Soft tissue tumors: Clear cell sarcoma

Malignant melanoma of the soft parts, Cancer, Oncology. EWSR1, ATF1, ">

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Soft tissue tumors: Clear cell sarcoma

Identity

Phylum Soft Tissue Tumors:Uncertain differentiation:Clear cell sarcoma of the soft tissue

Other names Clear cell sarcoma of the tendons and aponeuroses
Malignant melanoma of the soft parts

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

Clinics and Pathology

Disease Soft tissue tumour, presenting as a slow growing mass intimately associated with tendons and aponeuroses, in young adults.

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.

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.

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

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.

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

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

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

Genes involved and Proteins

Gene Name EWSR1

Location 22q13

Note also called EWS.

Dna / Rna 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 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

Location 12q13

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

Protein 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

Hybrid Gene

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.

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

Bibliography

Malignant melanoma of soft parts. A reassessment of clear cell sarcoma.

Chung EB, Enzinger FM

The American journal of surgical pathology. 1983 ; 7 (5) : 405-413.

PMID 6614306

Cytogenetic findings in clear cell sarcoma of tendons and aponeuroses. Malignant melanoma of soft parts.

Bridge JA, Sreekantaiah C, Neff JR, Sandberg AA

Cancer genetics and cytogenetics. 1991 ; 52 (1) : 101-106.

PMID 2009504

Clear cell sarcoma of soft tissues. Mayo Clinic experience with 35 cases.

Lucas DR, Nascimento AG, Sim FH

The American journal of surgical pathology. 1992 ; 16 (12) : 1197-1204.

PMID 1463095

Malignant melanoma of soft parts. Further cytogenetic characterization.

Speleman F, Colpaert C, Goovaerts G, Leroy JG, Van Marck E

Cancer genetics and cytogenetics. 1992 ; 60 (2) : 176-179.

PMID 1606560

EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts.

Zucman J, Delattre O, Desmaze C, Epstein AL, Stenman G, Speleman F, Fletchers CD, Aurias A, Thomas G

Nature genetics. 1993 ; 4 (4) : 341-345.

PMID 8401579

The EWS-ATF-1 gene involved in malignant melanoma of soft parts with t(12;22) chromosome translocation, encodes a constitutive transcriptional activator.

Fujimura Y, Ohno T, Siddique H, Lee L, Rao VN, Reddy ES

Oncogene. 1996 ; 12 (1) : 159-167.

PMID 8552387

Malignant 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, Delattre O, Peter M, Hauben E, Van Roy N, Van Marck E

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 1997 ; 10 (5) : 496-499.

PMID 9160316

Clear cell sarcoma of soft tissues in children and young adults: the St. Jude Children's Research Hospital experience.

Parasuraman S, Rao BN, Bodner S, Cain A, Pratt CB, Merchant TE, Pappo AS

Pediatric hematology and oncology. 1999 ; 16 (6) : 539-544.

PMID 10599094

EWS-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, Siddique H, Lee L, Rao VN, Reddy ES

Oncogene. 2001 ; 20 (46) : 6653-6659.

PMID 11709699

Molecular diagnosis of clear cell sarcoma: detection of EWS-ATF1 and MITF-M transcripts and histopathological and ultrastructural analysis of 12 cases.

Antonescu CR, Tschernyavsky SJ, Woodruff JM, Jungbluth AA, Brennan MF, Ladanyi M

The Journal of molecular diagnostics : JMD. 2002 ; 4 (1) : 44-52.

PMID 11826187

Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses.

Panagopoulos I, Mertens F, D��biec-Rychter M, Isaksson M, Limon J, Kardas I, Domanski HA, Sciot R, Perek D, Crnalic S, Larsson O, Mandahl N

International journal of cancer. Journal international du cancer. 2002 ; 99 (4) : 560-567.

PMID 11992546

REVIEW articles automatic search in PubMed

Last year publications automatic se arch in PubMed

Contributor(s)

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

Citation

This paper should be referenced as such :
Poppe B, Forsyth R, Dhaene K, Speleman F . Soft tissue tumors: Clear cell sarcoma. Atlas Genet Cytogenet Oncol Haematol. November 2002 .
URL : http://AtlasGeneticsOncology.org/Tumors/ClearCellSarcID5074.html

This paper is referenced by INIST as such :

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Sat Mar 9 12:39:01 CET 2013

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Phylum	Soft Tissue Tumors:Uncertain differentiation:Clear cell sarcoma of the soft tissue
Other names	Clear cell sarcoma of the tendons and aponeuroses
	Malignant melanoma of the soft parts


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

Disease	Soft tissue tumour, presenting as a slow growing mass intimately associated with tendons and aponeuroses, in young adults.
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.


	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.


	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 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.


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


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

Gene Name	EWSR1
Location	22q13
Note	also called EWS.
Dna / Rna	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	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
Location	12q13
Dna / Rna	ATF1 is transcribed from centromere to telomere at 12q13. The coding sequence contains 816bp, comprising 6 exons and spans approximately 43kb.
Protein	ATF1 encodes a member of the CREB/ATF basic leucine-zipper type transcription factor family and binds to cAMP inducible promotors.

Hybrid Gene


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

REVIEW articles	automatic search in PubMed
Last year publications	automatic se arch in PubMed

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