To be distinguished from clear cell sarcoma of the kidney, to which it is unrelated.

mesoderm

rare sarcoma affecting primarily young adults

slowly growing tumour mass, causing pain or tenderness, particularly frequently (up to 95% of the cases) situated in the extremities, with a predilection for the foot and the ankle.

Polygonal or spindle shaped cells with abundant eosinophilic or clear cytoplasm displaying a uniform, nested to fascicular growth pattern, delineated by fibrous septa. Melanin deposits can be demonstrated using specific stains, but is more readily detectable by immunoreactivity against melanoma antigens (e.g. S100 and HMB45) in the vast majority of the cases.

radical surgical resection, adjuvant radiotherapy should be considered in incomplete resections, large (>5 cm) tumours and/or high grade lesions. Clear cell sarcomas seems to display little sensitivity to conventional soft tissue sarcoma multi-agent chemotherapy protocols.

special attention should be paid to the occurrence of late recurrences (median time to recurrence: 4.2 years).

Generally, clear cell sarcoma is characterised by an adverse prognosis, only 40 to 50% of the patients being long-term survivors. As recurrences may occur late, 5-year survival rates tend to misjudge prognosis. Established prognostic features include: tumour size, necrosis and local recurrence.

The cytogenetic hallmark of clear cell sarcoma is the presence of the t(12;22)(q13;q12). This translocation has been described in the majority of reported clear cell sarcoma cases, not however in other malignancies. The translocation is readily identifiable with G-, R- or Q-banding.

Fluorescence in situ hybridisation based approaches can be used to demonstrate the t(12;22), using chromosome painting probes or to demonstrate EWSR1 and ATF1 gene rearrangement, using gene specific probes.

EWSR1 probes: 5 EWSR1: G9 cosmid; 3 ATF1 probe: CCS2.2

Although the t(12;22) has been reported as the sole chromosomal aberration in clear cell sarcoma, most cases display additional cytogenetic anomalies, including +7, +8 and structural and numerical aberrations of chromosome 22.

No variant translocations, creating EWSR1/ATF1 fusion transcripts, have been described.

EWSR1 (Ewing sarcoma breakpoint region 1)

22q12.2

also called EWS.

EWSR1 is transcribed from centromere to telomere at 22q12. The coding sequence contains 1971 bp, comprising 17 exons and spans approximately 32kb. Alternative splicing creates the EWS-b variant, lacking exons 8 and 9.

The EWS protein contains a C-terminal RNA binding domain and has indeed been shown to display RNA binding properties. The functions of the EWS protein, however, largely remain elusive.

ATF1 (activating transcription factor 1)

12q13.12

ATF1 is transcribed from centromere to telomere at 12q13. The coding sequence contains 816bp, comprising 6 exons and spans approximately 43kb.

ATF1 encodes a member of the CREB/ATF basic leucine-zipper type transcription factor family and binds to cAMP inducible promotors.

The EWS/ATF1 fusion transcript is detectable in up to 90% of the clear cell sarcoma cases. As described in other EWS rearrangements, the transcript fuses 5 EWS to 3 heterologous sequences. The reciprocal ATF1/EWS fusion probably does not contribute to malignant transformation since it is out of frame.

Several alternatively spliced transcripts have been described, the more frequent being the type 1 fusion: EWS exon 8 fused to ATF1 exon 4.

The EWS/ATF1 oncoprotein converts ATF1 to a constitutive transcriptional activator that represses p53/CBP-mediated transactivation.