Soft Tissue Clear Cell Sarcoma

Edgar Zamora; Anna Greenwood; Sebastiano Cassaro

Soft Tissue Clear Cell Sarcoma

Earn CME/CE in your profession:

Free Review Questions

Continuing Education Activity

Clear cell sarcoma of soft tissue (CCSST) is an ultra-rare sarcoma originating from neural crest cells, most often presenting in young adults in the distal extremities. CCSST is histologically characterized by nests of clear cells separated by fibrous septa. These tumors share histological and immunohistochemical characteristics with malignant melanoma but are differentiated by a balanced gene translocation. Due to its benign appearance, CCSST is sometimes initially misdiagnosed. However, this disease has a highly aggressive course, with a 5-year survival rate of around 50%.

Diagnosis involves a combination of imaging, physical examination, and histological analysis, with confirmation through genetic testing for specific translocations. Treatment typically requires wide surgical resection with negative margins, though local recurrence and metastasis are common. Radiation and chemotherapy have shown limited effectiveness, and recent studies are exploring targeted therapies and immunotherapies. This activity for healthcare professionals is designed to enhance the learner's competence in recognizing the clinical features of CCSST, performing the recommended evaluation, and implementing an appropriate interprofessional management approach, including recent advances in systemic therapy to improve patient outcomes.

Objectives:

Identify the clinical presentation of clear cell sarcoma of soft tissue, including its common occurrence in young adults and distal extremities.
Differentiate clear cell sarcoma of soft tissue from malignant melanoma and other soft tissue tumors using histological, immunohistochemical, and genetic features.
Screen for clear cell sarcoma of soft tissue in patients presenting with suspicious soft tissue masses, particularly in the extremities of young adults.
Apply interprofessional team strategies to improve care coordination and outcomes for patients affected by clear cell sarcoma of soft tissue.

Introduction

Clear cell sarcoma of soft tissue (CCSST) is an ultra-rare sarcoma originating from neural crest cells, first described by Enzinger in 1965.[1][2][3] The neoplasm primarily affects young adults, often presenting as slowly enlarging masses in the extremities, particularly around tendons or aponeuroses. The average patient is 34, though cases range in those aged from 2 to 90 years. Due to its benign appearance, CCSST is sometimes misdiagnosed early on, but it is highly aggressive, with a 5-year survival rate of around 50%.

CCSST frequently metastasizes to the lungs, lymph nodes, and bone, with other sites like the brain and abdominal organs also reported. Despite ongoing research, the prognosis remains poor, particularly for larger tumors and metastatic disease, with survival heavily dependent on early detection and tumor stage.

Etiology

The cause of clear cell sarcoma of soft tissues is unknown. CCSST is characterized by the gene translocation t(12;22)(q13;q12) resulting in EWSR1:ATF1 fusion gene or t(2;22)(q34;q12) resulting in EWSR1:CREB1 fusion gene.[4][5][6]

Epidemiology

Clear cell sarcoma is classified as an ultra-rare sarcoma, with an incidence of 1 or less per 1,000,000 individuals.[1] The incidence is highest in White individuals, and CCSST is estimated to affect men and women equally.[7][8][9][10] The average age of patients presenting with CCSST is 34; case series report an age range of 2 to 90 years.[11][12][13][14][15][16][17][18] CCCST typically arises in the upper or lower extremities, particularly around the foot and ankle, and is associated with tendons and aponeuroses.[19][10][7] Rare kidney, truncal, pancreas, gastrointestinal tract, head, and neck presentations have been described.[7][9][11][13][14][20] The 5- and 10-year overall survival rates for clear cell sarcoma are reported to be 47% to 67% and 25% to 51.3%, respectively, with later stages (III and IV) having worse survival rates.[9][10][16][21][10]

Pathophysiology

CCSST presents as a slowly enlarging mass adjacent to or infiltrating into tendons and aponeurosis.[15][21] CCSST contains either t(12;22)(q13;q12) or t(2;22)(q34;q12) gene translocation resulting in ESR1/ATF1 fusion gene or EWSR1/CREB1 fusion gene, respectively, in 70% to 90% of cases.[4][5][6][22] EWSR1/ATF1 induces expression of microphthalmia-associated transcription factor, which promotes tumor cell survival and proliferation and accounts for melanocyte differentiation in clear cell sarcoma of soft tissues.[23]

Histopathology

Histologically, clear cell sarcoma contains nests of polygonal or spindle-shaped cells separated by sclerotic bands. The cells are characterized by pale to slightly eosinophilic cytoplasm with a single nucleus with prominent nucleoli.[11][14] The "clear-cell" appearance represents intracellular glycogen accumulation, as demonstrated by the periodic acid-Schiff stain.[24] Pigmented and unpigmented melanosomes, scattered multinucleated giant cells, and areas of focal necrosis are also commonly present.[15][24][25][26] Mitotic figures are usually <10 per high power field.[12] Immunohistochemical staining demonstrates positivity for S-100, a marker for neural crest-derived cells, and melanocyte-specific markers HMB45 and melan-A in most clear cell sarcomas.[26][18][24] These neoplasms usually stain negative for cluster of differentiation 68, a melanoma marker, and epithelial markers smooth muscle actin, desmin, and keratin.[12][18][12][27]

History and Physical

The average age of patients presenting with CCSST is 34; however, case series report an age range of 2 to 90 years.[16][17][18] Patients present with slowly enlarging masses ranging from 1 to 20 cm, most commonly in the distal extremities, with or without associated pain.[7][21][15][21][15] Rare kidney, truncal, pancreas, gastrointestinal tract, head, and neck presentations have been described.[20] Given its benign presentation, CCSST may be assumed to be benign at the initial presentation.

Evaluation

CCSST is usually diagnosed through physical examination, imaging studies, and histological exams. The initial evaluation should include a comprehensive history and physical examination. Patients should be asked about when the mass was noticed and its growth pattern. Clinicians should also evaluate for signs and symptoms that may help in early staging. Physical examination should be focused on determining size, depth, fixation to adjacent tissues, edema, or possible neurovascular compromise. Regional lymph nodes should also be examined.

Radiographs of the area of concern may reveal a soft tissue shadow consistent with a mass or, in some cases, erosive changes in the adjacent bone, especially with larger tumors in the foot and ankle.[28][29] Magnetic resonance imaging (MRI) of CCSST reveals a mass that is often homogeneous and hypointense-to-isointense to muscle on T1-weighted images and heterogeneously high-signal on T2-weighted images.[28][29][28][30] As a result, tumors with significant quantities of melanin can have higher signal intensity on T1 images and lower intensity on T2 images.[29] CCSST typically heterogeneously enhances with contrast. MRI can also reveal areas of internal necrosis or bone invasion. These imaging findings are, however, nonspecific.[28]

Definitive diagnosis is made through tissue sampling, either by incisional biopsy, core needle biopsy, or fine needle aspiration. Histochemical analysis suggests a diagnosis of clear cell sarcoma, but cytogenetic analysis via fluorescence in situ hybridization or reverse transcription-polymerase chain reaction confirms the diagnosis with identification of either t(12;22)(q13;q12) or t(2;22)(q34:q12) gene translocation.[4][5][31][5]

Treatment / Management

For localized lesions, the treatment of choice is wide surgical resection with negative margins.[16][21][32][16][33] The quality of the surgical resection is an important predictor of prognosis in the setting of localized disease.[13] Intralesional excision has been associated with higher recurrence rates.[15][34] Radiotherapy may improve outcomes in patients with microscopically positive margins but not in gross residual disease.[13] Chemotherapy is primarily employed in patients with metastatic disease. However, response rates are generally poor, with few patients having partial responses to conventional chemotherapeutic regimens such as doxorubicin-based and gemcitabine-based therapies.[13][35] Targeted and immunotherapy are under investigation.[33] After surgical excision, patients should be followed closely due to the high recurrence rates and development of late metastases and local recurrence.[15][16][15][18]

Differential Diagnosis

The differential diagnosis of clear cell sarcoma includes tumors that stain positive for S100 and melanocyte markers, including malignant melanoma, nerve sheath tumors, and perivascular epithelioid cell tumors. Compared to melanoma, CCSST usually occurs in the younger patient population, is located in deeper tissues, is associated with aponeuroses or tendons, and commonly lacks epidermal involvement. [34] Additionally, the t(12;22) translocation in CCSST has not been observed in malignant melanoma.[27] While both melanoma and CCSST stain positive for S100, HMB-45, and melan-A, melanoma is also positive for cluster of differentiation 68, while CCSST is not.[24][27]

Malignant peripheral nerve sheath tumor usually arises within large peripheral nerves and is negative for HMB-45.[36] Perivascular epithelioid cell family of tumors, which present commonly in the abdomen, usually in young patients' ligamentum teres of the liver.[27] Given the typical location of clear cell sarcoma deep in the distal extremities, the differential diagnosis includes synovial sarcoma and epithelioid sarcoma. Synovial sarcoma commonly shows a t(X;18)(p11.2;q11.2) translocation producing SYT/SSX1 or SYT/sSSX2 gene fusions, not seen in CCSST.[36][34]

Surgical Oncology

Surgical resection with negative margins is recommended, especially in the setting of localized disease. When feasible, limb-sparing surgery is preferred for extremity sarcomas, but in the setting of local recurrence or larger tumors, amputation may be required.[33] Clear cell sarcoma tends to metastasize to regional lymph nodes, but the value of sentinel lymph node biopsy or regional lymph node dissection has no consensus.[17][21][37]

Radiation Oncology

The role of radiation in managing clear cell sarcoma of soft tissues is unclear. In general, CCSST is considered to be insensitive to radiation.[38] Several case series have demonstrated no survival benefit to radiation.[16][21] There may, however, be a role for radiation in the case of microscopically positive margins.[13][15]

Medical Oncology

Conventional cytotoxic chemotherapy regimens have not conferred any survival benefit in published case series.[15] A minority of patients show a partial response to doxorubicin-based or gemcitabine-based regimens.[35] Japan Tumor registry data, including 117 patients treated from 2016 to 2017, demonstrated no difference in survival in patients treated with cytotoxic chemotherapy, immunotherapy, targeted therapy, or a combination.[39] Trabectin, a marine-derived alkaloid, alone or in combination with ipilimumab and nivolumab, has resulted in a partial response in some patients.[40][41]

The unique translocation and resulting gene fusion, EWSR1-ATF1, characteristic of CCSST, offers a target for new therapies. Studies are ongoing to investigate the effectiveness of targeted therapies, including tyrosine kinase inhibitors, mesenchymal-epithelial transition (MET) inhibitors, and immunotherapies.[33] Results of trials investigating crizotinib, a MET tyrosine kinase inhibitor, and tivantinib, a selective MET inhibitor, showed only partial response in less than 9% of patients.[42][43] Another MET inhibitor, ganitumab (AMG 337), was ineffective in a trial of 8 patients with advanced or metastatic clear cell sarcoma (https://clinicaltrials.gov/study/NCT03132155). Partial responses have also been seen in patients receiving the kinase inhibitor sunitinib.[43]

Nivolumab, a monoclonal antibody that binds PD-1, was administered to 11 patients with unresectable clear cell sarcoma in the OSCAR Trial/NCCH1510, and none of the patients had complete or partial response. A period of progression-free survival of 4.1 months was observed, though.[44] Administration of pembrolizumab plus radiation has been reported to result in complete response in a patient with recurrent mediastinal clear cell sarcoma.[45] On the other hand, the AcSé Pembrolizumab study included 3 patients with clear cell sarcoma, all of whom experienced disease progression.[46]

Currently, the following trials, including patients with CCSST, are underway:

GFR806 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults (NCT03618381)
Testing Atezolizumab in People 2-17 Years Old With Clear Cell Sarcoma or Advanced Chondrosarcoma (NCT04458922)
Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas (NCT03600649)
B7H3 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults (NCT04483778)
B7-H3-Specific Chimeric Antigen Receptor Autologous T-Cell Therapy for Pediatric Patients With Solid Tumors (3CAR) (NCT04897321)

Staging

Clear cell sarcoma metastasizes most commonly to the lungs, lymph nodes, and bone. Metastatic disease has also been reported in the brain, abdominal organs, adrenal glands, skin, and heart.[8][9][11][16][11][21]

The European Society of Musculoskeletal Radiology Guidelines from 2024 recommend the following staging studies for CCSST:

Chest computed tomography (CT)
Brain MRI
CT Abdomen and pelvis for lower extremity sarcomas to evaluate regional lymph nodes
CT Neck for upper extremity sarcomas to evaluate regional lymph nodes
Whole-body MRI or positron emission tomography/CT to evaluate for skeletal metastases [47]

Prognosis

Overall, the prognosis for clear cell sarcoma of soft tissues is poor, with 5-year survival rates reported as 47% to 67%.[8][9] In the case series published, tumor size and stage consistently correlate with prognosis. At the time of diagnosis, 4% to 30% of patients already have metastatic disease.[7][21]

Data from the Japan Tumor Registry, including 117 patients, demonstrated that patients with American Joint Committee on Cancer stage I or II disease at diagnosis had a 5-year survival rate of 61%. If stage III or IV, however, the 2-year survival rate was 19%, and excision of metastatic lesions, radiation, and chemotherapy did not affect survival.[39] Likewise, a review from the National Cancer Database from 2004 to 2014, which included 489 patients with clear cell sarcoma, assigned a probability of survivorship at 5 years to be 75% for stage I and 15% for stage IV.[7] Late development of metastatic disease, up to 20 years after diagnosis, is not uncommon.[15] Tumors greater than 5 cm, and in some series greater than 2 cm, were associated with a worse prognosis.[15][18][21][18][39] Specifically, for tumors greater than 5 cm at diagnosis, the reported incidence of metastatic disease was 79% to 100%.[9][21]

Complications

While many patients present with indolently growing mass in the lower extremity, around 30% to 60% of patients may present pain or tenderness; a minority of patients may present with ulceration of the overlying skin.[36] The incidence of local recurrence for CCSST ranges from 15% to 37%.[9][14] Untreated CCSST progresses to a widespread, deadly metastatic disease.[12]

Deterrence and Patient Education

Patients should be educated about the overall poor prognosis of CCSST and individual risk factors for local or metastatic recurrence and be provided with tumor staging before and after treatment. They should also be encouraged to follow up closely with their clinicians, as late metastases and local recurrence are not uncommon.[21]

Enhancing Healthcare Team Outcomes

Providing patient-centered care for individuals with CCSST requires a collaborative effort among healthcare professionals, including advanced clinicians, nurses, pharmacists, and others. First and foremost, clinicians must possess the necessary clinical skills and expertise when diagnosing, evaluating, and treating this condition, including proficiency in interpreting radiological findings, recognizing potential complications, and understanding the nuances of managing CCSST. Referral to a tertiary care center with experience in sarcoma treatment and management is essential. Orthopedic and surgical oncology consultations are central to treating clear cell sarcoma, especially in localized diseases.

Cases of CCSST should be brought before an interprofessional tumor board. A strategic approach involving evidence-based guidelines and individualized care plans tailored to each patient's unique circumstances is vital. Ethical considerations come into play when determining treatment options and respecting patient autonomy in decision-making. Responsibilities within the interprofessional team should be clearly defined, with each member contributing their specialized knowledge and skills to optimize patient care. Effective interprofessional communication fosters a collaborative environment where information is shared, questions are encouraged, and concerns are addressed promptly.

Last, care coordination is pivotal in ensuring seamless and efficient patient care. Advanced clinicians, nurses, pharmacists, and other healthcare professionals must work together to streamline the patient's journey, from diagnosis through treatment and follow-up. This coordination minimizes errors, reduces delays, and enhances patient safety, ultimately leading to improved outcomes and patient-centered care that prioritizes the well-being and satisfaction of those affected by clear cell sarcoma of soft tissues.

Details

References

[1]

Stacchiotti S, Frezza AM, Blay JY, Baldini EH, Bonvalot S, Bovée JVMG, Callegaro D, Casali PG, Chiang RC, Demetri GD, Demicco EG, Desai J, Eriksson M, Gelderblom H, George S, Gounder MM, Gronchi A, Gupta A, Haas RL, Hayes-Jardon A, Hohenberger P, Jones KB, Jones RL, Kasper B, Kawai A, Kirsch DG, Kleinerman ES, Le Cesne A, Lim J, Chirlaque López MD, Maestro R, Marcos-Gragera R, Martin Broto J, Matsuda T, Mir O, Patel SR, Raut CP, Razak ARA, Reed DR, Rutkowski P, Sanfilippo RG, Sbaraglia M, Schaefer IM, Strauss DC, Sundby Hall K, Tap WD, Thomas DM, van der Graaf WTA, van Houdt WJ, Visser O, von Mehren M, Wagner AJ, Wilky BA, Won YJ, Fletcher CDM, Dei Tos AP, Trama A. Ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities. Cancer. 2021 Aug 15:127(16):2934-2942. doi: 10.1002/cncr.33618. Epub 2021 Apr 28 [PubMed PMID: 33910263]

Level 3 (low-level) evidence

[2]

Mii Y, Miyauchi Y, Hohnoki K, Maruyama H, Tsutsumi M, Dohmae K, Tamai S, Konishi Y, Yamanouchi T. Neural crest origin of clear cell sarcoma of tendons and aponeuroses. Ultrastructural and enzyme cytochemical study of human and nude mouse-transplanted tumours. Virchows Archiv. A, Pathological anatomy and histopathology. 1989:415(1):51-60 [PubMed PMID: 2499978]

[3]

Bridge JA, Sreekantaiah C, Neff JR, Sandberg AA. Cytogenetic findings in clear cell sarcoma of tendons and aponeuroses. Malignant melanoma of soft parts. Cancer genetics and cytogenetics. 1991 Mar:52(1):101-6 [PubMed PMID: 2009504]

[4]

Peulvé P, Michot C, Vannier JP, Tron P, Hemet J. Clear cell sarcoma with t(12;22) (q13-14;q12). Genes, chromosomes & cancer. 1991 Sep:3(5):400-2 [PubMed PMID: 1797088]

[5]

Zucman J, Delattre O, Desmaze C, Epstein AL, Stenman G, Speleman F, Fletchers CD, Aurias A, Thomas G. EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts. Nature genetics. 1993 Aug:4(4):341-5 [PubMed PMID: 8401579]

[6]

Reeves BR, Fletcher CD, Gusterson BA. Translocation t(12;22)(q13;q13) is a nonrandom rearrangement in clear cell sarcoma. Cancer genetics and cytogenetics. 1992 Dec:64(2):101-3 [PubMed PMID: 1486556]

[7]

Gonzaga MI, Grant L, Curtin C, Gootee J, Silberstein P, Voth E. The epidemiology and survivorship of clear cell sarcoma: a National Cancer Database (NCDB) review. Journal of cancer research and clinical oncology. 2018 Sep:144(9):1711-1716. doi: 10.1007/s00432-018-2693-6. Epub 2018 Jun 30 [PubMed PMID: 29961184]

[8]

Malchau SS, Hayden J, Hornicek F, Mankin HJ. Clear cell sarcoma of soft tissues. Journal of surgical oncology. 2007 May 1:95(6):519-22 [PubMed PMID: 17192915]

[9]

Lucas DR, Nascimento AG, Sim FH. Clear cell sarcoma of soft tissues. Mayo Clinic experience with 35 cases. The American journal of surgical pathology. 1992 Dec:16(12):1197-204 [PubMed PMID: 1463095]

Level 3 (low-level) evidence

[10]

Li AB, Jiang BJ, Wang HH, Yang YS, Zhang XB, Lan GH, Shu WB. Prognostic Factors for Survival in Patients with Clear Cell Sarcoma: An Analysis of the Surveillance, Epidemiology, and End Results (SEER) Database. Medical science monitor : international medical journal of experimental and clinical research. 2019 Sep 15:25():6950-6956. doi: 10.12659/MSM.916705. Epub 2019 Sep 15 [PubMed PMID: 31522190]

[11]

Kindblom LG, Lodding P, Angervall L. Clear-cell sarcoma of tendons and aponeuroses. An immunohistochemical and electron microscopic analysis indicating neural crest origin. Virchows Archiv. A, Pathological anatomy and histopathology. 1983:401(1):109-28 [PubMed PMID: 6412444]

[12]

Hocar O, Le Cesne A, Berissi S, Terrier P, Bonvalot S, Vanel D, Auperin A, Le Pechoux C, Bui B, Coindre JM, Robert C. Clear cell sarcoma (malignant melanoma) of soft parts: a clinicopathologic study of 52 cases. Dermatology research and practice. 2012:2012():984096. doi: 10.1155/2012/984096. Epub 2012 May 30 [PubMed PMID: 22693489]

Level 3 (low-level) evidence

[13]

Ferrari A, Casanova M, Bisogno G, Mattke A, Meazza C, Gandola L, Sotti G, Cecchetto G, Harms D, Koscielniak E, Treuner J, Carli M. Clear cell sarcoma of tendons and aponeuroses in pediatric patients: a report from the Italian and German Soft Tissue Sarcoma Cooperative Group. Cancer. 2002 Jun 15:94(12):3269-76 [PubMed PMID: 12115360]

[14]

Eckardt JJ, Pritchard DJ, Soule EH. Clear cell sarcoma. A clinicopathologic study of 27 cases. Cancer. 1983 Oct 15:52(8):1482-8 [PubMed PMID: 6616410]

Level 3 (low-level) evidence

[15]

Deenik W, Mooi WJ, Rutgers EJ, Peterse JL, Hart AA, Kroon BB. Clear cell sarcoma (malignant melanoma) of soft parts: A clinicopathologic study of 30 cases. Cancer. 1999 Sep 15:86(6):969-75 [PubMed PMID: 10491522]

Level 3 (low-level) evidence

[16]

Clark MA, Johnson MB, Thway K, Fisher C, Thomas JM, Hayes AJ. Clear cell sarcoma (melanoma of soft parts): The Royal Marsden Hospital experience. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2008 Jul:34(7):800-4 [PubMed PMID: 18042498]

[17]

Blazer DG 3rd, Lazar AJ, Xing Y, Askew RL, Feig BW, Pisters PW, Pollock RE, Lev D, Hunt KK, Cormier JN. Clinical outcomes of molecularly confirmed clear cell sarcoma from a single institution and in comparison with data from the Surveillance, Epidemiology, and End Results registry. Cancer. 2009 Jul 1:115(13):2971-9. doi: 10.1002/cncr.24322. Epub [PubMed PMID: 19402173]

Level 2 (mid-level) evidence

[18]

Bianchi G, Charoenlap C, Cocchi S, Rani N, Campagnoni S, Righi A, Frisoni T, Donati DM. Clear cell sarcoma of soft tissue: a retrospective review and analysis of 31 cases treated at Istituto Ortopedico Rizzoli. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2014 May:40(5):505-510. doi: 10.1016/j.ejso.2014.01.016. Epub 2014 Feb 2 [PubMed PMID: 24560887]

Level 2 (mid-level) evidence

[19]

Takemori T, Ogura K, Morizane C, Satake T, Iwata S, Toda Y, Muramatsu S, Kondo H, Kobayashi E, Higashi T, Kawai A. Clear cell sarcoma in Japan: an analysis of the population-based cancer registry in Japan. Japanese journal of clinical oncology. 2024 Aug 28:():. pii: hyae112. doi: 10.1093/jjco/hyae112. Epub 2024 Aug 28 [PubMed PMID: 39196756]

[20]

Liu YJ, Zou C, Wu YY. Metastatic clear cell sarcoma of the pancreas: A rare case report. World journal of clinical cases. 2024 Mar 16:12(8):1448-1453. doi: 10.12998/wjcc.v12.i8.1448. Epub [PubMed PMID: 38576799]

Level 3 (low-level) evidence

[21]

Kawai A, Hosono A, Nakayama R, Matsumine A, Matsumoto S, Ueda T, Tsuchiya H, Beppu Y, Morioka H, Yabe H, Japanese Musculoskeletal Oncology Group. Clear cell sarcoma of tendons and aponeuroses: a study of 75 patients. Cancer. 2007 Jan 1:109(1):109-16 [PubMed PMID: 17133413]

[22]

Zhang ZH, Guo JT, Xie Y, Sun SY. Essential role of postoperative follow-up in the management of clear cell sarcoma. World journal of clinical cases. 2024 Aug 16:12(23):5299-5303. doi: 10.12998/wjcc.v12.i23.5299. Epub [PubMed PMID: 39156081]

Level 3 (low-level) evidence

[23]

Davis IJ, Kim JJ, Ozsolak F, Widlund HR, Rozenblatt-Rosen O, Granter SR, Du J, Fletcher JA, Denny CT, Lessnick SL, Linehan WM, Kung AL, Fisher DE. Oncogenic MITF dysregulation in clear cell sarcoma: defining the MiT family of human cancers. Cancer cell. 2006 Jun:9(6):473-84 [PubMed PMID: 16766266]

[24]

Abdouh S, Boujguenna I, Soleh A, Abkari I, Rais H. Navigating diagnostic challenges-distinguishing malignant melanoma and clear cell sarcoma of soft tissues: a case report and review of the literature. Journal of medical case reports. 2024 May 17:18(1):249. doi: 10.1186/s13256-024-04542-y. Epub 2024 May 17 [PubMed PMID: 38755643]

Level 3 (low-level) evidence

[25]

Kazakos CJ, Galanis VG, Giatromanolaki A, Verettas DA, Sivridis E. Clear cell sarcoma of the scapula. A case report and review of the literature. World journal of surgical oncology. 2006 Aug 7:4():48 [PubMed PMID: 16893467]

Level 3 (low-level) evidence

[26]

Hisaoka M, Ishida T, Kuo TT, Matsuyama A, Imamura T, Nishida K, Kuroda H, Inayama Y, Oshiro H, Kobayashi H, Nakajima T, Fukuda T, Ae K, Hashimoto H. Clear cell sarcoma of soft tissue: a clinicopathologic, immunohistochemical, and molecular analysis of 33 cases. The American journal of surgical pathology. 2008 Mar:32(3):452-60. doi: 10.1097/PAS.0b013e31814b18fb. Epub [PubMed PMID: 18300804]

Level 3 (low-level) evidence

[27]

Rodríguez-Martín M, Sáez-Rodríguez M, Esquivel B, Gonzáalez RS, Cabrera AN, Herrera AM. Clear cell sarcoma: a case mimicking primary cutaneous malignant melanoma. Indian journal of dermatology. 2009:54(2):168-72. doi: 10.4103/0019-5154.53193. Epub [PubMed PMID: 20101313]

Level 3 (low-level) evidence

[28]

Sharma K, Yadav SK, Valluru B, Liu L. Significance of MRI in the diagnosis and differentiation of clear cell sarcoma of tendon and aponeurosis (CCSTA): A case report. Medicine. 2018 Aug:97(31):e11012. doi: 10.1097/MD.0000000000011012. Epub [PubMed PMID: 30075493]

Level 3 (low-level) evidence

[29]

De Beuckeleer LH, De Schepper AM, Vandevenne JE, Bloem JL, Davies AM, Oudkerk M, Hauben E, Van Marck E, Somville J, Vanel D, Steinbach LS, Guinebretière JM, Hogendoorn PC, Mooi WJ, Verstraete K, Zaloudek C, Jones H. MR imaging of clear cell sarcoma (malignant melanoma of the soft parts): a multicenter correlative MRI-pathology study of 21 cases and literature review. Skeletal radiology. 2000 Apr:29(4):187-95 [PubMed PMID: 10855466]

Level 3 (low-level) evidence

[30]

Hourani M, Khoury N, Mourany B, Shabb NS. MR appearance of clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft parts): radiologic-pathologic correlation. Skeletal radiology. 2005 Sep:34(9):543-6 [PubMed PMID: 16132975]

[31]

Langezaal SM, Graadt van Roggen JF, Cleton-Jansen AM, Baelde JJ, Hogendoorn PC. Malignant melanoma is genetically distinct from clear cell sarcoma of tendons and aponeurosis (malignant melanoma of soft parts). British journal of cancer. 2001 Feb:84(4):535-8 [PubMed PMID: 11207050]

[32]

Abdollahi A, Khatami F, Tavangar SM. Clear Cell Sarcoma: A Case Report and Review of Literature. International journal of hematology-oncology and stem cell research. 2018 Jan 1:12(1):65-68 [PubMed PMID: 29951180]

Level 3 (low-level) evidence

[33]

Cornillie J, van Cann T, Wozniak A, Hompes D, Schöffski P. Biology and management of clear cell sarcoma: state of the art and future perspectives. Expert review of anticancer therapy. 2016 Aug:16(8):839-45. doi: 10.1080/14737140.2016.1197122. Epub 2016 Jun 20 [PubMed PMID: 27253849]

Level 3 (low-level) evidence

[34]

Mavrogenis A, Bianchi G, Stavropoulos N, Papagelopoulos P, Ruggieri P. Clinicopathological features, diagnosis and treatment of clear cell sarcoma/melanoma of soft parts. Hippokratia. 2013 Oct:17(4):298-302 [PubMed PMID: 25031505]

[35]

Smrke A, Frezza AM, Giani C, Somaiah N, Brahmi M, Czarnecka AM, Rutkowski P, Van der Graaf W, Baldi GG, Connolly E, Duffaud F, Huang PH, Gelderblom H, Bhadri V, Grimison P, Mahar A, Stacchiotti S, Jones RL. Systemic treatment of advanced clear cell sarcoma: results from a retrospective international series from the World Sarcoma Network. ESMO open. 2022 Jun:7(3):100522. doi: 10.1016/j.esmoop.2022.100522. Epub 2022 Jun 17 [PubMed PMID: 35717681]

Level 2 (mid-level) evidence

[36]

Suehara Y, Yazawa Y, Hitachi K, Terakado A. Clear cell sarcoma arising from the chest wall: a case report. Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. 2004:9(2):171-4 [PubMed PMID: 15045547]

Level 3 (low-level) evidence

[37]

Liu QK, Yu XJ, Wang YG, Lu R, Wang SX, Xu HR, Kang H. Risk factors for lymph node metastasis of soft tissue sarcomas of the head, neck, and extremities, and the clinical significance of negative lymph node dissection. Journal of orthopaedic surgery and research. 2022 Mar 18:17(1):167. doi: 10.1186/s13018-022-03050-3. Epub 2022 Mar 18 [PubMed PMID: 35303897]

[38]

Ikuta K, Nishida Y, Imagama S, Tanaka K, Ozaki T. The current management of clear cell sarcoma. Japanese journal of clinical oncology. 2023 Oct 4:53(10):899-904. doi: 10.1093/jjco/hyad083. Epub [PubMed PMID: 37451697]

[39]

Fujiwara T, Kunisada T, Nakata E, Mitsuhashi T, Ozaki T, Kawai A. Factors associated with survival in patients with clear cell sarcoma. The bone & joint journal. 2023 Nov 1:105-B(11):1216-1225. doi: 10.1302/0301-620X.105B11.BJJ-2022-0743.R3. Epub 2023 Nov 1 [PubMed PMID: 37907082]

[40]

Galera M, Álvarez R, Arregui M, Paniagua M, Álvarez A, González Crisostomo RA, Díazgranados A, Gutiérrez N, Calles A, Agra C. A Clear Cell Sarcoma Case: A Diagnostic and Treatment Challenge, with a Promising Response to Trabectedin. Case reports in oncology. 2023 Jan-Dec:16(1):1542-1550. doi: 10.1159/000534935. Epub 2023 Dec 6 [PubMed PMID: 38074516]

Level 3 (low-level) evidence

[41]

Gordon EM, Chawla SP, Tellez WA, Younesi E, Thomas S, Chua-Alcala VS, Chomoyan H, Valencia C, Brigham DA, Moradkhani A, Quon D, Srikureja A, Wong SG, Tseng W, Federman N. SAINT: A Phase I/Expanded Phase II Study Using Safe Amounts of Ipilimumab, Nivolumab and Trabectedin as First-Line Treatment of Advanced Soft Tissue Sarcoma. Cancers. 2023 Jan 31:15(3):. doi: 10.3390/cancers15030906. Epub 2023 Jan 31 [PubMed PMID: 36765863]

[42]

Wagner AJ, Goldberg JM, Dubois SG, Choy E, Rosen L, Pappo A, Geller J, Judson I, Hogg D, Senzer N, Davis IJ, Chai F, Waghorne C, Schwartz B, Demetri GD. Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor-associated tumors: results of a multicenter phase 2 trial. Cancer. 2012 Dec 1:118(23):5894-902. doi: 10.1002/cncr.27582. Epub 2012 May 17 [PubMed PMID: 22605650]

[43]

Schöffski P, Wozniak A, Stacchiotti S, Rutkowski P, Blay JY, Lindner LH, Strauss SJ, Anthoney A, Duffaud F, Richter S, Grünwald V, Leahy MG, Reichardt P, Sufliarsky J, van der Graaf WT, Sciot R, Debiec-Rychter M, van Cann T, Marréaud S, Lia M, Raveloarivahy T, Collette L, Bauer S. Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 'CREATE'. Annals of oncology : official journal of the European Society for Medical Oncology. 2017 Dec 1:28(12):3000-3008. doi: 10.1093/annonc/mdx527. Epub [PubMed PMID: 28950372]

[44]

Nishikawa T, Kakunaga S, Tamura K, Ando M, Ozaki T, Kawai A, Ueda T, Kawasaki M, Tomatsuri S, Okamura N, Kamikura M, Hamada A, Yoshida A, Hirakawa A, Shibata T, Nakamura K, Yonemori K. Efficacy and safety of nivolumab monotherapy in patients with unresectable clear cell sarcoma and alveolar soft part sarcoma (OSCAR Trial/NCCH1510). Cancer. 2024 Nov 15:130(22):3836-3844. doi: 10.1002/cncr.35483. Epub 2024 Jul 30 [PubMed PMID: 39077795]

[45]

Marcrom S, De Los Santos JF, Conry RM. Complete response of mediastinal clear cell sarcoma to pembrolizumab with radiotherapy. Clinical sarcoma research. 2017:7():14. doi: 10.1186/s13569-017-0079-1. Epub 2017 Jul 14 [PubMed PMID: 28725344]

[46]

Blay JY, Chevret S, Le Cesne A, Brahmi M, Penel N, Cousin S, Bertucci F, Bompas E, Ryckewaert T, Soibinet P, Boudou-Rouquette P, Saada Bouzid E, Soulie P, Valentin T, Lotz JP, Tosi D, Neviere Z, Cancel M, Ray-Coquard I, Gambotti L, Legrand F, Lamrani-Ghaouti A, Simon C, Even C, Massard C. Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial. The Lancet. Oncology. 2023 Aug:24(8):892-902. doi: 10.1016/S1470-2045(23)00282-6. Epub 2023 Jul 7 [PubMed PMID: 37429302]

Level 1 (high-level) evidence

[47]

Noebauer-Huhmann IM, Vanhoenacker FM, Vilanova JC, Tagliafico AS, Weber MA, Lalam RK, Grieser T, Nikodinovska VV, de Rooy JWJ, Papakonstantinou O, Mccarthy C, Sconfienza LM, Verstraete K, Martel-Villagrán J, Szomolanyi P, Lecouvet FE, Afonso D, Albtoush OM, Aringhieri G, Arkun R, Aström G, Bazzocchi A, Botchu R, Breitenseher M, Chaudhary S, Dalili D, Davies M, de Jonge MC, Mete BD, Fritz J, Gielen JLMA, Hide G, Isaac A, Ivanoski S, Mansour RM, Muntaner-Gimbernat L, Navas A, O Donnell P, Örgüç Ş, Rennie WJ, Resano S, Robinson P, Sanal HT, Ter Horst SAJ, van Langevelde K, Wörtler K, Koelz M, Panotopoulos J, Windhager R, Bloem JL. Soft tissue tumor imaging in adults: whole-body staging in sarcoma, non-malignant entities requiring special algorithms, pitfalls and special imaging aspects. Guidelines 2024 from the European Society of Musculoskeletal Radiology (ESSR). European radiology. 2024 Jul 20:():. doi: 10.1007/s00330-024-10897-z. Epub 2024 Jul 20 [PubMed PMID: 39030374]