Clear Cell Sarcoma

Clear cell sarcoma is an extremely rare and biologically aggressive tumor that originates from neural crest cells that produce the pigment melanin. It can occur anywhere in the body, although it most commonly affects the extremities, particularly the foot and ankle. The tumor is named for its characteristic clear cytoplasm, which distinguishes it from other soft tissue sarcomas and is caused by the accumulation of glycogen. Clear cell sarcoma has a poor prognosis due to its high frequency of metastasis to the lymph nodes and lungs.

The tumor’s origin from or close association with tendons and aponeuroses is how Enzinger defined it in his original 1965 paper (“clear cell sarcoma of tendons and aponeuroses”) and remains its most clinically recognizable anatomic feature.

Clear cell sarcoma has previously been referred to as “malignant melanoma of soft tissue,” but modern cytogenetic and immunohistochemical techniques have differentiated it from malignant melanoma. Clear cell sarcoma is one of five soft tissue sarcomas denoted by the mnemonic “SCARE” (Synovial sarcoma, Clear cell sarcoma, Angiosarcoma, Rhabdomyosarcoma, and Epithelioid sarcoma) that have an increased frequency of spread to lymph nodes.

Epidemiology

Clear cell sarcoma is rare and accounts for less than 1% of all sarcomas. Compared to other soft-tissue sarcomas, it tends to occur at a younger age and is most frequent in the fourth decade of life. It has a predilection for the lower extremities (e.g., foot, ankle), which account for 70% of cases.

Clinical Features

Unlike most high-grade sarcomas that grow rapidly, clear cell sarcoma presents indolently as a slow-growing, painless mass. Pain, swelling, and tenderness are late and non-specific findings. There may be ulceration of the affected area, especially if the tumor is located on the foot or ankle. This lack of specific clinical features often delays the diagnosis. Clear cell sarcoma might be discovered as part of a workup for symptoms suggesting an occult malignancy, such as unexplained weight loss, fatigue, or night sweats.

Radiologic Features

Clear cell sarcoma may be seen on plain radiographs (Figure 1) but as with most soft-tissue tumors, the most informative imaging study is magnetic resonance imaging (MRI). The typical MRI finding is a solid lesion that is hypointense on T1 images, hyperintense on T2 fat-suppressed and short tau inversion recovery (STIR) images and demonstrates enhancement. Unfortunately, this finding is typical of both benign and malignant soft-tissue tumors. Therefore, once a histologic diagnosis is confirmed, PET-CT scans will be useful given the propensity of clear cell sarcoma to metastasize to the lymph nodes and lungs.

Figure 1: Imaging of a clear cell sarcoma of the right proximal humerus. The x-ray to the left shows an ill-defined, destructive, osteolytic lesion and the MR image to the right shows an irregularly shaped extraosseous mass extending around the bone. Note that clear cell sarcoma is a soft tissue sarcoma; tumors arising primarily within bone itself are rare. (Image courtesy of World J Surg Onc 9, 163 (2011). https://doi.org/10.1186/1477-7819-9-163)

Pathology

Histologically, clear cell sarcoma is composed of sheets of neoplastic cells divided by thin fibrous septa. The cells themselves appear uniform with basophilic nuclei and clear cytoplasm (Figure 2). Clear cell sarcoma is named for its characteristic clear cytoplasm, which distinguishes it from other soft tissue sarcomas. The clear cytoplasm is caused by the accumulation of glycogen.

Figure 2: H&E stain of clear cell sarcoma demonstrating sheets of hypercellular uniform oval/spindle cells with fine chromatin and prominent nucleoli (image courtesy of Dr. Gord Zhu)

This tumor shares several immunohistochemical stains with malignant melanoma, including strong expression of S-100, HMB-45, Melan-A, and MITF. Cytogenetically, clear cell sarcoma contains a fusion product (EWS/ATF1) between the Ewing sarcoma oncogene (EWS) and a transcription factor gene (ATF1). This fusion product is the result of a translocation between chromosomes 12 (ATF1) and 22 (EWS). This chimeric protein is believed to play a role in the development and progression of the tumor.

Differential Diagnosis

Clear cell sarcoma can be challenging to diagnose because its clinical presentation and histological features overlap with other soft tissue tumors. The differential diagnosis list may include synovial sarcoma, angiosarcoma, rhabdomyosarcoma, and epithelioid sarcoma, the four other “SCARE” tumors, as well as melanoma.

Disease Course: Treatment and Prognosis

Given the biologically aggressive nature of clear cell sarcoma, typical 5- and 10-year disease-specific survival rates are about 65% and 50%, respectively. Additionally, given the tendency of these tumors to metastasize early, studies have found a 5-year disease-specific survival difference between tumors less than 3 cm (85%) and greater than 3 cm (45%). Multivariate Cox regression analyses have reported tumor stage and tumor size to be independent prognostic factors of survival. The primary treatment for clear cell sarcoma is wide resection. Radiation therapy is indicated in cases of inadequate margins after resection, although the contribution of radiation therapy to achieving adequate surgical margins in this tumor is uncertain. Chemotherapy has been utilized with limited efficacy in the treatment of patients with established metastatic disease.

Key Test Topics

Clear cell sarcoma differs from other soft tissue sarcomas in terms of prognosis and treatment. The prognosis is poor, especially with large lesions and these tumors have a propensity to metastasize to lymph nodes. Treatment is primarily wide surgical resection.
The main prognostic factors for clear cell sarcoma are tumor size and the presence of metastatic disease at diagnosis.
The molecular characteristics of clear cell sarcoma that distinguish it from other soft tissue tumors include cells with clear cytoplasm and strong expression of S-100, HMB-45, Melan-A, and MITF as well as a fusion product of the translocation between chromosomes 12 and 22 (EWS/ATF1).