Clear Cell Sarcoma of Soft Tissue

The American Joint Committee on Cancer (AJCC) or Union for International Cancer Control (UICC) TNM system may be used.

The genetic hallmark of CCS is the reciprocal translocation t(12;22)(q13;q12), present in 70–90% of cases, which fuses EWSR1 with ATF1. Exon 8 of EWSR1 fuses with exon 4 of ATF1 most frequently, and this has been designated as the type 1 fusion. In the resultant EWSR1-ATF1 chimeric fusion protein, the N-terminus of EWSR1 and the basic leucine zipper (bZIP) domain of ATF1 are linked. Consequently, ATF1, a transcription factor normally regulated by cAMP, becomes a cAMP-independent transcriptional activator and constitutively activates the promoter for MITF, a target of the MSH pathway. This activation is responsible for melanocytic differentiation and growth of CCS. ATF and CREB proteins are functionally similar, and a smaller subset of cases harbor a variant translocation, t(2;22)(q34;q12), resulting in an EWSR1-CREB1 fusion. An intradermal melanocytic neoplasm with a novel CRTC1-TRIM11 fusion, substantial morphological overlap with CCS, and metastatic potential, provisionally termed cutaneous melanocytoma, was recently described. Additional work is necessary to determine whether this tumor represents CCS with a novel fusion or a distinct entity. Although the majority of CCSs investigated have failed to show BRAF or NRAS mutations, BRAF p.Val600Glu mutations have been identified in a small subset of molecularly confirmed tumors.

Most CCSs measure 2–5 cm, but tumors > 15 cm have been reported. Gross examination reveals a circumscribed mass with a lobulated tan to greyish-white appearance, sometimes with a coarse or gritty texture. A subset of CCSs may show melanin pigmentation, necrosis, or cystic change.

On low-power examination, CCS exhibits a characteristic nested or fascicular architecture with epithelioid to plump spindled cells partitioned by thin fibrous septa. Tumors typically show notably infiltrative growth through dense fibrous tissue. Despite its name, CCS typically has tumor cells with palely eosinophilic cytoplasm and vesicular nuclei with macronucleoli, with only rare examples showing true cytoplasmic clearing. Substantial nuclear pleomorphism is generally absent, although scattered wreath-like multinucleated giant cells are relatively common. Melanin pigment is present in more than half of cases but is difficult to appreciate on H&E staining. Rare cases may show junctional tumor nests at the dermoepidermal interface. The mitotic count of CCS is frequently low (< 3 mitoses/mm², equating to < 5 mitoses per 10 high-power fields of 0.17 mm²), and necrosis is identified in roughly one third of cases. CCS shows consistent expression of S100, SOX10, melan-A, HMB45, and MITF.

The cytological features of CCS are similar to those of melanoma, with aspiration specimens showing single or small clusters of round to polygonal cells with pale cytoplasm and prominent nucleoli. Pleomorphism is not prominent.

CCS is an aggressive malignancy with recurrence rates approaching 40% and pulmonary or lymph node metastasis in at least 30–50% of patients. Metastasis often occurs more than a decade after initial diagnosis. Survival rates at 5, 10, and 20 years are approximately 60%, 35%, and 10%, respectively. Tumor size > 5 cm, necrosis, and regional lymph node involvement are unfavorable prognostic factors. Fusion variant and transcript type have not been found to have prognostic significance.

Demonstration of EWSR1 gene rearrangement or EWSR1-ATF1 gene fusion may be helpful.

Essential: characteristic nested or fascicular low-power architecture; plump spindle or ovoid cells with palely eosinophilic cytoplasm and prominent nucleoli; multinucleated wreath-like giant cells are common; expression of melanocytic markers, including S100, SOX10, melan-A, and HMB45; 70–90% of cases harbor EWSR1-ATF1 fusions, helping to differentiate these neoplasms from melanoma.