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

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


348 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
Figure 1. The classic variant of epithelioid sarcoma con-
sists of coalescent cystic nodules lined by festoons com- morphological differences. ES more often involves dis-
posed of polygonal and spindled cells. The spaces are filled tal structures including skin, while synovial sarcoma is
with a mixture of necrotic debris and hyalinized collagen. usually more proximal, and is rarely superficial. Classic
(Courtesy of A.P. Dei Tos.) synovial sarcoma, both monophasic and biphasic, does
not overlap morphologically with ES. However, a large
cell undifferentiated variant of synovial sarcoma has
nopositivity is present in half of cases.9 Granuloma been described that may cause diagnostic difficulties.
anulare and rheumatoid nodule represents the main In such cases genetic analysis may prove extremely
differential diagnoses for the classic ES subtype10; how- helpful by demonstrating the synovial sarcomaspecific
ever, immunonegativity for keratins and positivity for translocation t(X;18).
CD68/CD163 will permit separation. As mentioned, extra-renal rhabdoid tumor (ERT)
The fibroma-like variant consists predominantly of represents the main differential diagnosis for the prox-
spindle cells, with an inconspicuous epithelioid com- imal type of ES. If rhabdoid features predominate, sep-
ponent.11 Neoplastic cells show minima atypia and are aration may be virtually impossible. Clinically, ERT
set in an abundant collagen-rich stroma. Cytokeratin tends to occur in infants and young children and to
positivity is extremely helpful in this context. pursue an extremely aggressive behavior. Loss of INI1
The angiomatoid variant is perhaps the rarest of immunoreactivity is observed in both ES and ERT,17,18
the ES variants. Histologically, the tumors show cys- raising the possibility of the existence of a morpho-
tic, blood-filled spaces bordered by epithelioid and logic continuum between the two entities. However,
spindled cells. Endothelial differentiation markers it seems likely that different molecular mechanisms
are negative, therefore allowing separation from ep- may lead to INI1 abnormalities in several unrelated
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 Figure 2. Epithelioid sarcoma proximal type composed of
of ES seems to be associated with increased risk of polygonal cells exhibiting higher cytologic atypia than the
recurrence and metastasis.12,16 other variants of ES. (Courtesy of A.P. Dei Tos.)
Epithelioid soft tissue tumors 349

subsets of mesenchymal tumors.19 It appears that iate analysis, age under 16 years, negative nodes, local-
INI1 expression is not related to clinical outcome, by ized disease, and operability of primary disease inde-
multivariate analysis of one of the larger studies of pendently predicted survival.23
patients with ES.20 ES can respond to systemic agents such as doxoru-
Irrespective of subtype, ES is a unique tumor. ES bicin, ifosfamide, or cisplatin, but responses are gener-
shows a tendency to metastasize to regional nodes (at ally transient and did not affect disease-free survival in
variance with most other sarcomas), although lung is one series.24 Prospective studies are needed to identify
the most common site, like most sarcomas. Aggressive novel therapeutics for metastatic disease.
surgery still represents the primary treatment option
despite an 85% local-regional recurrence rate. The fre- ALVEOLAR SOFT PART SARCOMA
quency of regional lymph node metastasis is typically
between 22% 45%. Distant metastatic disease has been Alveolar soft part sarcoma (ASPS) represents a mes-
reported in up to 45% of patients with ES. The metas- enchymal malignancy first described by Christopher-
tasis is usually to the lung and pleura. Lymphatic and son in 1952.25 Its name accurately describes the proto-
pulmonary metastases occur particularly when there is typical histological picture, represented by a proliferation
vascular invasion. Unlike other sarcomas that are cur- of an epithelioid, polygonal cell population organized in
rently treated with limb-sparing surgery associated an alveolar growth pattern (Figure 3). Periodic acid-
with chemotherapy and/or radiotherapy, when ES Schiffpositive intracytoplasmic inclusion bodies can
arises in the distal extremity, consideration should be be observed in approximately 70% of cases. Clinically,
given to amputation, thereby preventing relentless ASPS occurs most frequently in the lower limbs of
proximal tumor progression.21 Patients must be moni- young adults, between 15 and 35 years of age. In
tored with yearly lung x-rays since recurrence or me- pediatric patients, it involves mostly the head and
tastasis may occur many years after the initial diagnosis neck region orbit and tongue. ASPS also has been
and treatment.22 described occasionally in a number of other sites,
Callister et al reviewed the records of 24 patients such as female genital tract, mediastinum, lung, stomach,
with localized ES treated at M.D. Anderson Cancer and bone.26,27
Center.22 All patients were treated with conservative ASPS exhibits an invariable tendency to metastatic
surgery and radiotherapy. At a median follow-up of 131 spread to the lungs, bones, and brain. The clinical
months, 14 patients had relapsed and 13 patients had course is prolonged; however, long-term follow-up in-
died. The actuarial overall and disease-free survival dicates that the vast majority of patients die of meta-
rates at 10 years were 50% and 37%, respectively. Local, static disease within 15 years from diagnosis. Lieber-
nodal, and metastatic failures occurred in 7, 4, and 10 man et al reported a 5-year survival rate of 60% and only
patients, respectively, yielding 10-year actuarial local, 15% of patients demonstrated long-term disease-free
nodal, and metastatic control rates of 63%, 81%, and survival.26 The line of differentiation and cell of origin
56%, respectively. Univariate analysis indicated that of ASPS remain elusive. Early reports of MyoD1 (a
size 5 cm and extremity location were favorable striated muscle differentiation marker) cytoplasmic im-
prognostic factors for overall, disease-free, and metas- munopositivity most probably represent technical arti-
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- Figure 3. Alveolar soft part sarcoma is composed of a
dence of ES during 2005 was 0.041 per 100,000, an proliferation of an epithelioid cell population organized in
increase of about 5% per year since 1973. By multivar- an alveolar growth pattern. (Courtesy of A.P. Dei Tos.)
350 A.P. Dei Tos et al

fact. ASPS is characterized by a specific chromosome amputation with wide surgical margins. None had local
translocation t(X;17)(p11;q25) leading to the fusion of recurrence. Chemotherapy was given for metastatic
the ASPL and TFE3 genes.28 Interestingly, the same tumor and included cisplatin, ifosfamide, doxorubicin,
translocation can be observed in a subset of pediatric carboplatin, methotrexate, interferon, and interleu-
renal cell carcinoma.29 Nuclear expression of TFE3 has kin-2 regimens, with no responses reported. Despite
been proposed as a confirmatory diagnostic finding,30 the lack of radiological responses, the overall survival
as is the demonstration of the associated chromosome rates at 5, 10, and 15 years were 56%, 23%, and 15%,
aberration.31 The relationships between TFE3 and the respectively. Metastasis at presentation, tumor size, and
MET signaling pathway may represent a potential ratio- bone involvement at the primary site were factors in-
nale for molecularly targeted therapy,32 as discussed by dicating a significantly (P .05) poorer survival.34
Mertens et al in this issue of Seminars in Oncology. Newly diagnosed patients with unresectable or meta-
Although slow-growing, ASPS has a fatal prognosis if static ASPS should be enrolled in phase I and II clinical
complete surgical resection is not possible. Reichardt trials in an attempt to identify novel active agents. The
et al reviewed 757 sarcomas cases: eight had ASPS; 60 striking finding of activity of a vascular endothelial
other cases from the literature with chemotherapy data growth factor (VEGF) receptor-directed oral kinase in-
also were reviewed. Seven of eight patients developed hibitor gives hope that even this chemotherapy-insen-
brain metastases with a median interval of 51 months sitive sarcoma will have an Achilles heel.35
from primary diagnosis. All patients were still alive after
12 months of surgical procedure under curative intent SCLEROSING EPITHELIOID FIBROSARCOMA
or palliation. Seven of the eight patients received an-
thracyclines or ifosfamide-containing first-line chemo- Sclerosing epithelioid fibrosarcoma (SEF) is a dis-
therapy. There were no objective responses.33 Of 33 tinctive variant of fibrosarcoma that morphologically
publications related to chemotherapy in ASPS, an an- closely mimics infiltrating carcinoma.36,37 SEF tends to
thracycline regimen was used in 29 of 47 patients. Six occur in the lower extremities, limb girdles, trunk, and
of 47 patients received second- and third-line chemo- head and neck of adults with a peak incidence in the
therapy. Best response to first-line chemotherapy was fourth decade.
as follows: three complete responses (CRs; one after Histologically, SEF is generally well circumscribed
thiotepa and two after an anthracycline regimen), no and is composed of nests and cords of eosinophilic to
partial responses (PRs), 17 stable disease (SD), and 27 clear cell epithelioid neoplastic cells, set in a densely
progressive disease (PD). Two of six patients treated sclerotic stroma (Figure 4). Mitotic count is generally
with second- and third-line therapies achieved a CR low. Immunohistochemically, vimentin is consistently
(one with anthracycline and other with interferon-al- positive. Rare cases may show focal EMA or even ker-
pha). Data from the Charit University in Berlin in 68 atin positivity.
patients, including 13 children were as follows: CR 4%, Local recurrences are observed in approximately
PR 3%, SD 41%, and PD 51%, resulting in an overall half of patients with an overall metastatic rate of 40%.
response rate of approximately 7%.The response rate SEF remains both a clinically and morphologically elu-
did not seem to be significantly higher for the subgroup sive neoplasm, at risk to represent a heterogeneous
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- Figure 4. Epithelioid sclerosing fibrosarcoma is composed
cision with preoperative or postoperative radiation of cords of eosinophilic to clear cell epithelioid neoplastic
therapy. None of them had local recurrence. Thirty-six cells, set in a densely sclerotic stroma. (Courtesy of A.P. Dei
patients had wide local excision and two patients had Tos.)
Epithelioid soft tissue tumors 351

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-
Figure 5. EHE is composed of rounded eosinophilic cells,
seven patients recurred after a of mean 36 months. organized in strands, cords or solid nests, sometimes har-
Patients with tumors larger than 10 cm more com- boring intracytoplasmic vacuoles. (Courtesy of A.P. Dei
monly had metastasis at diagnosis. Patients with head Tos.)
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 case series, EHE represented 10 of 30 primary liver
follow-up. SEF may be treated with wide resection, and sarcomas.45 In general, a visceral location is frequently
preoperative or postoperative radiation therapy should associated with multicentricity. Approximately half of
be considered.36 the cases appear to originate from a blood vessel. His-
Patients with metastatic disease should be consid- tologically, EHE is composed of rounded eosinophilic
ered for investigational trials as the response to chemo- cells, organized in strands, cords, or solid nests, some-
therapy is low. times harboring intracytoplasmic vacuoles (Figure 5).
Neoplastic cells are usually cytologically bland and are
set in a myxochondroid background. Low mitotic ac-
EPITHELIOID VASCULAR TUMORS tivity is generally observed. Immunohistochemically,
An epithelioid morphology can be shared by vascu- EHE express consistently factor VIII (FVIII)-related an-
lar neoplasm exhibiting a totally different clinical be- tigen, CD31, CD34, and the nuclear transcription factor
havior. It is possible that a spectrum of lesions exists FLI1.46
that includes benign lesions such as epithelioid (histio- Approximately 30% of cases feature marked cytolog-
cytoid) hemangioma,40,41 and malignant neoplasms ical atypia, foci of necrosis, and higher mitotic activity,
such as epithelioid hemangioendothelioma (EHE)42 and which is associated with aggressive behavior.44 EHE
the highly aggressive epithelioid angiosarcoma of soft tends to recur locally in about 20% of cases and, in its
tissue.43 It is common experience that transitional le- classic form, the metastatic rate is less than 20% and
sions exist to the extent that separation between atyp- mortality around 3%. The presence of atypical histology
ical forms of EHE and angiosarcoma appears to be raises mortality rates up to 20%. In consideration of this
challenging and sometimes somewhat arbitrary.44 The clinical behavior, EHE can no longer be included in the
term hemangioendothelioma should actually identify low-grade or borderline category. According to the
lesions belonging to the group of low-grade malig- definition provided by the most recent World Health
nancy. This is certainly true for the retiform, kaposi- Organization classification of soft tissue tumors, EHE
form, and composite types of EHE. In the case of should be regarded as a fully malignant neoplasm.
epithelioid EHE, the metastatic rate is high enough to Recently, an ES-like variant of EHE has been re-
justify inclusion in the malignant category. ported, which makes differential diagnosis even more
challenging.47 Interestingly, these lesions were consis-
tently positive for cytokeratin, CD31, and FLI1 but
Epithelioid Hemangioendothelioma negative for CD34, making immunohistochemistry cru-
EHE usually presents as a painful, deep soft tissue cial in the differential diagnosis with ES.
mass, most often located in the extremities of adult Liver EHE is a very rare vascular neoplasm with an
patients.42,44 The entity formerly known as intravascu- estimated incidence of one in 1,000,000, and a mean
lar bronchioloalveolar tumor (IVBAT) is currently re- age of presentation of 32 years. Mosoia et al found that
garded as a form of primary pulmonary EHE. Bone and surgical treatment offers good long-term results in pa-
liver also can be involved as primary sites. In a 23-year tients submitted to liver resection for monolobar intra-
352 A.P. Dei Tos et al

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 Figure 6. Neoplastic cells in epithelioid angiosarcoma ex-
a standard practice, but the prognostic value of lymph hibit a large eosinophilic cytoplasm along with vesicular,
node invasion remains statistically unclear because of macronucleolated nuclei. (Courtesy of A.P. Dei Tos.)
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- pleomorphism and expresses CD31 and FVIII. Drawing
sions also have been reported. Other proposed sys- the line between so-called malignant EHE and epithe-
temic therapies include corticosteroids, azathioprine, lioid angiosarcoma is sometimes difficult. However, the
multiple wedge resections, or simple follow-up. In pa- presence of solid growth generally should be regarded
tients with hemorrhagic symptoms only one report as a diagnostic clue in favor of epithelioid angiosar-
described a complete response to carboplatin and eto- coma.
poside chemotherapy; other treatments, including ma- Epithelioid angiosarcoma is a very aggressive mes-
jor pulmonary resection, were unsuccessful. The me- enchymal malignancy to the extent that half of the
dian 5-year survival is 60% and patients with anemia
patients are expected to die within 1 year from diag-
and hemorrhagic pleural effusion survive less than 1
nosis. Distant metastasis is most often detected in the
year.50 A variety of chemotherapy agents have been
lungs, lymph node, bone, and soft tissue. Nagano et al
used anecdotally against EHE with limited success (li-
reviewed nine cases of cutaneous angiosarcoma treated
posomal doxorubicin, other anthracyclines, taxanes,
with docetaxel. Six patients had a major response (two
interferon).
CRs and four PRs).The two patients who achieved a CR
had angiosarcoma of the scalp.54 Fata et al evaluated
Epithelioid Angiosarcoma nine patients at Memorial Hospital with cutaneous an-
Epithelioid angiosarcoma is a highly malignant vascular giosarcoma of the head and neck treated with pacli-
neoplasm, predominantly composed of large, epithelioid taxel 250 mg/m2 every 3 weeks or 90 mg/m2 weekly.
endothelial cells.43,51 Typically, neoplastic cells exhibit a Of the nine patients, eight had major responses (four
large eosinophilic cytoplasm along with vesicular, macro- PRs and four CRs), for a major response rate 89%. The
nucleolated nuclei (Figure 6). Although it was originally duration of response was 213 months (median, 5
recognized in the skin and in the thyroid gland,52,53 months). Responses were seen with both regimens.55
typical presentation is that of a deep-seated soft tissue Anthracycline-based therapy appeared slightly more ac-
mass located in the lower extremities. A significant tive than taxanes in one case series.56 A phase II study
number of patients are diagnosed with a primary ab- from France confirmed the activity of taxanes in angio-
dominal location or in other visceral sites. Lung and sarcoma, with five PRs after two cycles of therapy in 27
adrenal also represent relatively frequently affected evaluable patients, a median time to progression of 4
sites. Rare cases may feature a predominantly solid months, and median overall survival of 8 months.57
growth pattern mimicking an undifferentiated carci- Pasquier et al characterized two distinct effects of
noma. In addition to the expression of usual endothe- paclitaxel on human endothelial cells: cytostatic effects
lial markers, epithelioid angiosarcoma frequently ex- of paclitaxel at low concentrations and cytotoxic at
presses epithelial markers such EMA and keratins that high concentrations.58 The cytostatic effect of pacli-
represents a potential diagnostic pitfall. taxel is associated with increases in mitochondrial
Epithelioid angiosarcoma may mimic the angioma- membrane potential, p53 expression, and modification
tous variant of ES, both in morphology and by expres- of the Bax/Bcl-2 ratio, whereas the cytotoxic effect
sion of cytokeratin. However, it usually shows more involves an inhibition of endothelial cell proliferation
Epithelioid soft tissue tumors 353

without apoptosis induction and without any structural harbor a rearrangement of the EWS gene that can be
modification of the microtubule network.58 exploited for diagnostic purposes.
Angiosarcoma thus represents an appropriate model Clinical behavior for deep-seated tumors overlaps
to investigate angiogenesis and the results of clinical that of ordinary MPNST, with an overall survival at 5
trials with VEGF receptor and other kinase-directed years of approximately 50% in sporadic cases. Those
therapies are expected soon. half of cases arising in the superficial soft tissue pursue
a much better clinical course with prolonged surviv-
EPITHELIOID MALIGNANT PERIPHERAL NERVE al.59 Surgical resection remains the main primary treat-
SHEATH TUMOR ment option for these tumors with or without radiation
therapy. The role of chemotherapy remains controver-
Epithelioid malignant peripheral nerve sheath tumor
(MPNST) is a rare lesion and accounts for about 5% of sial in the adjuvant setting. In the metastatic setting,
all MPNSTs. Peak incidence is in the fourth decade. In- clinical trial may be the best option as there are very
terestingly, half of cases arise in the superficial soft tissue few cases of epithelioid MPNST described in the liter-
or even in the deep dermis. Rarely MPNST may occur as ature. Anecdotally, doxorubicin appears to be less ef-
an entirely epithelioid morphology and represents a dis- fective than ifosfamide-based therapy for MPNST. The
tinct clinicopathologic entity.59,60 The anatomic sites arrival of therapy directed against the kinase raf gives
most frequently affected are represented by the hope that these NF1-driven tumors will respond to
limbs and the inguinal region. Usually there is no such agents.
association with the NF1 syndrome. Histologically
epithelioid MPNST usually exhibits a multinodular
growth pattern and is composed of nests and cords of EPITHELIOID SMOOTH MUSCLE TUMORS
eosinophilic epithelioid cells harboring vesicular, ma- Epithelioid smooth muscle tumors (ESMTs) are ex-
cronucleolated nuclei (Figure 7). Cell clusters are sep- ceedingly rare. Most cases appear to occur in the uterus
arated by fibrous septa. Sometimes a mucinous back- with a peak incidence in the fourth decade. Biological
ground can be observed. Main differential diagnosis is behavior seems to be hardly predictable. The few data
with amelanotic malignant melanoma. Important differ- available indicate a low tendency to metastatic spread.
ential diagnostic clues are represented by the presence However, morphology appears not to predict reliably
of spindle cell areas (as in ordinary MPNST) and immu- the real risk of malignant behavior. Microscopically,
nonegativity for melanoma markers such as HMB45 or ESMT are most often composed of an epithelioid cell
Melan-A. At variance with usual MPNST, in which S-100 proliferation, featuring round nuclei surrounded by eo-
protein stains a minority of cells in no more than half of
sinophilic cytoplasm. The stroma varies from scanty to
cases, epithelioid MPNST usually exhibits strong immu-
abundant with a tendency to exhibit a hyaline appear-
nopositivity for S-100 in most neoplastic cells. Clear
ance, Necrosis is rare and mitotic activity rarely exceed
cell sarcoma (melanoma of soft parts) also must be
5 mitoses per 10 high-power fields. Immunohistochem-
differentiated from epithelioid MPNST. In addition to
ical analysis reveals expression of smooth muscle actin,
positivity for melanoma markers clear cell sarcoma
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
Figure 7. Epithelioid MPNST is composed of nests and outcome. These tumors are very uncommon and very
cords of eosinophilic epithelioid cells harboring vesicular, rarely metastasize.61 There are no significant data re-
macronucleolated nuclei. (Courtesy of A.P. Dei Tos.) garding chemotherapy for such lesions.
354 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
Figure 8. Epithelioid pleomorphic liposarcoma is com-
posed of a monomorphic rounded, epithelioid cell prolifer- complex and acts as a tumor-suppressor gene in malig-
ation, featuring focal pleomorphism and scattered pleo- nant rhabdoid tumors. Inactivation of this protein also
morphic lipoblasts. (Courtesy of A.P. Dei Tos.) 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
EPITHELIOID PLEOMORPHIC LIPOSARCOMA samples examined with multiple techniques.
Approximately one third of pleomorphic liposarco- As an example of the possible application of inactiva-
mas contain epithelioid areas in varying amounts. How- tion of SMARCB1/INI1 to a therapeutic approach that
ever, in 2000 Miettinen and Enziger reported a series of may be valid in malignant rhabdoid tumors and other
pleomorphic liposarcomas predominantly composed sarcomas, Modena et al have investigated the frequency
of epithelioid neoplastic cells (Figure 8), which repre- of SMARCB1/INI1 inactivation in larger series of epithe-
sents a major diagnostic challenge.62 Most often epithe- lioid sarcoma and synovial sarcoma patients (unpublished
lioid pleomorphic liposarcoma arises in the lower results). A total of 39 epithelioid sarcomas, 55 synovial
limbs of elderly patients, with a peak incidence in the sarcomas, and 10 high-risk GISTs have been examined,
sixth decade. Retroperitoneal and visceral sites also with seven rhabdoid tumors included as a control. Protein
represent relatively common anatomic locations. Mor- expression was investigated by immunohistochemistry
phologically the lesion is composed of a monomorphic and Western blotting. Gross gene deletions were analyzed
rounded, epithelioid cell proliferation, featuring high by fluorescence in situ hybridization (FISH) using bacte-
mitotic counts, focal pleomorphism, and scattered rial artificial chromosome (BAC) probes. Mutational anal-
pleomorphic lipoblasts.62 Immunohistochemically, ysis was performed by exon amplification and sequenc-
S-100 and cytokeratin positivity can be seen in approx- ing. Gene expression analysis was performed by real-time
imately half of cases. The clinical behavior of this high- polymerase chain reaction.
grade sarcoma parallels that of conventional pleomor- Rhabdoid tumors analyzed displayed the spectrum
phic liposarcoma, featuring a metastatic rate between of point mutations and deletions reported in the liter-
30%50% and an overall mortality ranging between ature, in combination with loss of protein expression.
40%50%. Regarding potential therapeutic options for In epithelioid sarcoma, the absence of SMARCB1 pro-
metastatic disease, There were two PRs and one SD for tein expression by immunohistochemistry was verified
more than 24 weeks in the three patients with pleo- in 21/39 (54%) the majority of cases. In 22 cases, FISH
morphic liposarcoma treated with gemcitabine do- analysis was performed and revealed retention of
cetaxel in a randomized study. Other responses were SMARCB1 in all 6/6 immunohistochemistry-positive
noted in that study in patients with leiomyosarcoma cases tested and loss of the entire SMARCB1 gene in
and malignant fibrous histiocytoma/high grade undif- half of immunohistochemistry-negative cases tested,
ferentiated pleomorphic sarcoma.63 Pleomorphic lipo- consistent with a larger recently published series.70
sarcomas appear more like MFH/HGUPS than other Mutational analysis in 13 cases for which frozen
sarcomas by gene expression array analysis, with ane- tissue was available did not reveal mutations, distin-
uploid karyotypes and a more undifferentiated state.64 guishing epithelioid sarcoma from rhabdoid tumors.19
SMARCB1 gene expression levels correlated with the
protein status. In synovial sarcoma, we identified ab-
MALIGNANT RHABDOID TUMORS
sence of SMARCB1 protein expression by immunohis-
Malignant rhabdoid tumors are the most aggressive tochemistry was not a rare event in 23/55 (42%) cases.
renal tumors in the pediatric population. The tumor Negative cases did not display homozygous deletions,
Epithelioid soft tissue tumors 355

suggesting that loss of protein expression is mediated 8. Miettinen M, Fanburg-Smith JC, Virolainen M, et al. Epi-
by transcriptional dysregulation. In contrast, high-risk thelioid sarcoma: an immunohistochemical analysis of
GISTs, which frequently carry chromosome 22q losses, 112 classical and variant cases and a discussion of the
retained SMARCB1 protein expression. Thus, inactiva- differential diagnosis. Hum Pathol. 1999;30:934 42.
9. Arber DA, Kandalaft PL, Mehta P, et al. Vimentin-negative
tion of SMARCB1 gene and loss of protein expression is
epithelioid sarcoma. The value of an immunohistochem-
a frequent event in specific sarcoma types. Appropriate
ical panel that includes CD34. Am J Surg Pathol. 1993;
model systems of SMARCB1-negative sarcomas need to 17:3027.
be tested for the potential therapeutic intervention 10. Wick MR, Manivel JC. Epithelioid sarcoma and isolated
using cyclin-dependent kinase (CDK)/cyclin D inhibi- necrobiotic granuloma: a comparative immunocytochemi-
tors, reported to efficiently inhibit in vitro and in vivo cal study. J Cutan Pathol. 1986;13:253 60.
models of in malignant rhabdoid tumors, and point out 11. Mirra JM, Kessler S, Bhuta S, et al. The fibroma-like
a critical cell cycle transition point to examine in these variant of epithelioid sarcoma. A fibrohistiocytic/myoid
tumors in the laboratory to find more effective thera- cell lesion often confused with benign and malignant
peutics. spindle cell tumors. Cancer. 1992;69:138295.
12. Guillou L, Wadden C, Coindre JM, et al. Proximal-type
epithelioid sarcoma, a distinctive aggressive neoplasm
CONCLUSIONS showing rhabdoid features. Clinicopathologic, immuno-
Mesenchymal tumors are notoriously difficult to di- histochemical, and ultrastructural study of a series. Am J
Surg Pathol. 1997;21:130 46.
agnosis. This challenge becomes even greater when-
13. Bittesini L, Dei Tos AP, Fletcher CD. Metastatic malignant
ever the morphologic pictures are unusual. A relatively
melanoma showing a rhabdoid phenotype: further evi-
large group of sarcomas tends to exhibit an epithelioid dence of a non-specific histological pattern. Histopathol-
morphology that often mimics that of a true epithelial ogy. 1992;20:16770.
neoplasm. The histopathological subclassification of 14. Parham DM, Weeks DA, Beckwith JB. The clinicopatho-
soft tissue sarcomas already plays a key role in the logic spectrum of putative extrarenal rhabdoid tumors.
therapeutic decision-making; however, an ever greater An analysis of 42 cases studied with immunohistochem-
role con be foreseen if we consider the rapid evolution istry or electron microscopy. Am J Surg Pathol. 1994;18:
of systemic therapies. The integration of clinical, mor- 1010 29.
phological, immunophenotypical, and, when applica- 15. Wick MR, Ritter JH, Dehner LP. Malignant rhabdoid tu-
ble, genetic findings allows distinction in most cases. mors: a clinicopathologic review and conceptual discus-
Admittedly, even in referral centers wherein diagnostic sion. Semin Diagn Pathol. 1995;12:233 48.
16. Chase DR. Do rhabdoid features impart a poorer prog-
expertise is greater, there remain lesions that, despite
nosis to proximal-type epithelioid sarcomas? Adv Anat
all efforts, cannot find a place within current classifica- Pathol. 1997;4:2939.
tion schemes, subjects, no doubt, of continued re- 17. Hoot AC, Russo P, Judkins AR, et al. Immunohisto-
search. chemical analysis of hSNF5/INI1 distinguishes renal
and extra-renal malignant rhabdoid tumors from other
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