Clear cell sarcoma of soft tissue

Last revised by Joachim Feger on 12 Dec 2022

Clear cell sarcomas (CCS) of soft tissue are malignant mesenchymal tumors with melanocytic differentiation and an extraordinary nested growth pattern. They are classified as soft tissue tumors of uncertain differentiation.

The term ‘malignant melanoma of soft parts’ has been discouraged 1.

Clear cell sarcoma is a rare tumor accounting for <1% of all soft tissue neoplasms. It is mostly found in the younger adult population in the third and fourth decade with women slightly more frequently affected than men 1-3.

Soft tissue clear cell sarcomas are diagnosed based on histology and immunohistochemistry 1.

Diagnostic criteria according to the WHO classification of soft tissue and bone tumors (5th edition) 1:

  • fascicular or nest-like architecture

  • plump to epithelioid spindle cells with prominent nucleoli and pale eosinophilic cytoplasm

  • wreath-like multinucleated giant cells

  • positive immunoreactivity for melanocytic markers such as S100, SOX10, melan A and HMB45

  • EWSR1-ATF1 fusions in a high number of cases

The typical clinical presentation is a palpable mass of variable duration, often months or years. Tenderness or pain is a feature described in about a third to half of the cases 1,4

Clear cell sarcomas show melanocytic differentiation and a distinctive fascicular growth pattern 1. The clear cell appearance is because of a pale eosinophilic cytoplasm due to glycogen accumulation 2,3.

The etiology of clear cell sarcomas is unknown 1.

Clear cell sarcomas are most often found in deep-seated regions of the extremities and have been associated with tendons and aponeuroses such as the ankle and foot, which are the most common sites. Less common and rare locations include head and neck, trunk and visceral regions as well as from skin and oral mucosa 1-4.

The macroscopic appearance of clear cell sarcomas usually shows a circumscribed mass with a lobulated form and a tannish-grey to white color with a coarse texture. Some of the clear cell sarcomas might display cystic changes necrosis or melanin pigmentation 1,2.

Microscopically clear cell sarcomas display the following histological features 1-3:

  • fascicular or nest-like architecture

  • epithelioid to plump spindled cells embedded by fibrous septa

  • pale eosinophilic cytoplasm and vesicular nuclei

  • wreath-like multinucleated giant cells

  • minimal pleomorphism

  • low mitotic count

Immunohistochemistry stains usually express melanocytic markers as S100, SOX10, melan A and HMB45 1-3.

Clear cell sarcomas of soft tissue are associated with EWSR1-ATF1 gene fusions in 70-90% 1-3 and EWSR1-CREB1 fusions in a subset of tumors 1,2.

Clear cell sarcomas have been characterized as well-defined homogeneous lesions with a benign-looking appearance 2.

MRI is considered the most suitable modality to identify the tumor and its relations to the adjacent structures, even if a definitive diagnosis cannot be made and differentiation from other malignant tumors is difficult 3. On MRI, clear cell sarcomas have been described as homogeneous, lobulated well-circumscribed lesions 2-4. Bone destruction is seen in a minority of cases 4.

  • T1: homogeneous iso to hyperintense compared to muscle

  • T2: heterogeneous with variable signal intensity and hypointense foci

  • STIR/PDFS: hyperintense

  • T1C+ (Gd): variable inhomogeneous and heterogeneous enhancement

The radiological report should include a description of the following:

  • form, location and size

  • tumor margins and transition zone

  • relations to the muscular fascia

  • relation to adjacent neurovascular structures

  • relations to bones

Clear cell sarcomas are aggressive tumors and treatment usually includes wide surgical excision with an acceptable amount of tumor-free surrounding tissue. Local recurrence is seen in up to 40% metastasis to lung or lymph nodes occurs in 30-50% of patients. Radiation therapy can be done to improve local tumor control in case of close resection margins. Chemotherapy is mostly administered in metastatic disease. Overall survival rates have been reported to be in the range of about 60%, 35% and 10% for 5, 10 and 20 years respectively. Tumor size >5 cm, tumor necrosis as well as nodal involvement, are considered unfavorable prognostic factors 1-3.

The “clear cell sarcoma of tendons and aponeuroses” was first described by the Austrian-American pathologist Franz Michael Enzinger in 1965 2-5.

Tumors or conditions which can mimic the presentation and/or appearance of clear cell sarcomas of soft tissue include 2,3:

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