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Soft Tissue Clear Cell Sarcoma
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%.
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.
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
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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](B2)
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.
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