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The full name of this sarcoma is Clear Cell Sarcoma of Tendons and Aponeuroses. If that isn't enough, it is also known as malignant melanoma of soft parts. It gets its peculiar designation when pathologists noted that many of the tumor cells contained melanin suggesting this tumor was an unusual form of melanoma arising in soft tissue and not from the skin. More sophisticated molecular analysis has now revealed a chromosomal translocation affecting the same gene that is affected in Ewing's sarcoma. The pathologist's job rests upon differentiating this sarcoma from a melanoma which has metastasized to soft tissue.


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SYNONYMS Clear Cell Sarcoma of Tendons and Aponeuroses
Malignant melanoma of soft parts



Establishment and characterisation of a human clear cell sarcoma model in nude mice.

Crnalic S, Panagopoulos I, Boquist L, Mandahl N, Stenling R, Lofvenberg R.

Department of Orthopaedics, University Hospital, Umea, Sweden.

Int J Cancer 2002 Oct 20;101(6):505-11 Abstract quote

We have established a new experimental model of human clear cell sarcoma, UM-CCS1, using serial subcutaneous transplantation of intact tumour tissue in nude mice. The heterotransplanted nude mouse tumours retained characteristic morphological features of the primary clear cell sarcoma.

Immunohistochemical analysis showed the retained expression patterns of S-100 protein, melanoma-associated antigen HMB-45 and vimentin in the xenografts as compared to the primary tumour. DNA index showed low variations both between the xenografts in the same passage and between the serial passages. Cytogenetic analysis of the primary tumour and the xenografts showed the unbalanced translocation der(6)t(6;12)(p23;q13). Based on the combined genetic data a reasonable interpretation of our findings is that there was a complex chromosomal rearrangement resulting in a cytogenetically cryptic EWS-ATF1 fusion gene. Analysis of cell kinetics using in vivo incorporation of iododeoxyuridine and flow cytometry showed generally short potential doubling time (T(pot)) of the xenografts. Volume doubling time showed low variations without correlation with T(pot).

The retained phenotypic and genotypic characteristics of the primary tumour and the morphological and structural stability over time makes the model suitable for studies on the tumour biology and treatment of clear cell sarcoma.


Newly established clear cell sarcoma (malignant melanoma of soft parts) cell line expressing melanoma-associated Melan-A antigen and overexpressing C-MYC oncogene.

Moritake H, Sugimoto T, Asada Y, Yoshida MA, Maehara Y, Epstein AL, Kuroda H.

Department of Pediatrics, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki, Japan.

Cancer Genet Cytogenet 2002 May;135(1):48-56 Abstract quote

Clear cell sarcoma (CCS), malignant melanoma of soft parts, is a rare malignant tumor with a poor prognosis. In this study, a CCS cell line, designated MP-CCS-SY, was established from a metastatic tumor of a 17-year-old Japanese girl that originated in the left Achilles tendon. A small number of melanosomes were detected in the cytoplasm by electron microscopy.

The melanosomes immunoreacted with two melanoma-associated antibodies, HMB45 and Melan-A. A Western blot demonstrated the existence of a Melan-A antigen in this cell line. Although a t(12;22)(q13;q12), which is characteristic of CCS, was not identified by a chromosomal analysis with conventional banding techniques, fluorescence in situ hybridization analysis with painting probes of chromosomes 12 and 22 revealed the insertion of a chromosome 12 fragment into one of the long arms of chromosome 22. The chimeric EWS/ATF1 transcript was detected by the reverse transcriptase polymerase chain reaction. Extra copies and structural abnormalities of chromosome 8 were observed. Overexpression of c-myc mRNA was detected by Northern blot analysis and may have a role in malignant progression of CCS.

The availability of this MP-CCS-SY cell line will help to understand the molecular biology of this malignancy and should be useful as a tool for developing an immunotherapy.

Dual-color, break-apart fluorescence in situ hybridization for EWS gene rearrangement distinguishes clear cell sarcoma of soft tissue from malignant melanoma.

Patel RM, Downs-Kelly E, Weiss SW, Folpe AL, Tubbs RR, Tuthill RJ, Goldblum JR, Skacel M.

1Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.

Mod Pathol. 2005 Dec;18(12):1585-90. Abstract quote  

Clear cell sarcoma of soft tissue (malignant melanoma of soft parts) is a soft tissue sarcoma with melanocytic differentiation that typically occurs in the tendons and aponeuroses of young adults. As demonstrated by cytogenetics and reverse-transcriptase polymerase chain reaction, between 70% and over 90% of clear cell sarcomas have a t(12;22) translocation, fusing the EWS and ATF1 genes on chromosomes 22q12 and 12q13, respectively. Identification of this translocation distinguishes clear cell sarcoma from histologic mimics, most importantly conventional malignant melanoma.

We report our experience with a commercially available, dual-color, break-apart fluorescence in situ hybridization (FISH) probe, which allows detection of EWS (22q12) gene rearrangement in formalin-fixed, paraffin-embedded tissues. Histologically and immunophenotypically well-characterized cases of clear cell sarcoma (n=10) and malignant melanoma (n=32) were evaluated with a 22q12 dual-color, break-apart probe (Vysis, Downer's Grove, IL, USA), which spans the known common breakpoints in the EWS gene on chromosome 22 (introns 7-10). Signals from tumor cell nuclei were counted under a fluorescence microscope and the presence of red-green break-apart signals was recorded. Of the clear cell sarcoma cases, seven of 10 showed evidence of an EWS gene rearrangement with a mean of 81.6% positive cells per sample (range: 60-95%). All cases of malignant melanoma (n=32) showed virtually absent break-apart signals in the EWS gene (less than 4% cells per case). FISH detects EWS gene rearrangement in a substantial proportion of clear cell sarcomas, with excellent specificity.

Importantly, EWS FISH is negative in malignant melanoma, a clinically dissimilar tumor, which may closely mimic clear cell sarcoma histologically and immunohistochemically. As the studied probe can be utilized in routinely processed tissue, FISH provides an excellent alternative to reverse-transcriptase polymerase chain reaction in cases where fresh tissue is unavailable.
EWS-ATF1 fusion transcripts in gastrointestinal tumors previously diagnosed as malignant melanoma.

Covinsky M, Gong S, Rajaram V, Perry A, Pfeifer J.
Hum Pathol. 2005 Jan;36(1):74-81. Abstract quote  

Summary Background Clear cell sarcoma (CCS) is classically a deep soft tissue tumor associated with tendons or aponeuroses, although cases of primary CCS of the gastrointestinal (GI) tract have recently been reported. Because it is difficult to distinguish CCS from metastatic melanoma based on morphology, immunohistochemical profile, and ultrastructural features, it is possible that some GI tumors diagnosed as metastatic melanoma actually represent primary GI CCS. Because the EWS-ATF1 fusion transcript and the associated t(12;22)(q13;q12) translocation occur in CCS but not cutaneous melanoma, we investigated the use of molecular-based testing for discriminating CCS from metastatic melanoma (MM) in GI tumors.

Methods Patients with GI tumors diagnosed as MM were identified from departmental files. The tumors were tested for the EWS-ATF1 fusion transcript by RT-PCR and for t(12;22)(q13;q12) by fluorescence in situ hybridization.

Results Detailed review of medical records revealed that 16 (80%) of the 20 had a documented history of cutaneous melanoma. Two cases (10%) harbored the EWS-ATF1 fusion transcript, and fluorescence in situ hybridization confirmed the presence of t(12;22) in both cases. Of the 2 positive tumors, 1 developed in a patient who had no history of cutaneous melanoma, and the other developed in a patient with a remote history of vulvar melanoma.

Conclusion Based on molecular genetic findings, a subset of GI tumors diagnosed as MM by routine histopathologic evaluation represents CCS.

Malignant melanoma is genetically distinct from clear cell sarcoma of tendons and aponeurosis (malignant melanoma of soft parts).

Langezaal SM, Graadt van Roggen JF, Cleton-Jansen AM, Baelde JJ, Hogendoorn PC.

Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.


Br J Cancer 2001 Feb;84(4):535-8 Abstract quote

Clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft parts) and conventional malignant melanoma may demonstrate significant morphologic overlap at the light microscopic and ultrastructural level. Consequently, the clinically relevant distinction between primary clear cell sarcoma and metastatic melanoma in the absence of a known primary cutaneous, mucosal or ocular tumour may occasionally cause diagnostic problems. A balanced translocation, t(12;22)(q13;q13), which can be detected, amongst others, using the reverse transcriptase polymerase chain reaction (RT-PCR) or fluorescent in situ hybridization (FISH), has been identified in a high percentage (50-75%) of clear cell sarcomas and is presumed to be tumour specific. Whether this chromosomal rearrangement is present in malignant melanoma has, to date, not as yet been studied by molecular genetic or molecular cytogenetic techniques.

Using RT-PCR and FISH, a series of metastases from 25 known cutaneous melanomas and 8 melanoma cell lines (5 uveal and 3 cutaneous) were screened for the t(12;22)(q13;q13) translocation. Primers for RT-PCR were chosen based upon published breakpoint sequences. The Cosmids G9 and CCS2.2, corresponding to the 5' region of EWS and 3' region of ATF-1 respectively, were used as probes. The translocation was not identified in any of the melanomas or melanoma cell lines analysed in this study; in contrast this translocation was identified in 3 out of 5 clear cell sarcomas using these techniques.

This allows distinction between translocation positive cases of clear cell sarcoma and malignant melanoma at a molecular genetic level. Consequently, in diagnostically challenging cases, this represents a valuable tool for the clinicopathologic differentiation between these two entities, with an important impact on patient management and prognosis.

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.

Department of Patholog, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

J Mol Diagn 2002 Feb;4(1):44-52 Abstract quote

Clear cell sarcoma (CCS), also known as melanoma of soft parts, is an uncommon deep soft tissue tumor presenting typically in the lower extremities of young adults. Previous cytogenetic studies have established the specificity of the recurrent t(12;22)(q13;q12), resulting in a EWS-ATF1 fusion, for CCS. The prevalence of the EWS-ATF1 fusion in CCS remains unclear, since most genetically confirmed CCS have been reported as isolated cytogenetic or molecular diagnostic case reports.

We therefore studied histologically confirmed CCS from 12 patients for the presence of EWS-ATF1 by reverse-transcriptase polymerase chain reaction (RT-PCR), using RNA extracted from either frozen (four cases) or formalin-fixed paraffin-embedded (eight cases) material. All primary tumors were located in the deep soft tissues of the extremities. Histologically, 10 cases had a typical epithelioid nested appearance. Most or all cases showed immunostaining for HMB45 (12 of 12), S-100 protein (10 of 12), and MITF (12 of 12). Ultrastructural analysis showed melanosomes in six of seven cases. The presence of an EWS-ATF1 fusion transcript was identified by RT-PCR in 11 of 12 cases (91%), all of which showed the same fusion transcript structure, namely the previously described in-frame fusion of EWS exon 8 to ATF1 codon 65. RT-PCR analysis for the melanocyte-specific splice form of the MITF transcript was positive in all cases tested (4 of 4).

These data confirm that EWS-ATF1 detection can be used as a highly sensitive diagnostic test for CCS and that CCS expresses the melanocyte-specific form of the MITF transcript, further supporting its genuine melanocytic differentiation.

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

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

Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.

Int J Cancer 2002 Jun 1;99(4):560-7 Abstract quote

Clear cell sarcoma (CCS) is a rare malignant soft tissue tumor particularly associated with tendons and aponeuroses. The cytogenetic hallmark is the translocation t(12;22)(q13;q12) resulting in a chimeric EWS/ATF1 gene in which the 3'-terminal part of EWS at 22q is replaced by the 3'-terminal part of ATF1 at 12q. To date, only 13 cases of CCS have been analyzed for fusion genes at the transcription level, and there is no information about the breakpoints at the genomic level.

In the present study, we describe the molecular genetic characteristics of CCS from 10 patients. Karyotypes were obtained from 10 cases, 7 of which showed the characteristic t(12;22). As an initial step in the characterization of the EWS/ATF1 and ATF1/EWS chimeras, we constructed an exon/intron map of the ATF1 gene. The entire ATF1 gene spanned >40 kb and was composed of 7 exons. Intron 3, in which most of the genomic breakpoints occurred, was to a large extent (83%) composed of repetitive elements. RT-PCR amplified EWS/ATF1 cDNA fragments in all patients and ATF1/EWS cDNA fragments in 6 of 10 patients. Four types of EWS/ATF1 chimeric transcript, designated types 1-4, were identified.

The most frequent chimeric transcript (type 1) was an in-frame fusion of exon 8 of EWS with exon 4 of ATF1. This was the only chimeric transcript in 5 patients but found together with other variants in 3 tumors. The type 2 transcript of EWS/ATF1, an in-frame fusion of exon 7 of EWS with exon 5 of ATF1, was detected in 4 patients, as the only transcript in 1 case and together with other variants in 3 cases. An in-frame fusion of exon 10 of EWS with exon 5 of ATF1 (type 3) was found in 1 patient as the only transcript, and an out-of-frame fusion of EWS exon 7 with ATF1 exon 7 (type 4) was detected in 1 patient together with type 1 and type 2 transcripts. Sequencing of the amplified ATF1/EWS cDNA fragments showed in 5 patients that ATF1 exon 3 was fused with EWS exon 10, resulting in an out-of-frame chimeric transcript. In 1 case, nt 428 of ATF1 (exon 4) was fused with EWS exon 8; at the junction, there was an insertion of 4 nucleotides, also resulting in an out-of-frame transcript. Genomic extra long PCR and sequence analysis mapped the genomic breakpoints to introns 7, 8 and 9 of EWS and intron 3 and exon 4 of ATF1.

While a simple end-to-end fusion was observed in 2 cases, additional nucleotides were found at the junctions in 2 other cases. In addition, topoisomerase I consensus sequences were found close to the junctions, suggesting that this enzyme may participate in the genesis of the EWS/ATF1 fusion.



Malignant melanoma of soft tissues (clear cell sarcoma) of the foot. Is MRI able to perform a specific diagnosis? Report of one case and review of the radiological literature.

Gandolfo N, Martinoli C, Cafiero F, Peressini A, Nicolo M, Dellacha A, Derchi LE.

Istituto di Radiologia, Universita di Genova, Largo Rosanna Benzi, 8, I-16132 Genova, Italy.

Anticancer Res 2000 Sep-Oct;20(5C):3993-8 Abstract quote

The magnetic resonance (MR) findings in malignant melanoma of soft tissues, also called clear cell sarcoma of tendons and aponeuroses, have been described as a focal abnormality with a specific MR pattern of increased signal intensity (relative to normal muscle) on T1 weighted sequences and variably decreased signal intensity on T2 weighted sequences (relative to surrounding fat).

We have reported here a case of malignant melanoma of soft tissues of the foot, studied with ultrasonography (US) and MR, in which MR showed T1-hypointensity, T2-hyperintensity and marked gadolinium uptake. We have described the relationship between the intracytoplasmic melanin amount of and these atypical MR findings.



Clear cell sarcoma arising in the retroperitoneum.

Katabuchi H, Honda R, Tajima T, Ohtake H, Kageshita T, Ono T, Okamura H.

Department of Obstetrics and Gynecology, Kumamoto University School of Medicine, Honjo 1-1-1, Kumamoto City, Kumamoto 860-8556, Japan.

Int J Gynecol Cancer 2002 Jan-Feb;12(1):124-7 Abstract quote

Clear cell sarcoma is a rare soft-tissue neoplasm, arising most commonly in the tendons and aponeuroses of young adults.

We report here the first female case of clear cell sarcoma arising in the retroperitoneum with clinical features similar to those of malignant ovarian tumors. Aspects of clinical presentation, histopathologic evaluation, and treatment are described.


Clear Cell Sarcoma of Soft Tissue: A Clinicopathologic, Immunohistochemical, and Molecular Analysis of 33 Cases.

*Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu †Department of Pathology and Laboratory Medicine, Kohnodai Hospital, Ichikawa ‡Department of Molecular Bone and Cartilage Pathology, Hard Tissue Genome Research Center, Tokyo Medical and Dental University ∥Department of Surgical Pathology, Teikyo University School of Medicine, Tokyo §Department of Pathology, Chang Gung Memorial Hospital, Taipei, Taiwan Departments of ¶Pathology ♯Orthopedics, Saitama Cancer Center, Saitama **Division of Anatomic and Surgical Pathology, Yokohama City University Hospital, Yokohama ††Department of Pathology, Seirei Hamamatsu General Hospital, Hamamatsu ‡‡Department of Tumor Pathology, Graduate School of Medicine §§Department of Laboratory Science, School of Health Sciences, Gunma University, Maebashi ∥∥Section of Orthopaedic Surgery, Department of Frontier Surgical Therapeutics, Division of Advanced Therapeutical Sciences, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.

Am J Surg Pathol. 2008 March 32(3);452-460. Abstract quote

Clear cell sarcoma (CCS) of soft tissue is a rare sarcoma with morphologic similarities to malignant melanoma but a distinct genetic background including a chromosomal translocation, t(12;22)(q13;q12), or a resultant EWSR1-ATF1 fusion gene. In addition, the tumors occurring in the gastrointestinal tract may have a variant fusion gene EWSR1-CREB1.

This study analyzed the clinicopathologic and molecular genetic features of 33 CCSs of soft tissue. The patients' ages ranged from 13 to 73 years (median, 30 y), and there was a male predominance (20 males, 13 females). The tumors were located in the deep soft tissues of the extremities (N=25) or in the trunk or limb girdles (N=8). The median tumor size was 4 cm (range, 1 to 15 cm). The tumor cells were either spindle or epithelioid, and they were arranged predominantly in a short fascicular (N=19) or a solid sheetlike growth pattern (N=14). Minor histologic variations included the existence of rhabdoid cells (N=8), bizarre pleomorphic cells (N=6), alveolar structures due to loss of cellular cohesion (N=3), and a seminomalike pattern (N=2). Tumor necrosis was evident in 14 tumors, and the mitotic activity ranged from 0 to 43 mitotic figures (MF)/10 high-power fields (HPF) (mean: 4 MF/10 HPF). Immunohistochemically, the tumors were consistently positive for S-100 protein (33/33) and variably or focally for HMB45 (32/33), microphthalmia transcription factor (26/32), Melan A (23/32), CD57 (25/33), bcl-2 (30/32), synaptophysin (14/32), CD56 (7/32), epithelial membrane antigen (12/33), cytokeratin (AE1/AE3) (1/32), CD34 (3/32), c-erbB-2 (10/32), c-kit (5/32), and c-met (5/32). alpha-Smooth muscle actin, desmin, and cytokeratin (CAM5.2) were negative. Reverse transcription-polymerase chain reaction using RNA extracted from formalin-fixed, paraffin-embedded tissues demonstrated transcripts of the EWSR1-ATF1 (31/33) or EWSR1-CREB1 fusion gene (2/33). In 26 cases with available clinical information, local recurrences and metastases developed in 2 and 15 patients, respectively. Ten patients were dead of the disease, and the overall survival rate was 63% at 5 years. However, no clinicopathologic or molecular variables associated with the patients' prognosis were identified.

This study confirms that CCS is an aggressive soft tissue tumor with a melanocytic phenotype and wider morphologic variations than had been generally considered. In cases with unusual histologic findings, molecular detection of the EWSR1-ATF1/CREB1 fusion genes provides critical information regarding the diagnosis of the tumor.

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

Lucas DR, Nascimento AG, Sim FH.

Section of Surgical Pathology, Mayo Clinic, Rochester, Minnesota 55905.

Am J Surg Pathol 1992 Dec;16(12):1197-204 Abstract quote

Thirty-five cases of clear cell sarcoma of soft tissues were studied to determine the clinical or morphologic features that are important in predicting prognosis.

Tumors occurred most commonly in the extremities, and the majority of the patients were young women. Surgery was the elected treatment in every case. Five patients experienced local recurrences, and metastases developed in 22. Fifty-four percent of the patients died of tumor, 11% are alive with disease, and the remaining 34% are alive and well; the average survival for each group was 67 months, 113 months, and 103.5 months, respectively. This sarcoma is characterized by small clusters of polygonal to spindle cells featuring clear to slightly basophilic cytoplasm and vesicular nuclei with prominent nucleoli. The clusters are separated by delicate fibrous septa. In a deletion, clear cell sarcoma has low mitotic activity, little or no necrosis, and mild nuclear pleomorphism.

Tumor size and the presence of necrosis are statistically significant predictors of prognosis. All 12 patients with tumors measuring > 5 cm died of disease or are alive with disease. Eleven of the 20 patients with tumors measuring < 5 cm are alive with no evidence of disease. Tumor necrosis was present in 10 cases; eight of these patients died of disease and one is alive with disseminated metastases.


Clear-cell sarcoma diagnosis by fine-needle aspiration: cytologic, histologic, and ultrastructural features; potential pitfalls; and literature review.

Tong TR, Chow TC, Chan OW, Lee KC, Yeung SH, Lam A, Yu CK.

Department of Pathology, Room G-1414, Princess Margaret Hospital, Kowloon, Hong Kong SAR, People's Republic of China

Diagn Cytopathol 2002 Mar;26(3):174-80 Abstract quote

A definitive diagnosis of clear-cell sarcoma of soft parts (CCSSP) is possible by fine-needle aspiration (FNA) biopsy alone. The aspirates are markedly cellular, consisting predominantly of discohesive cells but also of cohesive cells.

The cytoplasm is eosinophilic and eccentric. The nuclei are round and contain macronucleoli. CCSSP should be considered when FNA of a soft-tissue tumor shows uncharacteristically high cellularity and relatively uniform cells with macronucleoli. Cohesion of some tumor cells does not rule out CCSSP. Melanin pigment and cytoplasmic clearing are infrequent and not necessary for the diagnosis. Sufficient material should always be procured for immunohistochemical studies on the cell block. Seven other cases are found in the literature, all correctly diagnosed by FNA.

Although it is rare, CCSSP is a highly malignant tumor that can be diagnosed readily by FNA without resorting to incisional biopsy.

Cytologic Features of Clear Cell Sarcoma (Malignant Melanoma) of Soft Parts A Study of Fine-Needle Aspirates and Exfoliative Specimens

Andrew J. Creager, MD
Martha B. Pitman, MD
and Kim R. Geisinger, MD

Am J Clin Pathol 2002;117:217-224 Abstract quote

We describe the cytologic features of clear cell sarcoma of soft tissue (CCS) in 11 fine-needle aspiration biopsy (FNAB) specimens and 6 exfoliative specimens from 11 patients.

In 3 patients, FNAB was the initial method of tumor evaluation. In 6 of 11 cases, immunostaining with S-100 or HMB-45 was evaluated. Electron microscopic evaluation was performed in 1 case. Both the FNAB and exfoliative specimens varied in overall cellularity, although reproducible cytologic features were identified. A significant diagnostic pitfall, namely the potential of CCS to form microacinar structures mimicking adenocarcinoma, is described with particular reference to CCS metastatic to regional lymph nodes. A rare case of the granular cell variant of CCS is illustrated as well. Owing to the rarity of CCS, the diagnosis on cytologic smears is extremely difficult and is aided substantially by pertinent clinical data.

The diagnosis can be made conclusively by FNAB in conjunction with immunocytochemical confirmation of HMB-45 or S-100 protein expression, cytogenetic demonstration of the t(12;22) translocation, or electron microscopic studies demonstrating melanosomes.

Myxoid clear cell sarcoma.

Kim YC, Vandersteen DP, Jung HG.

Department of Dermatology, Ajou University School of Medicine, Suwon, Korea.
Am J Dermatopathol. 2005 Feb;27(1):51-5. Abstract quote  

Clear cell sarcoma is a rare soft-tissue tumor presenting typically in the extremities of young adults. It has been also known as malignant melanoma of the soft parts because of the presence of melanin and cytoplasmic melanosomes. However, clear cell sarcoma is, at present, usually considered as a unique lesion because the t(12;22)(q13;q12) translocation is present only in clear cell sarcoma. Myxoid malignant melanoma is now a well-recognized morphologic variant of malignant melanoma. However, a myxoid variant of clear cell sarcoma has not been well described yet.

We report a case of myxoid clear cell sarcoma occurring on the heel in a 22-year-old man. The tumor was composed of nests and fascicles of oval to fusiform cells with clear to pale eosinophilic cytoplasm, often separated by fibrous septa. The tumor cells were reactive for S-100 protein, HMB-45, and MART-1. Variably sized cysts lined by one or several layers of tumor cells were observed. Alcian blue and mucicarmine stains demonstrated prominent mucin deposition in the tumor stroma and especially in the lumen of the cysts.

Fluorescence in situ hybridization for the Ewing sarcoma gene showed rearrangement in nearly all of the neoplastic cells.


Immunoperoxidase HMB45 and S100 postive
Microphtalmia Transcription Factor

Mod Pathol 2001;14:6-9

Used antibody D5
8/12 tumors positive (75%)
S100 12/12
HMB45 11/12

Melan-A in 3/7 (43%)

Clear cell sarcoma shows immunoreactivity for microphthalmia transcription factor: further evidence for melanocytic differentiation.

Granter SR, Weilbaecher KN, Quigley C, Fletcher CD, Fisher DE.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

Mod Pathol 2001 Jan;14(1):6-9 Abstract quote

Microphthalmia transcription factor, a melanocytic nuclear protein critical for the embryonic development and postnatal viability of melanocytes, is a master regulator in modulating extracellular signals. Recently, microphthalmia transcription factor expression was shown to be both a sensitive and specific marker of epithelioid melanoma.

We investigated the sensitivity of D5, an anti-microphthalmia transcription factor antibody, for diagnosis of clear cell sarcoma (also known as malignant melanoma of soft parts). Immunoreactivity in a nuclear pattern for D5 was present in 8 of 12 (75%) tumors. D5 staining was strong in three tumors, moderate in two, and weak in three. S-100 protein expression was seen in all 12 cases that had clear cell sarcoma examined. HMB-45 staining was seen in 11 of 12 (92%) tumors. Focal Melan-A positivity was seen in 3 of 7 (43%) tumors.

Although D5 was shown in a previous study to be a highly sensitive and specific marker for epithelioid melanomas, the results of this study expand the spectrum of tumors showing immunoreactivity for D5. D5 immunoreactivity in clear cell sarcoma provides further evidence for melanocytic differentiation in this unusual tumor.

Diagnostic utility of microphthalmia transcription factor in malignant melanoma and other tumors.

Chang KL, Folpe AL.

Department of Pathology, City of Hope National Medical Center, Duarte, California 91010, USA.

Adv Anat Pathol 2001 Sep;8(5):273-5 Abstract quote

The diagnosis of malignant melanoma is sometimes challenging. Immunohistochemistry for specific markers of melanocytic differentiation such as HMB-45 and Melan-A can be very valuable in proving melanocytic differentiation in poorly differentiated or spindled forms of melanoma.

Microphthalmia-associated transcription factor (MiTF) is the most recently described and the only nuclear melanocytic marker. This article reviews the biology of MiTF and those published studies that have addressed its diagnostic sensitivity and specificity. MiTF may be very valuable for the diagnosis of melanoma, including desmoplastic variants; melanocytic soft tissue tumors, such as clear cell sarcoma; and the unusual group of tumors that show combined melanocytic and myoid differentiation, the perivascular epithelioid cell family of tumors (PEComas).

Utility of CD117 immunoreactivity in differentiating metastatic melanoma from clear cell sarcoma.

Garcia JJ, Kramer MJ, Mackey ZB, O'Donnell RJ, Horvai AE.

Department of Pathology, University of California, San Francisco, CA, USA.

Arch Pathol Lab Med. 2006 Mar;130(3):343-8. Abstract quote  

CONTEXT: Clear cell sarcoma is a malignant soft tissue tumor with melanocytic differentiation. Molecular methods are sometimes necessary to identify the unique t(12; 22)(q13;q12) translocation and differentiate clear cell sarcoma from melanoma.

OBJECTIVE: To determine whether CD117 immunoreactivity may be useful in separating melanoma from clear cell sarcoma.

DESIGN: We identified 20 tumors listed in our surgical pathology files that were diagnosed as clear cell sarcoma or in which clear cell sarcoma was strongly considered. These were tested for the presence of the t(12;22) translocation by reverse transcriptase/polymerase chain reaction and sequencing from paraffin-embedded tissue. Tumors with a t(12;22) translocation were immunostained with an antibody to CD117 and compared with 16 similarly stained metastatic melanomas.

RESULTS: Twelve tumors from 9 patients demonstrated t(12;22). No metastatic melanomas demonstrated t(12;22). None of the 12 clear cell sarcomas showed membrane or cytoplasmic staining for CD117. Conversely, 10 (63%) of 16 metastatic melanomas were, at least focally, positive for CD117; this difference was significant (P < .001). Interestingly, 3 tumors in which clear cell sarcoma was initially considered as a diagnosis, but which lacked t(12;22), were also positive for CD117.

CONCLUSIONS: Reverse transcriptase/polymerase chain reaction, performed on paraffin-embedded tissue, is a useful, rapid tool for identifying the presence of t(12;22) in clear cell sarcoma. The CD117 immunoreactivity may prove useful in the differential diagnosis of deep soft tissue or visceral lesions with melanocytic differentiation; positive staining results exclude clear cell sarcoma, but are compatible with metastatic melanoma.





Clear cell sarcoma. A clinicopathologic study of 27 cases.

Eckardt JJ, Pritchard DJ, Soule EH. C

Cancer 1983 Oct 15;52(8):1482-8 Abstract quote

Clear cell sarcoma is an indolent tumor of uncertain histogenesis.

Twenty-seven patients ranging in age from 9 to 57 years (average, 28.5 years) were followed an average of 7.0 years. Females outnumbered males by 2 to 1. Distal extremity locations predominated. At presentation, the tumor was localized in 21 patients, regionally metastatic in 5, and disseminated in 1.

Surgery was the primary therapy for 26 patients. Adjuvant treatment was nonstandardized, and its effectiveness is undetermined. Local recurrence developed in 10 patients, regional metastases in 9, and widespread dissemination in 12. Twelve patients died of the disease from 7 months to 10 years after diagnosis. Only 11 patients remained free of disease.

It would appear that wide excision, or perhaps even radical excision or amputation, is the surgical treatment of choice.

Malignant melanoma of soft parts (clear cell sarcoma). A study of 17 cases, with emphasis on prognostic factors.

Sara AS, Evans HL, Benjamin RS.

Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston 77030

Cancer 1990 Jan 15;65(2):367-74 Abstract quote

Seventeen cases of malignant melanoma of soft parts (clear cell sarcoma) are reported.

The patients ranged from 9 to 70 years of age, but 13 were between 10 and 40 years of age. There were eight male patients and nine female patients. The most common tumor location (seven patients) was the foot, followed by the area around the knee (four patients). The usual histologic pattern was that of variably sized nests of uniform plump spindle cells with clear to pale cytoplasm separated by fine to coarse fibrous septa; however, variants with a substantial proportion of epithelioid cells, moderate to marked nuclear pleomorphism, predominantly diffuse growth, or a microcystic pattern were seen. Patient survival was relatively poor overall (median, 49 months; ten deaths due to tumor) and was determined mainly by distant metastasis (11 patients).

Both survival and distant metastasis were correlated with tumor size (P less than 0.01 for patients with tumors greater than or equal to 5 cm versus less than 5 cm). Other clinical and pathologic factors, including patient age, sex, and race, tumor location, duration of symptoms, initial therapy, mitotic rate, tumor necrosis, proportion of epithelioid cells, and nuclear pleomorphism had no significant relation to survival or distant metastasis when tumor size was taken into account. Local recurrence and regional lymph node metastasis each occurred in four patients.

Clear cell sarcoma (malignant melanoma) of soft parts: A clinicopathologic study of 30 cases.

Deenik W, Mooi WJ, Rutgers EJ, Peterse JL, Hart AA, Kroon BB.

Department of Surgery, Netherlands Cancer Institute (Antoni van Leeuwenhoek ziekenhuis), Amsterdam, The Netherlands.

Cancer 1999 Sep 15;86(6):969-75 Abstract quote

BACKGROUND: Clear cell sarcoma, or malignant melanoma of soft parts, is a rare tumor that occurs predominantly in the extremities of young adults. The importance of surgery has been well established. However, the role of adjuvant radiotherapy has yet to be determined.

METHODS: Thirty cases of clear cell sarcoma that occurred in The Netherlands between 1978 and 1992 were studied retrospectively. Follow-up information on 29 patients was obtained; the follow-up period ranged from 4 to 241 months, with a median of 30 months. All tumors occurred in the extremities, mostly of young adults.

RESULTS: The 5-year survival rate of the 29 patients was 54%. For the 23 patients who presented with localized disease, the 5-year survival and 5-year disease free survival were 65%. Eleven of these patients remained disease free after resection of the primary tumor. Patients with a tumor 2 cm or smaller had better survival than patients with a larger but still-localized tumor (P = 0.009). Adjuvant radiotherapy to the primary tumor site also seemed to have a beneficial effect on survival (P = 0.036). All patients with a local recurrence (8 patients) or regional lymph node metastasis (13 patients) developed distant metastasis. Fourteen of 18 patients with distant spread died of their disease; 2 patients were still alive with disease and 2 patients were disease free, 7 and 32 months after resection of solitary distant metastases.

CONCLUSIONS: Early diagnosis and initial radical surgery are essential for a favorable outcome. Once regional lymph node metastasis or hematogenous dissemination has occurred, the prognosis is dismal.

Clear cell sarcoma: the Roswell Park experience.

Finley JW, Hanypsiak B, McGrath B, Kraybill W, Gibbs JF.

Division of General Surgery, Geisinger Medical Center, Penn State Geisinger Health System, Danville, Pennsylvania, USA.

J Surg Oncol 2001 May;77(1):16-20 Abstract quote

BACKGROUND AND OBJECTIVES: Clear cell sarcoma of the tendons and aponeuroses (CCSTA) is an aggressive, rare soft-tissue tumor with approximately 300 reported cases. Although it appears to be histogenetically related to melanoma, its clinical behavior resembles soft tissue sarcoma with a propensity for lymph node metastases. We report our experience at a tertiary cancer center.

METHODS: Eight cases of CCSTA evaluated at Roswell Park Cancer Institute between 1970 and 1998 were reviewed retrospectively. Patient data analyzed included patient age, gender, anatomic location, size of tumor, development of local, regional and distant recurrence, and patient status at last follow up.

RESULTS: Six of eight patients were alive at 2 years, while three of seven patients were alive at 5 years. Of the patients alive with no evidence of recurrence, two had tumors of less than 2 cm, and the remaining patient had incomplete information regarding tumor size. Five patients recurred within 2 years of definitive surgical management. Four had tumors > 5 cm. All five patients progressed to metastatic disease at a median follow up of 20 months (range 1-108 months) following definitive surgical management and all eventually died of their disease at a median of 3 months (range 0-24 months) from presentation with metastatic disease. Four of five patients with lesions > 5 cm received adjuvant chemotherapy with intent to cure, but all eventually died of disease at 4, 22, 34, and 41 months from initial presentation.

CONCLUSIONS: CCSTA is an aggressive tumor of the soft tissues. Early recognition and management are associated with an excellent long-term prognosis. Tumors greater than 5 cm warrant aggressive surgical management and treatment, and are at high risk of the development of distant disease. Aggressive multiagent chemotherapy appeared to have no impact on outcome. Other adjuvant therapeutic options including immunotherapy should be investigated.

Clear cell sarcoma of tendons and aponeuroses in pediatric patients: a report from the Italian and German Soft Tissue Sarcoma Cooperative Group.

Ferrari A, Casanova M, Bisogno G, Mattke A, Meazza C, Gandola L, Sotti G, Cecchetto G, Harms D, Koscielniak E, Treuner J, Carli M.

Pediatric Oncology Unit, Istituto Nazionale Tumori, Milan, Italy.

Cancer 2002 Jun 15;94(12):3269-76 Abstract quote

BACKGROUND: Clear cell sarcoma (CCS) of tendons and aponeuroses is extremely rare in childhood and little information is available on its clinical management. Originally believed to be a type of melanoma of soft tissue origin, CCS is now considered a distinct clinicopathologic entity that behaves like a high-grade soft tissue sarcoma. We report on a series of 28 pediatric patients treated from 1980 to 2000 by the Soft Tissue Sarcoma Italian Cooperative Group and the German Cooperative Group.

METHODS: Patients were treated with a multimodality therapeutic approach. Surgical resection was complete in 17 patients (mutilating in 3), radiotherapy was administered to 8 patients, and 20 patients received chemotherapy.

RESULTS: After a median follow-up of 102 months (range, 19-238 months), the 5-year and event-free survival rates were 66.4% and 63.3%, respectively. Seventeen patients were alive in first remission, two were alive in second remission, and nine had died of disease. The response to chemotherapy in the 7 evaluable patients included one partial remission, one minor response, and five no responses. Radiotherapy contributed to achieving local control in four of six Intergroup Rhabdomyosarcoma Study (IRS) Group II patients. Statistically significant differences in outcome were evident according to IRS group, tumor size, and site.

CONCLUSIONS: Our study confirms the aggressive behavior of CCS. Complete surgical resection represents the mainstay of treatment, and even the only treatment for patients with small tumors. Radiotherapy may control microscopic residual disease after surgery. Chemotherapy is ineffective and the prognosis is unfavorable for patients with unresectable and large tumors.

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