network.58
Angiosarcoma thus represents an appropriate model
to investigate angiogenesis and the results of clinical
trials with VEGF receptor and other kinase-directed
therapies are expected soon.
EPITHELIOID MALIGNANT PERIPHERAL NERVE
SHEATH TUMOR
Epithelioid malignant peripheral nerve sheath tumor
(MPNST) is a rare lesion and accounts for about 5% of
all MPNSTs. Peak incidence is in the fourth decade. In-
terestingly, half of cases arise in the superficial soft tissue
or even in the deep dermis. Rarely MPNST may occur as
an entirely epithelioid morphology and represents a dis-
tinct clinicopathologic entity.59,60 The anatomic sites
most frequently affected are represented by the
limbs and the inguinal region. Usually there is no
association with the NF1 syndrome. Histologically
epithelioid MPNST usually exhibits a multinodular
growth pattern and is composed of nests and cords of
eosinophilic epithelioid cells harboring vesicular, ma-
cronucleolated nuclei (Figure 7). Cell clusters are sep-
arated by fibrous septa. Sometimes a mucinous back-
ground can be observed. Main differential diagnosis is
with amelanotic malignant melanoma. Important differ-
ential diagnostic clues are represented by the presence
of spindle cell areas (as in ordinary MPNST) and immu-
nonegativity for melanoma markers such as HMB45 or
Melan-A. At variance with usual MPNST, in which S-100
protein stains a minority of cells in no more than half of
cases, epithelioid MPNST usually exhibits strong immu-
nopositivity for S-100 in most neoplastic cells. Clear
cell sarcoma (melanoma of soft parts) also must be
differentiated from epithelioid MPNST. In addition to
positivity for melanoma markers clear cell sarcoma
Figure 7. Epithelioid MPNST is composed of nests and
cords of eosinophilic epithelioid cells harboring vesicular,
macronucleolated nuclei. (Courtesy of A.P. Dei Tos.)
353
harbor a rearrangement of the EWS gene that can be
exploited for diagnostic purposes.
Clinical behavior for deep-seated tumors overlaps
that of ordinary MPNST, with an overall survival at 5
years of approximately 50% in sporadic cases. Those
half of cases arising in the superficial soft tissue pursue
a much better clinical course with prolonged surviv-
al.59 Surgical resection remains the main primary treat-
ment option for these tumors with or without radiation
therapy. The role of chemotherapy remains controver-
sial in the adjuvant setting. In the metastatic setting,
clinical trial may be the best option as there are very
few cases of epithelioid MPNST described in the liter-
ature. Anecdotally, doxorubicin appears to be less ef-
fective than ifosfamide-based therapy for MPNST. The
arrival of therapy directed against the kinase raf gives
hope that these NF1-driven tumors will respond to
such agents.
EPITHELIOID SMOOTH MUSCLE TUMORS
Epithelioid smooth muscle tumors (ESMTs) are ex-
ceedingly rare. Most cases appear to occur in the uterus
with a peak incidence in the fourth decade. Biological
behavior seems to be hardly predictable. The few data
available indicate a low tendency to metastatic spread.
However, morphology appears not to predict reliably
the real risk of malignant behavior. Microscopically,
ESMT are most often composed of an epithelioid cell
proliferation, featuring round nuclei surrounded by eo-
sinophilic cytoplasm. The stroma varies from scanty to
abundant with a tendency to exhibit a hyaline appear-
ance, Necrosis is rare and mitotic activity rarely exceed
5 mitoses per 10 high-power fields. Immunohistochem-
ical analysis reveals expression of smooth muscle actin,
desmin, and h-caldesmon in most cases. CD10 immu-
nonegativity associated with h-caldesmon positivity is
helpful in the differential diagnosis with endometrial
stromal sarcoma. When dealing with advanced intra-
abdominal disease, the main differential diagnosis is
with metastatic epithelioid gastrointestinal stromal tu-
mor (GIST). However, the latter most often lacks ex-
pression of desmin, while it consistently exhibits im-
munopositivity for KIT and DOG1. Molecular analysis
of KIT and PDGFRA genes may important confirmatory
diagnostic role in KIT-negative GIST.
In a retrospective study of 18 patients, mean age 45
years, with uterine smooth muscle tumors, Prayson et
al separated cases into three groups depending on the
nuclear grade.61 All patients had surgical resections of
the tumor. Those with grade 23 nuclear atypia, tumor
cell necrosis, and higher mitotic activity had the worse
outcome. These tumors are very uncommon and very
rarely metastasize.61 There are no significant data re-
garding chemotherapy for such lesions.
354
Figure 8. Epithelioid pleomorphic liposarcoma is com-
posed of a monomorphic rounded, epithelioid cell prolifer-
ation, featuring focal pleomorphism and scattered pleo-
morphic lipoblasts. (Courtesy of A.P. Dei Tos.)
EPITHELIOID PLEOMORPHIC LIPOSARCOMA
Approximately one third of pleomorphic liposarco-
mas contain epithelioid areas in varying amounts. How-
ever, in 2000 Miettinen and Enziger reported a series of
pleomorphic liposarcomas predominantly composed
of epithelioid neoplastic cells (Figure 8), which repre-
sents a major diagnostic challenge.62 Most often epithe-
lioid pleomorphic liposarcoma arises in the lower
limbs of elderly patients, with a peak incidence in the
sixth decade. Retroperitoneal and visceral sites also
represent relatively common anatomic locations. Mor-
phologically the lesion is composed of a monomorphic
rounded, epithelioid cell proliferation, featuring high
mitotic counts, focal pleomorphism, and scattered
pleomorphic lipoblasts.62 Immunohistochemically,
S-100 and cytokeratin positivity can be seen in approx-
imately half of cases. The clinical behavior of this high-
grade sarcoma parallels that of conventional pleomor-
phic liposarcoma, featuring a metastatic rate between
30%50% and an overall mortality ranging between
40%50%. Regarding potential therapeutic options for
metastatic disease, There were two PRs and one SD for
more than 24 weeks in the three patients with pleo-
morphic liposarcoma treated with gemcitabine do-
cetaxel in a randomized study. Other responses were
noted in that study in patients with leiomyosarcoma
and malignant fibrous histiocytoma/high grade undif-
ferentiated pleomorphic sarcoma.63 Pleomorphic lipo-
sarcomas appear more like MFH/HGUPS than other
sarcomas by gene expression array analysis, with ane-
uploid karyotypes and a more undifferentiated state.64
MALIGNANT RHABDOID TUMORS
Malignant rhabdoid tumors are the most aggressive
renal tumors in the pediatric population. The tumor
A.P. Dei Tos et al
metastasizes widely early and causes death in most
patients within 12 months of presentation. Rhabdoid
tumors typically affect infants, with a median age of
presentation of 11 months and presentation rare after
age 3.65 There is a 3:2 predominance of males over
females. There is an occasional association with embry-
onal tumors of the central nervous system66 and para-
neoplastic hypercalcemia67 as well. The appearance of
the cytoplasm in the large polygonal cells of this tumor
similar to that of a developing rhabdomyoblast gave
these tumors their name.
Truncating mutations or deletion of the SMARCB1
(hSNF5)/INI1 gene, which encodes a protein involved in
chromatin remodeling, are characteristic of malignant rh-
abdoid tumor.68,69 The SMARCB1/INI1 gene encodes for
an invariant subunit of SWI/SNF chromatin remodeling
complex and acts as a tumor-suppressor gene in malig-
nant rhabdoid tumors. Inactivation of this protein also
may be important for other sarcomas. For example, a
study of SMARCB1/INI1 in patients with epithelioid sar-
coma showed inactivation of this protein in six of 11
samples examined with multiple techniques.
As an example of the possible application of inactiva-
tion of SMARCB1/INI1 to a therapeutic approach that
may be valid in malignant rhabdoid tumors and other
sarcomas, Modena et al have investigated the frequency
of SMARCB1/INI1 inactivation in larger series of epithe-
lioid sarcoma and synovial sarcoma patients (unpublished
results). A total of 39 epithelioid sarcomas, 55 synovial
sarcomas, and 10 high-risk GISTs have been examined,
with seven rhabdoid tumors included as a control. Protein
expression was investigated by immunohistochemistry
and Western blotting. Gross gene deletions were analyzed
by fluorescence in situ hybridization (FISH) using bacte-
rial artificial chromosome (BAC) probes. Mutational anal-
ysis was performed by exon amplification and sequenc-
ing. Gene expression analysis was performed by real-time
polymerase chain reaction.
Rhabdoid tumors analyzed displayed the spectrum
of point mutations and deletions reported in the liter-
ature, in combination with loss of protein expression.
In epithelioid sarcoma, the absence of SMARCB1 pro-
tein expression by immunohistochemistry was verified
in 21/39 (54%) the majority of cases. In 22 cases, FISH
analysis was performed and revealed retention of
SMARCB1 in all 6/6 immunohistochemistry-positive
cases tested and loss of the entire SMARCB1 gene in
half of immunohistochemistry-negative cases tested,
consistent with a larger recently published series.70
Mutational analysis in 13 cases for which frozen
tissue was available did not reveal mutations, distin-
guishing epithelioid sarcoma from rhabdoid tumors.19
SMARCB1 gene expression levels correlated with the
protein status. In synovial sarcoma, we identified ab-
sence of SMARCB1 protein expression by immunohis-
tochemistry was not a rare event in 23/55 (42%) cases.
Negative cases did not display homozygous deletions,
Epithelioid soft tissue tumors
suggesting that loss of protein expression is mediated
by transcriptional dysregulation. In contrast, high-risk
GISTs, which frequently carry chromosome 22q losses,
retained SMARCB1 protein expression. Thus, inactiva-
tion of SMARCB1 gene and loss of protein expression is
a frequent event in specific sarcoma types. Appropriate
model systems of SMARCB1-negative sarcomas need to
be tested for the potential therapeutic intervention
using cyclin-dependent kinase (CDK)/cyclin D inhibi-
tors, reported to efficiently inhibit in vitro and in vivo
models of in malignant rhabdoid tumors, and point out
a critical cell cycle transition point to examine in these
tumors in the laboratory to find more effective thera-
peutics.
CONCLUSIONS
Mesenchymal tumors are notoriously difficult to di-
agnosis. This challenge becomes even greater when-
ever the morphologic pictures are unusual. A relatively
large group of sarcomas tends to exhibit an epithelioid
morphology that often mimics that of a true epithelial
neoplasm. The histopathological subclassification of
soft tissue sarcomas already plays a key role in the
therapeutic decision-making; however, an ever greater
role con be foreseen if we consider the rapid evolution
of systemic therapies. The integration of clinical, mor-
phological, immunophenotypical, and, when applica-
ble, genetic findings allows distinction in most cases.
Admittedly, even in referral centers wherein diagnostic
expertise is greater, there remain lesions that, despite
all efforts, cannot find a place within current classifica-
tion schemes, subjects, no doubt, of continued re-
search.
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