Soft Tissues: Clear cell sarcoma

2002-11-01   Bruce Poppe , Ramses Forsyth , Karl Dhaene , Frank Speleman 

1.Center for Medical Genetics, Ghent University Hospital MRB, De Pintelaan 185, 9000 Ghent, Belgium

Summary

Atlas Image
Nests of clear polygonal cells delineated by fibrous septa (H&E, 200x).

Clinics and Pathology

Note

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

Embryonic origin

mesoderm

Epidemiology

rare sarcoma affecting primarily young adults

Clinics

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.
Atlas Image
Cellular smear almost exclusively showing dispersed spindle cells. Their oval nuclei are only slightly irregular and contain a large nucleolus. The cytoplasm is rather scant (MGG, 400x) (Courtesy of Dr. J. Willems, Onze-Lieve-Vrouw Ziekenhuis Aalst, Belgium).

Pathology

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.
Atlas Image
Left to right: A: Typical clear cell sarcoma with eosinophilic cytoplasm (H&E, 400x); B: A reticulin meshwork surrounds the individual nests (reticulin, 200x); C: Strong S100 immunoreactivity, a consistent feature (S100, 400x).

Treatment

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.

Evolution

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

Prognosis

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.

Cytogenetics

Atlas Image
The t(12;22)(q13;q12), as identified by G-banding.

Cytogenetics morphological

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.

Cytogenetics molecular

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.
Atlas Image
dual colour in situ hybridisation the EWS cosmid G9 (green) and the ATF1 CCS2.2 cosmid (red) demonstrating a juxtaposition of 5 EWS to 3 ATF1 sequences, indicating the presence of a EWS/ATF1 genomic fusion (arrowheads).

Probes

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

Additional anomalies

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.

Variants

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

Genes Involved and Proteins

Gene name

EWSR1 (Ewing sarcoma breakpoint region 1)

Location

22q12.2

Note

also called EWS.

Dna rna description

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.

Protein description

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.

Gene name

ATF1 (activating transcription factor 1)

Location

12q13.12

Dna rna description

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

Protein description

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

Result of the chromosomal anomaly

Atlas Image
detection protocole: as described by Antonescu et al. (the data given are virtually identical to the Table 1 from the mentioned reference)

Description

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.

Transcript

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

Oncogenesis

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

Bibliography

Pubmed IDLast YearTitleAuthors
118261872002Molecular diagnosis of clear cell sarcoma: detection of EWS-ATF1 and MITF-M transcripts and histopathological and ultrastructural analysis of 12 cases.Antonescu CR et al
20095041991Cytogenetic findings in clear cell sarcoma of tendons and aponeuroses. Malignant melanoma of soft parts.Bridge JA et al
66143061983Malignant melanoma of soft parts. A reassessment of clear cell sarcoma.Chung EB et al
117096992001EWS-ATF-1 chimeric protein in soft tissue clear cell sarcoma associates with CREB-binding protein and interferes with p53-mediated trans-activation function.Fujimura Y et al
14630951992Clear cell sarcoma of soft tissues. Mayo Clinic experience with 35 cases.Lucas DR et al
119925462002Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses.Panagopoulos I et al
105990941999Clear cell sarcoma of soft tissues in children and young adults: the St. Jude Children's Research Hospital experience.Parasuraman S et al
91603161997Malignant melanoma of the soft parts (clear-cell sarcoma): confirmation of EWS and ATF-1 gene fusion caused by a t(12;22) translocation.Speleman F et al
84015791993EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts.Zucman J et al

External Links

Citation

Bruce Poppe ; Ramses Forsyth ; Karl Dhaene ; Frank Speleman

Soft Tissues: Clear cell sarcoma

Atlas Genet Cytogenet Oncol Haematol. 2002-11-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/5074/soft-tissues-clear-cell-sarcoma