CCS Research Articles

Clear Cell Sarcoma (CCS) of soft tissue is a rare and highly malignant neoplasm primarily affecting young adults, often presenting in the deep soft tissues of the extremities. Despite morphological and immunophenotypic similarities to melanoma, CCS arises from connective tissues and is characterized by a distinct genetic hallmark: the EWSR1-ATF1 fusion resulting from t(12;22)(q13;q12) translocation. This genetic signature is absent in melanoma, making molecular diagnosis essential for accurate differentiation. Additionally, recent evidence highlights the utility of PRAME as an immunohistochemical marker to distinguish CCS from melanoma and other neoplasms. Clinically, CCS commonly involves tendons and aponeuroses, with metastatic potential leading to poor prognoses despite optimal local disease management. Histologically, CCS features lobular growth, spindle- to-epithelioid cells with clear cytoplasm, and low mitotic activity, often necessitating a multimodal diagnostic approach incorporating histopathology, immunohistochemistry, and molecular testing. Therapeutically, wide surgical excision remains the cornerstone for localized disease, with sentinel lymph node biopsy aiding in staging. Adjuvant radiotherapy is considered in select cases, while chemotherapy has limited efficacy in metastatic settings. Emerging treatments, including targeted therapies focusing on EWSR1-ATF1-driven pathways and immune checkpoint inhibitors, offer hope for improved outcomes. This review synthesizes current knowledge on CCS, emphasizing diagnostic challenges, the role of PRAME, and advancements in therapeutic strategies to enhance patient care.

Background: Clear cell sarcoma is rare, so no reports have previously characterized its national profiles. We examined the nationwide epidemiology and clinical outcomes of patients with clear cell sarcoma based on the National Cancer Registry in Japan.
Methods: Overall, 23 522 patients with soft tissue sarcoma-entered in the National Cancer Registry in 2016-2019 using the International Classification of Diseases for Oncology, Third Edition cancer topography and morphology codes-were enrolled in either the clear cell or the non-clear cell sarcoma group. Data extracted included: demographics (sex and age), tumor details (reason for diagnosis, tumor location, histology and stage), hospital volume and facility type, treatment and prognosis for each patient.
Results: Of 23 522 soft tissue sarcoma patients, 122 were enrolled in the clear cell sarcoma group and 23 400 in the non-clear cell sarcoma group. The incidence of clear cell sarcoma was 0.52% of all soft tissue sarcoma, with an age-adjusted incidence of 0.024/100 000/year. The age at diagnosis was significantly younger, and more tumors were at the localized stage in the clear cell than the non-clear cell sarcoma group. In addition, the overall survival in the clear cell group was worse than in the non-clear cell group (P < 0.001). Of 122 patients with clear cell sarcoma, the localized stage, surgical treatment and treatment without chemotherapy were associated with better overall survival in the univariate analyses.
Conclusions: The present study is the first to have clarified the epidemiology, clinical features, treatment, prognosis and significant factors affecting the prognosis of patients with clear cell sarcoma in Japan.
Keywords: National Cancer Registry; clear cell sarcoma; clinical outcome; epidemiology; prognostic factors.

Introduction: Clear cell sarcoma (CCS) is a rare and aggressive soft tissue sarcoma. CCS is
characterized by the translocation t(12;22) (q13;q12), involving the fusion of EWSR1 and ATF1
genes, and less frequently the fusion gene EWSR1-CREB1. Usually, CCSs are considered poorly
responsive to conventional chemotherapy. However, trabectedin has shown activity against
translocation-related sarcomas. Furthermore, preclinical results suggest that trabectedin is a
promising antitumor agent for CCS, potentially inducing melanocytic differentiation. Case
Presentation: We report the case of a challenging anatomopathological diagnosis in a pa-
tient with an aggressive metastatic CCS. Following the diagnosis of CCS, the patient experienced a clinical and radiological tumor response to trabectedin after four lines of treatment.
Conclusion: This is a novel report of CCS treated with trabectedin that resulted in a partial
response and suggests the need for further research on trabectedin as a therapeutic option
for CCS.

Malignant gastrointestinal neuroectodermal tumors (MGNETs), also known as “gastrointestinal clear cell sarcoma like tumors”, are very rare, aggressive sarcomas characterized by enteric location, distinctive pathologic features, and EWSR1/FUS::ATF1/CREB1 fusions. Despite identical genetics, the clinicopathologic features of MGNET are otherwise quite different from those of clear cell sarcoma of soft parts. Only exceptional extraenteric MGNET (E-MGNET) has been reported. We report a series of 11 EMGNETs, the largest to date. Cases diagnosed with MGNET and occurring in nonintestinal locations were retrieved. A clinical follow-up was obtained. The tumors occurred in 3 men and 8 women (range, 14-70 years of age; median, 33 years) and involved the soft tissues of the neck (3), shoulder (1), buttock (2), orbit (1), tongue/parapharyngeal space (1), urinary bladder (1), and falciform ligament/liver (1). Tumors showed morphologic features of enteric MGNET (small, relatively uniform, round to ovoid cells with round, regular nuclei containing small nucleoli growing in multinodular and vaguely lobular patterns, with solid, pseudoalveolar, and pseudopapillary architecture). Immunohistochemical results were S100 protein (11/11), SOX10 (11/11), synaptophysin (3/10), CD56 (7/9), CD117 (3/9), DOG1 (0/4), ALK (4/8), chromogranin A (0/10), HMB-45 (0/11), Melan-A (0/11), tyrosinase (0/4), and MiTF (0/11). Nextgeneration sequencing results were EWSR1::ATF1 (7 cases), EWSR1::CREB1 (3 cases), and EWSR1::PBX1 (1 case). The EWSR1::PBX1 positive tumor was similar to other cases, including osteoclastlike giant cells, and negative for myoepithelial markers. A clinical follow-up (range, 10-70 months; median, 34 months) showed 4 patients dead of disease (10.5, 12, 25, and 64 months after diagnosis), 1 patient alive with extensive metastases (43 months after diagnosis), 1 patient alive with persistent local disease (11 months after diagnosis), and 4 alive without disease (10, 47, 53, and 70 months after diagnosis). One case is too recent for the follow-up. The clinicopathologic and molecular genetic features of rare E-MGNET are essentially identical to those occurring in intestinal locations. Otherwise, typical EMGNET may harbor EWSR1::PBX1, a finding previously unreported in this tumor type. As in enteric locations, the behavior of E-MGNET is aggressive, with metastases and/or death from disease in at least 50% of patients. E-MGNET should be distinguished from clear cell sarcoma of soft parts and other tumors with similar fusions. ALK expression appears to be a common feature of tumors harboring EWSR1/FUS::ATF1/CREB1 fusion but is unlikely to predict the therapeutic response to ALK inhibition. Future advances in our understanding of these unusual tumors will hopefully lead to improved nomenclature.
© 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.

Background: Clear cell sarcoma (CCS) is a translocated aggressive malignancy with a high incidence of metastases and poor prognosis. There are few studies describing the activity of systemic therapy in CCS. We report a multi-institutional retrospective study of the outcomes of patients with advanced CCS treated with systemic therapy within the World Sarcoma Network (WSN).

Materials and methods: Patients with molecularly confirmed locally advanced or metastatic CCS treated with systemic therapy from June 1985 to May 2021 were included. Baseline demographic and treatment information, including response by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, was retrospectively collected by local investigators. Descriptive statistics were carried out.

Results: Fifty-five patients from 10 institutions were included. At diagnosis, the median age was 30 (15-73) years and 24% (n = 13/55) had metastatic disease. The median age at diagnosis was 30 (15-73) years. Most primary tumours were at aponeurosis (n = 9/55, 16%) or non-aponeurosis limb sites (n = 17/55, 31%). The most common fusion was EWSR1-ATF1 (n = 24/55, 44%). The median number of systemic therapies was 1 (range 1-7). The best response rate was seen for patients treated with sunitinib (30%, n = 3/10), with a median progression-free survival of 4 [95% confidence interval (CI) 1-7] months. The median overall survival for patients with advanced/metastatic disease was 15 months (95% CI 3-27 months).

Conclusions: Soft tissue sarcoma-type systemic therapies have limited benefit in advanced CCS and response rate was poor. International, multicentre prospective translational studies are required to identify new treatments for this ultra-rare subtype, and access to early clinical trial enrolment remains key for patients with CCS.

Keywords: CCS; EWSR1–ATF1; chemotherapy; clear cell sarcoma; soft tissue sarcoma; sunitinib; systemic therapy.

Clear cell sarcoma (CCS) previously known as malignant melanoma (MM) of the soft tissue, although, similar in morphology to MM, contemporary histopathologic and cytogenetic techniques have made this diagnosis obsolete, as it is now possible to distinguish between CCS and MM. CCS is often diagnosed in young adults with median age of 25 years. Overall mortality is generally poor, and the 5-year survival is between 40 and 60%. Hence, early diagnosis and radical surgery are key in the treatment of this extremely rare malignancy of the soft tissue comprising only about 1% of all sarcomas. This article present an overview of this rare malignancy.