Resident Short Review
Alveolar Soft Part Sarcoma
Omar I. Jaber, MD; Patricia A. Kirby, MD
 Alveolar soft part sarcoma is a rare neoplasm usually
arising in the soft tissues of the lower limbs in adults and in
the head and neck region in children. It presents primarily
as a slowly growing mass or as metastatic disease. It is
characterized by a specific chromosomal alteration,
der(17)t(X:17)(p11:q25), resulting in fusion of the tran-
scription factor E3 (TFE3) with alveolar soft part sarcoma
critical region 1 (ASPSCR1) at 17q25. This translocation is
diagnostically useful because the tumor nuclei are positive
for TFE3 by immunohistochemistry. Real-time polymerase
chain reaction to detect the ASPSCR1-TFE3 fusion tran-
script on paraffin-embedded tissue blocks has been shown
to be more sensitive and specific than detection of TFE3 by
immunohistochemical stain. Cathepsin K is a relatively
recent immunohistochemical stain that can aid in the
diagnosis. The recent discovery of the role of the ASPSCR1-
TFE3 fusion protein in the MET proto-oncogene signaling
pathway promoting angiogenesis and cell proliferation
offers a promising targeted molecular therapy.
(Arch Pathol Lab Med. 2015;139:14591462; doi:
10.5858/arpa.2014-0385-RS)
A lveolar soft part sarcoma (ASPS) is a rare neoplasm. It
represents 0.2% to 0.9% of all soft tissue sarcomas1 and
tends to occur between ages 15 to 35 years and is rare in
patients younger than 5 years and older than 50 years.2 It is
more common in females than it is in males with a 2:1 ratio.
This ratio is seen more in the first 3 decades of life but shows
a slightly male predominance thereafter.3,4 In adults, ASPS
tends to involve the deep soft tissues in the thigh or buttock.
In children and infants, ASPS has a predilection for the head
and neck region, with the tongue and orbit being the most
common sites.2 Other organs reported include the urinary
bladder,5 breast,6 larynx,7 and the uterine cervix.8 Bone
involvement, although rare, can occur. The most commonly
involved sites are the fibula, tibia, and ileum. A recent case
report also mentioned the involvement of less-common
sites, such as the clavicle and meninges. The meningeal
involvement was thought to be either primary or metastasis
disease.9 Typically, patients note a painless, slowly growing
mass. An unusual clinical presentation with rapidly growing
Accepted for publication September 5, 2014.
From the Department of Pathology, University of Iowa Hospitals
and Clinics, Iowa City.
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Omar I. Jaber, MD, Department of Pathology, University
of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA
52242 (e-mail: Omar-jaber@uiowa.edu).
Arch Pathol Lab MedVol 139, November 2015
ASPS of the cheek has been recently reported.10 Some
patients present primarily with metastatic disease, especially
of the brain or lungs. Metastasis can also occur long after
resection of the primary tumor, even if there is no local
recurrence.11 On imaging, because of the very vascular
nature of this tumor, it is contrast enhancing.12 In addition,
ASPS tends to have high signal intensity on T1- to T2-
weighted images on magnetic resonance imaging.13
PATHOLOGY
Gross Morphology
Alveolar soft part sarcoma is usually a poorly circum-
scribed mass with a soft and rubbery consistency that has a
tan-pale to yellow cut surface, which may be accompanied
by areas of hemorrhage or necrosis, especially in large
tumors.
Microscopic Features
Alveolar soft part sarcoma has a distinctive and charac-
teristic, nested or organoid growth pattern. The nests tend
to be uniform in size and shape, although some variation
may be present. The nests are separated by delicate
sinusoidal vascular channels lined by a flattened, single
layer of endothelial cells. The cells may appear discohesive
with focal necrosis in the center of the nests giving rise to
the so-called, commonly seen, pseudoalveolar pattern. In
infants and children, the tumor may show a solid, diffuse
growth pattern with no nested architecture or intervening
vascular channels.14 This should be remembered when
ASPS is suspected in this age population. Nevertheless, the
histologic features of ASPS have no prognostic significance,2
and the better prognosis reported for tumors with this solid
growth is due to their occurrence in the pediatric patient
population and their propensity to involve the head and
neck region.15,16
The neoplastic cells are uniform in size, polygonal to
round, with well-defined cellular borders. The cytoplasm is
abundant, eosinophilic, and glycogen-rich and can have a
clear to vacuolated appearance. The nuclei are uniform,
round, centrally located, and contain 1 or 2 prominent
nucleoli (Figure 1). Pleomorphic features have been
reported,15 and mitotic figures are rare.14 Vascular invasion
is frequently seen.
A characteristic feature of ASPS is the presence of
intracytoplasmic, periodic acidSchiff, diastase-resistant
rhomboid- or rod-shaped crystals (Figure 2). They are
present in both primary and metastatic disease, are found in
approximately 80% of cases, and vary in number from
absent to very few in some cases to numerous in others.14 In
addition, the periodic acidSchiff, diastase-resistant gran-
Alveolar Soft Part SarcomaJaber & Kirby 1459
Figure 1. Alveolar soft part sarcoma. Nests of tumor cells with abundant eosinophilic cytoplasm and central nuclei with prominent nucleoli
(hematoxylin-eosin, original magnification 3200).
Figure 2. Alveolar soft part sarcoma. Periodic acidSchiff, diastase-resistant intracytoplasmic crystals (original magnification 3600).
Figure 3. Transcription factor E3 (TFE3) staining in alveolar soft part sarcoma. Note the strong nuclear staining pattern (original magnification 3200).
Figure 4. Cathepsin K staining in alveolar soft part sarcoma. Note the cytoplasmic staining (original magnification 3200).

ules digestion are also present in almost all cases and are
thought to contain monocarboxylate transporter 1 and
CD147.17
Immunohistochemistry
Alveolar soft part sarcoma is consistently positive for an
antibody that detects the carboxyl terminal portion of the
transcription factor E3 (TFE3) gene retained in the fusion
protein.2 The pattern of expression is strong nuclear staining
(Figure 3).18 Cathepsin K is a protease whose expression is
driven by microphthalmia transcription factor (MITF) in
osteoclasts.19 Cathepsin K is consistently and diffusely
positive in ASPS (Figure 4).19 Although these 2 immuno-
histochemical stains are highly sensitive, they are not
entirely specific because other tumors also show positivity
(described below). Often, ASPS is positive for desmin and
muscle-specific actin.16 S100 is rarely positive. Myogenin
and Myo D1 were initially thought to be promising markers;
however, subsequent studies have not identified convincing
expression of either.20,21 The positive Myo D1 cytoplasmic
1460 Arch Pathol Lab MedVol 139, November 2015
staining pattern that can be seen in ASPS is mostly related
to cross-reactivity with undetermined cytoplasmic antigen.21
Alveolar soft part sarcoma is consistently negative for
keratin, epithelial membrane antigen (EMA), paired box 8
(PAX8), human melanoma black (HMB-45), synaptophysin,
chromogranin, and hepatocyte paraffin 1 (HepPar1).
Cytogenetics
Alveolar soft part sarcoma is characterized by a specific
chromosomal alteration, der(17)t(X:17)(p11:q25), resulting
in the fusion of the TFE3 transcription factor gene (from
Xp11) with alveolar soft part sarcoma critical region 1
(ASPSCR1), also known as alveolar soft part sarcoma locus
(ASPL) at 17q25. The detection of the fusion transcript
(ASPSCR1-TFE3) by real-time polymerase chain reaction
and fluorescence in situ hybridization for TFE3 rearrange-
ment are considered high-yield methods for diagnosis. The
same gene fusion is also seen in a subset of translocation-
associated renal cell carcinomas (RCCs). However, in ASPS,
the translocation is unbalanced, whereas it is balanced in
Alveolar Soft Part SarcomaJaber & Kirby
 Differential Expression of Transcription Factor E3
(TFE3) and Cathepsin K Among Alveolar Soft Part
Sarcoma (ASPS) and Potential Mimickers
Differential Diagnosis TFE3 Cathepsin K
ASPS Positive Positive
ASPSCR1-TFE3
translocation RCC Positive Negative
PEComa Positive Positive
Granular cell tumor Positive/negative Positive
Clear cell sarcoma Negative Positive/negative
Melanoma Negative Positive
Abbreviations: ASPSCR1-TFE3, alveolar soft part sarcoma critical region
1transcription factor E3; PEComa, perivascular epithelioid cell
neoplasm; RCC, renal cell carcinoma.
translocation associated RCC. The ASPSCR1-TFE3 fusion
protein acts as an aberrant transcription factor resulting in
activation of the MET signaling pathway believed to
promote angiogenesis and cell proliferation.2 In a study
performed by Tsuji et al,22 they showed the sensitivity and
specificity of TFE3 immunohistochemistry for ASPS to be
92% and 92%, respectively. The same group showed the
sensitivity and specificity of ASPSCR1-TFE3 fusion transcript
detected by real-time polymerase chain reaction obtained
from formalin-fixed, paraffin-embedded tissue for ASPS to
be 100% for both. They concluded that detection of
ASPSCR1-TFE3 fusion transcript has superior sensitivity as
compared with TFE3 immunohistochemical stain. This is
especially helpful in cases where ASPS presents with an
unusual histology or location.
Differential Diagnosis
The differential diagnosis includes other primary soft
tissue neoplasms, such as rhabdomyoma, hibernoma, clear
cell sarcoma of soft tissue, perivascular epithelioid cell
neoplasm (PEComa), paraganglioma, and granular cell
tumor. Metastatic tumors with similar cytologic features
can mimic ASPS, such as clear cell RCC, hepatocellular
carcinoma, adrenocortical carcinoma, and melanoma.
Rhabdomyoma is a benign, skeletal muscle tumor that has
large polygonal cells with vacuolated cytoplasm and no
nuclear atypia. Although cytoplasmic granules and rodlike
inclusions can be seen, which may mimic the granules and
crystals seen in ASPS, the tumor cells are positive for muscle
markers desmin and myogenin. Hibernomas have large cells
with eosinophilic cytoplasm and central nuclei with no
prominent nucleoli. No nested growth pattern is seen, and
S100 can be positive.
Clear cell sarcoma is composed of epithelioid cells with
clear to eosinophilic cytoplasm usually grouped into nests
separated by collagenous strands. Alveolar architecture can
also be seen. Melanoma markers, such as S100, HMB-45,
and melanoma-associated antigen recognized by T cells
(Mart-1), are consistently positive. Unlike melanoma, clear
cell sarcoma has a reciprocal translocation t(12:22) resulting
in the fusion of EWS RNA-binding protein 1 (EWSR1) with
activating transcription factor 1 (ATF1) in more than 90% of
cases. In a study performed by Zheng et al,23 cathepsin K
showed positivity in 3 of 12 cases (25%) of clear cell sarcoma
(one showed focal positivity). They suggested that a diffuse
staining pattern favors ASPS.
A PEComa can look similar to ASPS because it may
contain cytoplasmic eosinophilic granules positive for
periodic acidSchiff and show TFE3 positivity. However, a
Arch Pathol Lab MedVol 139, November 2015
PEComa is positive for MART-1 and HMB-45, whereas
ASPS is negative.16 A recently reported24 PEComa of the
urinary bladder showed positive TFE3 by immunohisto-
chemical stain, showed TFE3 rearrangement by fluorescence
in situ hybridization, had a malignant behavior, and caused
the death of the patient. Paraganglioma and granular cell
tumor also enter the differential diagnosis. The first is
positive for neuroendocrine markers synaptophysin and
chromogranin and shows positivity for S100 in the
sustentacular cells. In addition, primary paragangliomas
are almost never seen in the limbs.16 Granular cell tumors,
unlike ASPS, lack the fine intercellular vascularity and are
positive for S100, SOX10, inhibin, and nestin. This panel
showed 100% sensitivity and specificity to distinguish
granular cell tumor from ASPS in a study performed by
Chamberlain et al.25 One pitfall to consider is that a subset
of granular cell tumors is positive for TFE3.18 Interestingly,
10 out of 11 (91%) of the granular cell tumors showed TFE3
positivity in the same study.25 Unlike ASPS, both paragan-
glioma and granular cell tumor lack cytoplasmic glycogen.14
Although EMA, PAX8, and RCC are positive in clear cell
RCC, they are negative in ASPS. Hepatocellular carcinoma
is positive for Hep-Par1, glypican-3, and polyclonal
carcinoembryonic antigen (P-CEA). Renal cell carcinoma
and adrenocortical carcinoma are usually readily diagnosed
clinically and radiographically. Also, adrenocortical carcino-
ma is positive for Mart-1, inhibin, and synaptophysin,
whereas ASPS is negative.
As mentioned, immunolabeling for cathepsin K can be
helpful in the differential diagnosis of ASPS because it is
negative in conventional RCC, ASPSCR1-TFE3 translocation
RCC, adrenocortical carcinoma, and paraganglioma.19
However, its role in differentiating ASPS from other
potential mimickers is relatively limited because it is positive
in melanoma, granular cell tumor, and other tumors19
(Table). Therefore, the best practical application for cathep-
sin K in this setting is when the clinical, radiologic,
histomorphologic, and immunohistochemical data are
competing between ASPS and ASPCR1-TFE3 translocation
RCC, where both will be positive for TFE3 immunohisto-
chemical stain, whereas cathepsin K will show positivity in
the former but not in the latter.
However, whether the differential expression of either
marker (ie, TFE3 and cathepsin K) in ASPS is diagnostically
significant is not known, and to our knowledge, has not
been reported.
Treatment and Prognosis
Alveolar soft part sarcoma has a high incidence of
metastatic disease, which may precede the detection of the
primary tumor.11,26 Local recurrence occurs in 20% to 30%
of cases.16 Prognosis is largely dependent on the initial
presentation (localized versus metastatic disease), tumor
size, and age.4,11,15,27 Patients with localized disease at
presentation have a 71% 5-year survival rate, compared
with 20% for patients with metastatic disease at time of
diagnosis.4 Patients who present with large tumors are most
likely to have metastasis at the time of diagnosis.11,15 Of
note, children have an excellent 5-year survival rate of up to
100%, especially if the tumor arises in the head and neck.15
More recent data28 report a 5-year survival rate for children
to be 83%. The better prognosis among children is not well
understood. Differences in biologic characteristics of pedi-
atric and adult ASPS have been proposed as a possible
explanation.15 In a case-series study reported by Ogura et
Alveolar Soft Part SarcomaJaber & Kirby 1461
al,29 pediatric tumors tended to be smaller than those in
adult patients, with the larger tumor size resulting in
increased risk of distant metastasis. Radical resection is the
treatment of choice for localized disease. Metastatic ASPS is
usually resistant to conventional chemotherapy and radio-
therapy. The recent identification of the role of ASPSCR1-
TFE3 in the MET signaling pathway promoting tumor cell
proliferation and angiogenesis is considered the cornerstone
for targeted molecular therapy in ASPS, namely antiangio-
genic drugs and MET kinase inhibitors, with ongoing
clinical trials showing promising initial results.30,31 More
specifically, the ASPSCR1-TFE3 fusion protein induces
strong overexpression of MET receptor tyrosine kinase,
leading to strong autophosphorylation and activation of the
downstream kinase cascade. Therefore, inhibiting expres-
sion of MET will lead to decreased cell growth. Because the
detection of TFE3 by immunohistochemical stain is not
entirely specific, the detection of the fusion transcript gene
(for example, by real-time polymerase chain reaction) may
represent an additional tool to support the diagnosis and
confirm the presence of the translocation. Monoclonal
antibodies against cathepsin K have been studied in women
with metastatic breast cancer to the bones, and because
cathepsin K is expressed in ASPS, it may represent a
potential therapeutic target.32,33
We thank Andrew M. Bellizzi, MD, and Jason L. Hornick, MD,
for graciously providing the TFE3 and cathepsin K immunohisto-
chemical stained slides.
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Alveolar Soft Part SarcomaJaber & Kirby