Download COTM0313 - California Tumor Tissue Registry

“A 33 Year Old Woman with a Mass
in the Thigh”
California Tumor Tissue Registry’s
Case of the Month
CTTR COTM Vol. 15:6
March, 2013
www.cttr.org
A 33 year-old woman presented with a palpable, 6 cm mass in the thigh. At surgery, it was found
to deeply reside within the anterior compartment where it involved muscle. Osseous involvement
was not seen. The excised specimen was poorly circumscribed, and had a cut surface that was
fleshy tan-grey.
The tumor was compartmentalized, showing islands of cells separated into large and small
nodules by fibrous stroma (Figs 1,2). Smaller nests were bounded by sinusoidal vascular
structures, a few of which were dilated (Fig. 3,4). Some of these smaller compartments showed
central necrosis and many exhibited clearing around the cells with poor cellular cohesion (Fig. 5).
The cells were uniform in both shape and size, and contained abundant pink granular cytoplasm
and eccentrically placed, rounded, vesicular nuclei, most having prominent nucleoli (Fig. 6,7).
There were scattered binucleated cells (Fig. 7). Mitoses were rare and no significant
pleomorphism was present. A PAS stain showed abundant PAS positive granular and crystalloid
material within the cytoplasm of many cells (Fig. 8).
Diagnosis: “Alveolar Soft Part Sarcoma”
Cody S. Carter, MSIV, Donald R. Chase, M.D.
Department of Pathology and Human Anatomy, Loma Linda University and Medical
Center, Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California
Alveolar soft part sarcoma (ASPS) is a rare entity of unknown origin accounting for less than 1%
of sarcomas. It usually occurs in ages 15-35, and predominantly affects females, especially in
younger patients. In adults, the majority of tumors occur in the lower extremities, especially in
the anterior thigh and buttocks. In children, these tumors typically present in the head and neck,
especially the orbit and tongue, and tend to be smaller, likely due to earlier detection in these
locations. The tumor most commonly presents as a slow-growing painless mass, but can often
present with respiratory symptoms or neurologic symptoms like headache, visual changes and
nausea due to their striking proclivity for early metastasis to the lung and brain. ASPS are
typically very vascular and may be associated with an audible bruit. Radiologically, the diagnosis
my be suggested byits hypervascularity with prolonged capillary staining and locally dilated veins
on angiography and CT scan.
Grossly, ASPS is usually poorly circumscribed and highly vascular, with increased risk of
significant blood loss at the time of surgery. The cut surface is usually yellow-white to gray and
can feature areas of necrosis or hemorrhage, making the tumor soft and friable.
CTTR’s COTM
March, 2013
Page 1
Microscopically, ASPS shows little variability. Compartments and nests are divided by fibrous
stroma, thin-walled sinusoidal channels, usually lined by flattened endothelial cells. A lack of
cellular cohesion and central necrosis is often seen. The dominant pattern of peripherally viable
tumor cells with partial central clearing likens this neoplasm to the alveoli of the lung. While
these features generally make a histologic diagnosis straightforward, the nest-like pattern can, on
rare occasion, be absent, and large sheets of cells are seen together. This variant is primarily seen
in infants and young children.
Cells within the nests are large, rounded, and fairly uniform, with eosinophilic granular cytoplasm
and vesicular nuclei with distinct nucleoli. Cellular pleomorphism is only rarely present.
Vascular invasion is almost invariably present, and reflects the tendency for early blood
metastasis. The characteristic histologic pattern can usually be relied on for diagnosis, and the
unreliable staining exhibited by ASPS makes immunohistochemistry most important in excluding
other neoplasms. Of the histologic stains, PAS will likely show positively staining, diastaseresistant granules or rhomboid and rod-shaped crystals within the cytoplasm. These structures are
composed of monocarboxylate tansporter 1 and its chaperone protein CD147. ASPS fails to
express cytokeratin, EMA, neurofilament, GFAP, serotonin, synaptophysin and chromogranin. It
can sometimes be positive for S-100 and neuron-specific enolase, but these seem to have no
significant diagnostic value. Stains for MyoD1 and myogenin have been controversially positive,
with one study using positivity in several tumors as support for skeletal muscle differentiation,
but several subsequent studies have since failed to reproduce the results.
Cytogenetics may be a useful tool as the unbalanced translocation t(X;17)(p11.2q25) leads to an
ASPL-TFE3 fusion gene that is both sensitive and specific for ASPS within the realm of soft
tissue sarcomas (a small subset of pediatric renal cell carcinomas have also shown this same
fusion gene). This can be more easily confirmed with an immunohistochemical stain for TFE3.
This fusion gene has been linked to the overexpression of the promitotic MET receptor tyrosine
kinase, which has suggested a model for oncogenesis, as well as a source of targeted therapy that
is currently being tested in ongoing clinical trials.
Alveolar soft tissue sarcoma displays indolent growth, but overall prognosis is poor due to early
metastasis, which can often be present at initial presentation. ASPS differs from most other adult
sarcomas in that local recurrence is less likely after radical excision, but late metastasis can occur
years after resection of the primary, and indeed metastases upwards of 30 years later have been
recorded. Poorer prognosis is associated with increasing age and increasing tumor size at
diagnosis, as well as metastases at initial presentation. Histologic grading is not contributory to
prognosis.
Due to slow growth of the tumor, radical surgical excision of both primary and metastatic lesions
is the most effective treatment, and conventional radiotherapy and chemotherapy have thus far
been shown to be ineffective. Recent advances in targeted therapy are promising, and clinical
trials are ongoing.
Differential diagnosis includes:

Renal cell carcinoma (RCC) can look similar to the histology of ASPS, especially because
some variants of the sarcoma can have less eosinophilic cells, and some RCCs can have quite
eosinophilic cytoplasm. RCC can be distinguished by its distinct lack of PAS-positive
crystalline structures or granules. Also, RCC is immunoreactive to EMA and keratin, but
ASPS shows absent staining. TFE3 positivity can also be helpful, but some RCCs can
CTTR’s COTM
March, 2013
Page 2
express this antigen in the pediatric population. In this situation, radiologic correlation with
renal imaging may be essential.

Paraganglioma can be differentiated by its positivity for neuroendocrine markers, which are
consistently negative in ASPS. Vesicular nuclei and prominent nucleoli are also not
characteristics of paraganglioma. Also, paragangliomas typically present in patients over 40
years of age and are not found in the extremities; in contrast, those alveolar soft part sarcomas
that arise in the head and neck region are found in pediatric patients.

Granular cell tumors typically have a solid architecture with cells exhibiting more densely
eosinophilic cytoplasm, and can exhibit spindling of the cells, a feature not present in ASPS.
Also, cells are uniformly positive for S-100, while ASPS shows variably positivity.

Alveolar rhabdomyosarcoma (AR) is characterized by smaller cells that are often more
pleomorphic and feature dense nuclei. They are also much more likely to mark for desmin,
MyoD1, and other muscle markers. The clusters of cells in an AR are surrounded by actual
fibrous septa, as opposed to sinusoidal vessels.
Suggested Reading:
Portera CA Jr, Ho V, Patel SR, Hunt KK, Feig BW, Respondek PM, Yasko AW, Benjamin RS,
Pollock RE, Pisters PW. Alveolar soft part sarcoma: clinical course and patterns of metastasis in
70 patients treated at a single institution. Cancer. 2001 Feb 1;91(3): 585-91.
Lieberman PH, Brennan MF, Kimmel M, Erlandson RA, Garin-Chesa P, Flehinger BY. Alveolar
soft-part sarcoma. A clinico-pathologic study of half a century. Cancer. 1989 Jan 1;63(1):1-13.
Mitton B. Federman N. Alveolar soft part sarcomas: molecular pathogenesis and implications for
novel targeted therapies. Sarcoma; 2012:428789. Epub 2012 Apr 8.
Folpe AL, Deyrup AT. Alveolar soft-part sarcoma: a review and update. J Clin Pathol. 2006
Nov;59(11): 1127-32.
Kayton ML, Meyers P, Wexler LH, Gerald WL, LaQuaglia, MP. Clinical presentation, treatment
and outcome of alveolar soft part sarcoma in children, adolescents, and young adults. J Ped Surg.
2006 Jan;41(1): 187-93.
M. Ladanyi, M. Y. Lui, C. R. Antonescu et al. The der(17)t(X;17)(p11;q25) of human alveolar
soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25.
Oncogene. 2001 Jan 4;20(1):48-57.
Tsuji K, Ishikawa Y, Imamura T. Technique for differentiating alveolar soft part sarcoma from
other tumors in paraffin-embedded tissue: comparison of immunohistochemistry for TFE3 and
CD147 and of reverse transcription polymerase chain reaction for ASPSCR1-TFE3 fusion
transcript. Hum Pathol. 2012 Mar;43(3):356-63.
Weiss S, Goldblum J. Enzinger & Weiss’s Soft Tissue Tumors (5th ed).
Mosby/Esevier Inc. 177-92, 2008.
CTTR’s COTM
March, 2013
Philadelphia:
Page 3