FIG 1 - uploaded by Julia A Bridge
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A (upper). The Tl-weighted magnetic resonance image of the foot demonstrates the anatomic location of the mass adjacent to the normal marrow signal of the os calcis, confirming the absence of osseous involvement. B (lower). The sagittal view of the cut specimen shows the anatomic relationship of the plantar fascia and tumor. Grossly, the lesion was firm and gray-white with focal hemorrhage secondary to the recent biopsy.
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Cytogenetic analysis was performed on three specimens of clear cell sarcoma, a rare neoplasm of uncertain histogenesis. Chromosomal analysis of clear cell sarcoma has not been reported previously. Two of the specimens analyzed consisted of the primary foot lesion and subsequent lymph node metastasis in a 29-year-old male. The other specimen was a p...
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... Diagnostic challenges arise owing to morphological similarities with malignant melanoma, historically leading to its classification as malignant soft tissue melanoma. Advances in molecular biology, particularly the identification of the t(12;22) (q13;q12) translocation and the resultant chimeric EWSR1/ATF1 gene fusion, have significantly enhanced diagnostic precision [4]. Although CCSST typically presents in the third and fourth decades, sporadic occurrences in the pediatric population have been documented [5]. ...
Background
Within the spectrum of melanocytic-differentiated tumors, the challenge faced by pathologists is discerning accurate diagnoses, with clear cell sarcoma of soft tissues standing out as a rare and aggressive neoplasm originating from the neural crest. Accounting for 1% of all soft tissue sarcomas, clear cell sarcoma of soft tissues poses diagnostic complexities, often misidentified owing to its phenotypic resemblance to malignant melanoma. This chapter delves into the intricacies of clear cell sarcoma of soft tissues, its epidemiology, characteristic manifestations, and the imperative need for a comprehensive diagnostic approach involving immunohistochemical and molecular analyses.
Case presentation
A compelling case unfolds as a 25-year-old male from Morocco, initially misdiagnosed with malignant melanoma, experiences tumor recurrence on the second toe. With no history of trauma or familial neoplasia, the patient’s clinical journey is explored, emphasizing the importance of detailed clinical examinations and radiological assessments. The chapter elucidates the histopathological findings, immunohistochemical spectrum, and the correlation between clinical parameters and diagnostic inference, ultimately leading to metatarsal amputation. This clinical vignette highlights the multidimensional diagnostic process in soft tissue neoplasms, emphasizing the synergistic role of clinical, radiological, and histopathological insights.
Conclusion
The diagnostic challenges inherent in melanocytic-differentiated tumors, exemplified by the rarity of soft tissue clear cell sarcoma, underscore the essential role of an integrated diagnostic approach. This concluding chapter emphasizes the perpetual collaboration required across pathology, clinical medicine, and radiology for nuanced diagnostic precision and tailored therapeutic strategies. The rarity of these soft tissue malignancies necessitates ongoing interdisciplinary engagement, ensuring the optimization of prognosis and treatment modalities through a comprehensive understanding of the diagnostic intricacies presented by clear cell sarcoma of soft tissues.
... Enzinger was the first to describe CCSs systematically in 1965 [90] (Enzinger 1965), also called melanoma of soft parts, because of overlapping morphological and immunohistochemical features with melanoma [91]. In the years 1990, 1991, and 1992, the translocation (12;22)(q13;q12) was found [92][93][94], one year after the EWSR1-ATF1 gene fusion by Zucman et al. 1993 [95]. Later on, it became apparent that CREB1 and CREM are substituents of ATF1 involving a smaller subset of cases [72,96,97]. ...
... Young adults (30-40 years) with equal sex distribution are the main group of patients. However, there is a broad age range from children to the elderly [90][91][92][97][98][99][100][101][102]. Additionally, there is a race distribution with the overwhelming majority of patients being Caucasian, whereas black people and Asians are uncommonly afflicted [101]. ...
... Symptoms depend on site and are nonspecific. Tumors can be large (up to 15 cm) [90][91][92]97,98,[101][102][103][104]. ...
EWSR1 belongs to the FET family of RNA-binding proteins including also Fused in Sarcoma (FUS), and TATA-box binding protein Associated Factor 15 (TAF15). As consequence of the multifunctional role of EWSR1 leading to a high frequency of transcription of the chromosomal region where the gene is located, EWSR1 is exposed to aberrations such as rearrangements. Consecutive binding to other genes leads to chimeric proteins inducing oncogenesis. The other TET family members are homologous. With the advent of widely used modern molecular techniques during the last decades, it has become obvious that EWSR1 is involved in the development of diverse benign and malignant tumors with mesenchymal, neuroectodermal, and epithelial/myoepithelial features. As oncogenic transformation mediated by EWSR1-fusion proteins leads to such diverse tumor types, there must be a selection on the multipotent stem cell level. In this review, we will focus on the wide variety of soft tissue and bone entities, including benign and malignant lesions, harboring EWSR1 rearrangement. Fusion gene analysis is the diagnostic gold standard in most of these tumors. We present clinicopathologic, immunohistochemical, and molecular features and discuss differential diagnoses.
... [2] Bridge et al. noted a distinct chromosomal translocation t (12;22)(q13, q12) involving EWSR1-activating transcription factor 1 (ATF1) in CCSTA, which is also shared by the tumors of CCS-GI. [3] This makes them an entity different from malignant melanoma. Subsequently, few cases primarily arising from the GI tract with clear cell morphology and immunophenotyping and sharing the same molecular features with CCSTA were reported. ...
Malignant gastrointestinal (GI) neuroectodermal tumor is an extremely rare entity that was first described by Zambrano et al. in 2003 as "clear cell sarcoma (CCS)-like tumor of the GI tract." It shares some of the histopathological features of CCS but lacks the immunohistochemical (IHC) reactivity for melanocytic markers. Most mesenchymal neoplasms of the GI tract belong to the category of GI stromal tumors and are characterized by the IHC expression of c-KIT. In cases, without detectable KIT receptor expression, several differential diagnoses have to be taken into consideration. In this article, we describe such a case and present a review of all the reported cases till date. We also present the current available knowledge on its pathology and molecular genetics along with the limitations in its diagnosis. Here, we report a case of a 32-year-old man with a tumor of the small bowel composed of polygonal tumor cells arranged in solid nests, alveolar pattern, and pseudopapillary and admixed with numerous osteoclast-like multinucleated giant cells. Immunohistochemically, the tumor cells strongly expressed S-100 protein only. HMB-45, melan-A, CD117, cytokeratin, desmin, smooth muscle actin, and CD-34 were absent. Ki-67 index was 15%. The diagnosis was further confirmed by fluorescence in situ hybridization (FISH) demonstrating the presence of EWSR1 (22q12) translocation. A final diagnosis of malignant gastroneuroectodermal tumor was rendered. The patient is disease-free for 20 months of postsurgery. The diagnosis of this entity should be considered in the presence of S-100-positivity and multinucleated osteoclastic giant cells and the absence of melanocytic differentiation in a tumor arising from GI tract. Further confirmation can be done by performing FISH analysis.
... Los rearreglos documentados fueron la formación de quiméricos de fusión con ATF1 (50%) y CREB1 (25%). A la fecha, se desconoce el origen de este tipo de neoplasia, pero los datos anteriores, sumados a análisis ultraestructurales que han identificado diferenciación neural 3,6,7 , sugieren que el precursor es de linaje neuroectodérmico; por esto, algunos autores consideran más apropiado el termino GNET 3,8 . No debe confundirse con el diagnóstico de tumores neuroendocrinos gastrointestinales, que corresponde a una patología completamente distinta 9 . ...
El tumor neuroectodérmico gastrointestinal maligno (GNET) es una entidad extremadamente rara recientemente descrita en la literatura médica y que también es conocida con el nombre de tumor similar al sarcoma de células claras en el tracto gastrointestinal (CCSLGT) por su similitud morfológica y molecular con el sarcoma de células claras de tendones y aponeurosis (CCS), pero, dada la presencia de rearreglos de gen EWSR1 y la diferenciación neuroectodérmica, se ha considerado por algunos autores más apropiado el término GNET. Es una enfermedad con pobre pronóstico, alta tasa de recurrencia y casi siempre metastásica desde el diagnóstico, lo que contrasta con el comportamiento relativamente indolente del CSS. En nuestro conocimiento, existen menos de 50 casos reportados de esta patología y a la fecha este sería el primero con primario localizado en hígado y con sobrevida libre de recaída prolongada luego de manejo quirúrgico adecuado y quimioterapia adyuvante.
... As mentioned, recurrent cytogenetic aberrancies are the hallmark of CCS, 57,58,63,64 and most tumors are associated with reciprocal t(12;22) (q13;q12) translocation resulting in EWSR1-ATF1 fusions. A small subset bears the EWSR1-CREB1 fusion, resulting from a t(2;22) (q33;q12) translocation. ...
In this article, we focus on the histologic features, differential diagnosis, and potential pitfalls in the diagnosis of epithelioid sarcoma, alveolar soft part sarcoma, clear-cell sarcoma, ossifying fibromyxoid tumor, and malignant extrarenal rhabdoid tumor. Numerous other soft tissue tumors also may have epithelioid variants or epithelioid features. Examples include epithelioid angiosarcoma, epithelioid malignant peripheral nerve sheath tumor, epithelioid gastrointestinal stromal tumor, and perivascular epithelioid cell tumor, among others.
Published by Elsevier Inc.
... These sarcomas commonly harbor a translocation fusing EWSR1 on chromosome 22 to ATF1 on chromosome 12. This translocation was discovered in 1990 and occurs in approximately 90% of patients with this type of tumor [50,51] . ...
Studies over the past decades have uncovered fusion genes, a class of oncogenes that provide immense diagnostic and therapeutic advantages because of their tumor-specific expression. Originally associated with hemotologic cancers, fusion genes have recently been discovered in a wide array of solid tumors, including sarcomas, carcinomas, and tumors of the central nervous system. Fusion genes are attractive as both therapeutic targets and diagnostic tools due to their inherent expression in tumor tissue alone. Therefore, the discovery and elucidation of fusion genes in various cancer types may provide more effective therapies in the future for cancer patients.
... These melanocytic features often make the distinction from malignant melanoma (MM) difficult. However, in contrast to MM, CCS is characterized by a chromosomal translocation, t(12;22)(q13;q12), that leads to the fusion of activating transcription factor 1 (ATF1) gene localized to 12q13 to Ewing's sarcoma oncogene (EWS) gene at 22q12 in up to 90% of cases, resulting in expression of the EWS/ATF1 fusion gene (10)(11)(12). Given that CCS and MM have such similar characteristics, it has been proposed that CCSs may arise from a neural crest progenitor. ...
Clear cell sarcoma (CCS) is an aggressive soft tissue malignant tumor characterized by a unique t(12;22) translocation that leads to the expression of a chimeric EWS/ATF1 fusion gene. However, little is known about the mechanisms underlying the involvement of EWS/ATF1 in CCS development. In addition, the cellular origins of CCS have not been determined. Here, we generated EWS/ATF1-inducible mice and examined the effects of EWS/ATF1 expression in adult somatic cells. We found that forced expression of EWS/ATF1 resulted in the development of EWS/ATF1-dependent sarcomas in mice. The histology of EWS/ATF1-induced sarcomas resembled that of CCS, and EWS/ATF1-induced tumor cells expressed CCS markers, including S100, SOX10, and MITF. Lineage-tracing experiments indicated that neural crest-derived cells were subject to EWS/ATF1-driven transformation. EWS/ATF1 directly induced Fos in an ERK-independent manner. Treatment of human and EWS/ATF1-induced CCS tumor cells with FOS-targeted siRNA attenuated proliferation. These findings demonstrated that FOS mediates the growth of EWS/ATF1-associated sarcomas and suggest that FOS is a potential therapeutic target in human CCS.
... Rearrangements of this gene occur in Ewing sarcoma, hyalinizing clear cell carcinoma of salivary gland, 5 myoepithelial carcinoma, 15 extraskeletal myxoid chondrosarcoma, myxoid liposarcoma, angiomatoid fibrous histiocytoma, and desmoplastic small round cell tumors. 37 The fusion translocation EWSR1-ATF1 has been noted in CCSTA, 9 hyalinizing clear cell carcinoma of salivary gland, 5 polyphenotypical round cell sarcoma of bone, 35 and in angiomatoid fibrous histiocytoma. 4,20,33 The fusion translocation EWSR1-CREB1 has been identified in CCSTA, angiomatoid fibrous histiocytoma, 4 primary pulmonary myxoid sarcoma, 39 and small blue round cell tumor of the interosseous membrane. ...
The clinical, histologic, immunophenotypic, ultrastructural, and molecular features of a distinctive gastrointestinal tumor are described. Sixteen patients, 8 women and 8 men aged 17 to 77 years (mean age, 42 y; 63% less than 40 y) presented with abdominal pain, intestinal obstruction, and an abdominal mass. Mean tumor size was 5.2 cm (range, 2.4 to 15.0 cm). The tumors arose in the small bowel (10), stomach (4), and colon (2) and were histologically characterized by a sheet-like or nested population of epithelioid or oval-to-spindle cells with small nucleoli and scattered mitoses. Five cases showed focal clearing of the cytoplasm. Scattered osteoclast-type multinucleated giant cells were present in 8 cases. The tumor cells were positive for S-100 protein, SOX10, and vimentin in 100% of cases, for CD56 in 70%, for synaptophysin in 56%, for NB84 in 50%, for NSE in 45%, and for neurofilament protein in 14% of cases. All cases tested were negative for specific melanocytic, gastrointestinal stromal tumors, epithelial, and myoid markers. Ultrastructural examination of 5 cases showed features of primitive neuroectodermal cells with clear secretory vesicles, dense-core granules, occasional gap junctions, and no evidence of melanogenesis. EWSR1 gene rearrangement was assessed by fluorescence in situ hybridization in 14 cases. Twelve cases (86%) showed split EWSR1 signal consistent with a chromosomal translocation involving EWSR1. One case showed extra intact signals, indicating that the nuclei possessed either extra copies of the EWSR1 gene or chromosome 22 polysomy. Only 1 case showed no involvement of the EWSR1 gene. Six cases demonstrated rearrangement of the partner fusion gene ATF1 (46%), and 3 showed rearrangement of CREB1 (23%); 2 cases lacked rearrangement of either partner gene. Clinical follow-up was available in 12 patients and ranged from 1.5 to 106 months. Six patients died of their tumors (mean survival, 32 mo; 83% less than 24 mo). At last follow-up, 4 patients were alive with regional, lymph node, and liver metastases, and 2 patients were alive with no evidence of disease. The tumor described here is an aggressive form of neuroectodermal tumor that should be separated from other primitive epithelioid and spindle cell tumors of the gastrointestinal tract. The distinctive ultrastructural features and absence of melanocytic differentiation serve to separate them from soft tissue clear cell sarcomas involving the gastrointestinal tract. The designation "malignant gastrointestinal neuroectodermal tumor" is proposed for this tumor type.
... Clear cell sarcomas of soft tissue, also known as malignant melanomas of soft parts, have hypodiploid to hypertriploid karyotypes of moderate complexity [85,86]. A characteristic t(12;22)(q13;q12) is present in 70% of the tumors and is thought to be the primary genetic event. ...
Studies on the molecular mechanisms behind soft tissue sarcoma development have disclosed that these malignancies are as genetically heterogeneous as they are clinically and morphologically diverse. Much of the genetic information on soft tissue sarcomas is still limited to the genomic level, as detected by chromosome banding analysis or comparative genomic hybridization. Based on the results of such studies, soft tissue sarcomas may be broadly dichotomized into one group, accounting for approximately 20% of the cases, characterized by specific balanced translocations, and one group typically showing massive chromosomal rearrangements leading to recurrent, but non-specific, structural and numerical rearrangements. As summarized in this review, the genomic characterization of soft tissue sarcomas has not only provided cell biologists with decisive information on the parts of the genome that may harbor genes that are essential for tumor development but also given the clinicians involved in the management of these patients a valuable diagnostic tool.
... Frequently, the mass is attached to tendons or aponeuroses, but there is no direct connection with overlying skin 6 . On microscopic analysis, epithelioid cells with pale nuclei and deeply basophilic nucleoli are aggregated in compact nests surrounded and separated from adjacent nests by fibrous tissue septa 7 . Mitoses are generally sparse and necrosis and haemorrhage are rare 8 . ...
... CCS and MM demonstrate significant morphologic overlap at light microscopic and ultrastructural levels, as well as similar immunohistochemical features, so the distinction may be difficult 5 . However, the behavior of CCS is decidedly different from that of MM, demonstrating a more indolent course 7 . CCS is a deep seated tumor that rarely shows the degree of anaplasia, necrosis, and mitotic activity usually associated with MM. ...
Clear cell sarcoma is a rare malignant tumor representing about 1% of soft tissue tumors. It usually presents in the distal extremities of young adults, frequently attached to tendons or aponeuroses. This slowly progressive tumor tends to recur and results in eventual development of metastatic growth. Early recognition of the disease and prompt wide excision of tumor are essential to get a favorable outcome. We report a rare case of clear cell sarcoma in a 57 year-old female who presented with an erythematous hard nodule on her abdomen.
