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Clear cell sarcoma of tendons and aponeuroses: a review.

* Clear cell sarcoma of tendons and aponeuroses, also referred to as malignant melanoma of soft parts, is a rare malignancy derived from neural crest cells. It usually presents in the distal lower extremities of young adults, frequently attached to tendons or aponeuroses. It behaves like a high-grade soft tissue sarcoma and is associated with poor overall survival. Magnetic resonance imaging studies of the lesion reveal T1 hypointensity, T2 hyperintensity, and gadolinium uptake. Grossly, the tumor is usually circumscribed with a histologic pattern of uniform polygonal to fusiform cells with clear to pale eosinophilic cytoplasm divided into variably sized clusters by fibrous septa. Immunohistochemical studies in most cases show that the neoplastic cells are positive with HMB-45 and react with antibody against S100 protein. Most cases show a reciprocal cytogenetic translocation t(12;22)(q13;q12) that creates a unique chimeric fusion EWSR1/ATF1 gene transcript. Metastasis occurs mainly to regional lymph nodes and lungs. Poor prognostic indicators include a tumor size equal to or more than 5 cm, presence of metastasis, and necrosis. The mainstay of treatment is wide excision of the tumor. The use of sentinel lymph node biopsy may become an important procedure in detecting occult regional metastasis and guiding the extent of surgery. The beneficial effects of adjuvant chemotherapy and radiotherapy have not been fully evaluated. This article provides a short overview of the current knowledge of clear cell sarcoma of tendons and aponeuroses.


Clear cell sarcoma of tendons and aponeuroses (CCSTA), a rare tumor that was first described in 1968, (1) is also referred to as malignant melanoma of soft parts. This soft tissue neoplasm is thought to derive from neural crest cells. There is evidence for melanocyte differentiation by immunohistochemical, ultrastructural, and genomic profiling studies. (2-8) Because of these melanocytic features, its distinction from malignant melanoma (MM) may be difficult. However in contrast to MM, CCSTA is characterized by the t(12;22)(q13;q12) that leads to the fusion of the ATF1 gene localized to 12q13 to the EWSR1 gene at 22q12 in up to 90% of cases. (3,9-14) This translocation can be demonstrated by conventional cytogenetics, reverse transcriptase polymerase chain reaction, and fluorescent in situ hybridization (FISH). Consequently CCSTA is a distinct entity in its own right. It has a predilection for the distal extremities of young adults, especially the lower limbs, and a high propensity for regional or distant metastases. CCSTA has been observed to be more prevalent in Caucasians than in African Americans or Asians. The clinical course is difficult to predict because it can be protracted, with metastases appearing after a quiescent period of time, or it can occur with a rapid and fatal progression. (15,16)


The major clinical features of CCSTA are summarized in Table 1. The clinical presentation, which is usually different from MM, is characterized by indolent growth of a soft tissue mass, accompanied by tenderness or pain in 30% to 60% of cases. The gender distribution is approximately equal. However, the true incidence of this neoplasm remains unknown. Most cases of CCSTA present in adolescents and young adults, with rare reports in children. (15) It typically arises in the deep soft tissues of the distal extremities particularly the foot and ankle, although cases presenting in the kidney, trunk, penis, gastrointestinal tract, head, and neck have been reported. (17) As the name suggests, it often originates juxtaposed to tendons, fascia, or aponeuroses. (1,2,16,18,19) A history of antecedent trauma is not unusual. Ulceration of the overlying skin is not usually seen; however, the overlying dermis and subcutaneous tissue may be involved.


Gross pathologic examination of CCSTA reveals a localized, tan-grey, firm, and somewhat circumscribed mass, and size can range from 0.4 cm up to 14.5 cm in greatest dimension. The tumor shows infiltration into the tendons and aponeuroses.

The tumor is highly infiltrative and organized in a haphazard arrangement into small compact nests and fascicles of uniform neoplastic cells dissecting along the dense fibrous connective tissue of tendons, fascia, and aponeuroses. (1,4,18) The stroma may be barely visible, fibrotic, or hyalinized. These cellular clusters or aggregates are divided into lobules by a fine collagenous framework of variable thickness (Figure 1) that can be highlighted with Masson trichrome stain. The neoplastic cells are polygonal to fusiform with clear or pale eosinophilic cytoplasm and centrally located round to ovoid vesicular nuclei that show prominent basophilic nucleoli (Figure 2). The clear cell appearance is due to the accumulation of glycogen as can be demonstrated with periodic acid-Schiff (PAS) and PAS with diastase (PAS-D) stains. The neoplastic cells show no or minimal pleomorphism. There is paucity of mitotic figures that is in concordance with the slow-growing behavior of the tumor, although the course of this tumor is aggressive. Scattered multinucleated tumor giant cells are commonly present and areas of focal necrosis may be noted. Variants have been described including a case of myxoid clear cell sarcoma, a case with an alveolar pattern of growth because of loss of cellular cohesion, and 2 cases with a microcystic pattern. (4,19,20) There should be no evidence of biphasic differentiation.


On cytologic specimens of CCSTA, features include cohesive groups of varied cellularity that may show 3-dimensional clustering and pseudoacinar structures mimicking adenocarcinoma, admixed with dispersed single cells. The individual cells may be epithelioid, round to polygonal, with abundant cytoplasm. They have round to bean-shaped eccentric and vesicular nuclei with moderate pleomorphism, intranuclear cytoplasmic inclusions, and single or multiple nucleoli. (21,22) Multinucleated tumor giant cells and binucleate cells may also be observed.

Immunohistochemical studies of CCSTA show that the tumor cells express antigens associated with melanin synthesis including diffuse cytoplasmic immunoreactivity with HMB-45 (Figure 3), nuclear and cytoplasmic immunoreactivity to S100 protein (Figure 4), and reactivity with the microphthalmia transcription factor. There may be reactivity with Melan-A, CD99, neuron specific enolase, and vimentin (Table 2). Cytokeratin (CK), epithelial membrane antigen, carcinoembryonic antigen, desmin, and smooth muscle actin are usually negative. (5)


Ultrastructural analysis shows tumor cells closely apposed to each other by continuous basal laminae and rudimentary cell junctions.3 Cells show abundant cytoplasm containing numerous mitochondria and aggregates of glycogen. Unpigmented and pigmented melanosomes in different stages of development are also present in most cases. (3,4)


Clear cell sarcoma of tendons and aponeuroses is characterized by the reciprocal chromosome translocation, t(12;22)(q13;q12), which can be detected by conventional chromosome analysis (Figure 5), FISH, and reverse transcriptase polymerase chain reaction. This translocation results in fusion of the 3' portion of the Ewing sarcoma (EWSR1) oncogene on chromosome 22q with the 3' portion of the activating transcription factor 1 (ATF1) oncogene on chromosome 12q, giving rise to the EWSR1/ATF1 chimeric transcript. (23) Figure 6, A, depicts a normal interphase nucleus using the EWSR1 break-apart probe. There are 2 red/green fusion signals, each showing 1 red 5' EWSR1 centromeric signal and 1 green 3' EWSR1 telomeric signal. Figure 6, B depicts an interphase nucleus with 1 normal red/green fusion signal and separation of the second signal into a red and a green signal indicating EWSR1 gene rearrangement. The 5' EWSR1 end of the probe remains on the derivative chromosome 22, whereas the 3' EWSR1 end of the probe moves to the derivative chromosome 12. The EWSRI gene rearrangement has been detected in 70% to 90% of CCSTA. (3,9,10-17,24) Conventional cytogenetic analysis of tumor tissue requires fresh tissue for cell culture, whereas reverse-transcriptase polymerase chain reaction analysis can be performed on fresh, snap frozen tissue for RNA extraction, as well as with paraffin-embedded tissue. FISH may be performed if fresh, frozen, or paraffin-embedded tissue is available. Touch preparations of fresh tissue, frozen tissue, or paraffin-embedded tissue sections may be hybridized using DNA probes for FISH analysis. Therefore, in instances in which fresh tissue is unavailable, FISH evaluation of formalin-fixed, paraffin- embedded tissue is an important ancillary diagnostic test for confirmation of the EWSRI gene rearrangement. In addition to the diagnostic t(12;22), polysomy of chromosome 8 has been observed as a secondary abnormality in many cases of CCSTA. (9,25,26)



The differential diagnosis of a tumor located in close proximity to tendons and aponeuroses in an extremity includes the recently described paraganglioma-like dermal melanocytic tumor, clear cell myomelanocytic tumor, MM, malignant peripheral nerve sheath tumor, and synovial sarcoma, especially the monophasic type. In contrast to CCSTA, paraganglioma-like dermal melanocytic tumor is primarily a tumor of the extremities of females, presents as a dermal nodule, and is composed of clear to amphophilic oval cells of low nuclear grade arranged in a packetlike fashion reminiscent of a paraganglioma. A study of 5 cases of paraganglioma-like dermal melanocytic tumor found no EWS gene locus rearrangement. (27) Clear cell myomelanocytic tumor belongs to the perivascular epithelioid cell family of tumors (PEComas). (28) It commonly arises within the abdomen of young patients with predilection for the falciform ligament and ligamentum teres of the liver; it is characterized by fascicular and nested proliferation of uniform spindle cells and less prominent nucleoli and lacks multinucleation. Malignant peripheral nerve sheath tumor is usually associated with a large peripheral nerve or with manifestations of neurofibromatosis, significant myxoid stroma, hyperchromatic nuclei, brisk mitotic activity, and negativity with HMB-45. No recurring cytogenetic abnormality has been identified in malignant peripheral nerve sheath tumors. Malignant melanoma, which is the most important mimic of CCSTA in the soft tissue, occurs in patients who generally have a preceding history of cutaneous melanoma. However, CCSTA and MM demonstrate significant morphologic overlap at light microscopic and ultrastructural levels, as well as similar immunohistochemical features. In patients without a known primary cutaneous, mucosal, or ocular tumor, the distinction may be difficult. The t(12;22) translocation and EWSR1/ATF1 gene rearrangement observed in the majority of cases of CCSTA has never been found in MM. Approximately 50% of MMs show deletions of the short arm of chromosome 9 at the interferon alfa locus. However, the finding of the melanocyte-specific splice form of the microphthalmia transcription factor transcript in some cases of CCSTA may point to a histogenetic relationship between CCSTA and MM. Synovial sarcoma can be distinguished from CCSTA by the characteristic and diagnostic chromosomal translocation t(X;18)(p11.2;q11.2) or by SYT/ SSX1 or SYT/SSX2 gene fusion transcripts detected by reverse transcriptase polymerase chain reaction or FISH.


Treatment of CCSTA involves wide excision of the tumor as soon as the diagnosis is established. (29,30) Chemotherapy and radiotherapy have not been shown to be of benefit. Poor prognosis is associated with tumor size more than 5 cm, presence of necrosis, metastasis, and local recurrence. Wide excision or amputation versus simple excision resulted in mean survival periods of 10 and 6 years, respectively. (1) In studies of 11 cases, 8 cases, and 26 cases, overall 5-year survival approximated 48%, 55%, and 54%, respectively. (15,16) Tumors <5 cm are much less likely to recur or metastasize, whereas those >5 cm are associated with metastatic disease. (15) Lymph node metastasis is noted in a significant percentage of cases and is associated with a poor prognosis. (16,19,29) Patients with regional metastasis eventually go on to develop distant metastasis. (1,15,16,30) The most common metastatic sites include the lung, skin, bone, liver, heart, and brain. (18) The use of sentinel lymph node biopsy has been proposed as an effective means of determining early occult regional metastasis. (31) This may become useful in guiding the extent of surgery with a view to improving survival. In addition, lifelong follow-up is mandatory because local recurrence or metastases may occur as late as 29 years after initial surgical excision. (2) Overall, the clinical course is not only variable but difficult to predict at the present time.

Accepted for publication August 3, 2006.


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Daniel C. Dim, MD; Linda D. Cooley, MD; Roberto N. Miranda, MD

From the Department of Pathology, University of Missouri at Kansas City School of Medicine/Truman Medical Center (Drs Dim and Miranda) and the Department of Pathology and Laboratory Medicine, Section of Medical Genetics & Molecular Medicine, Children's Mercy Hospital (Dr Cooley), Kansas City, Mo.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Roberto N. Miranda, MD, Department of Pathology, Truman Medical Center, 2301 Holmes St, Kansas City, MO 64108-2677 (e-mail:
Table 1. Clinical Features of Clear Cell Sarcoma of
Tendons and Aponeuroses (CCSTA) *

Age 2-83 y (mean, 22 y)

Sex ratio M-F = 1:1

Race Caucasian > African American >

Primary site Lower extremity > upper extremity
 > trunk

Tumor size Range, 0.4-14.5 cm; 7.5 cm average

Growth Usually indolent

MRI T1, hypointensity; T2, hyperintensity;
 and gadolinium uptake

Incidence Unknown, considered rare

Symptoms Pain and/or tenderness

 Asymptomatic (months to years)

 +/- History of trauma

Metastasis Regional lymph node > lung > skin
 > bone > liver > heart

 Frequent with tumors > 5 cm

Local recurrence 14-348 mo

Radio-/chemotherapy Benefit not substantiated

Prognosis (5-year 52%

* MRI indicates magnetic resonance imaging. Data compiled from

Table 2. Immunohistochemical Profile of Clear Cell
Sarcoma of Tendons and Aponeuroses *

Antibody Positive, %

Vimentin 96
HMB-45 90
S100 64
Melan-A103 50
Melan-A 43
NSE 20
CD99 8
Synaptophysin 4

* MITF indicates microphthalmia transcription factor; NSE,
neuronspecific enolase. Source: Immunoquery, Immunohistochemistry
Literature Database Query System (
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Author:Dim, Daniel C.; Cooley, Linda D.; Miranda, Roberto N.
Publication:Archives of Pathology & Laboratory Medicine
Date:Jan 1, 2007
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