Clear Cell Sarcoma: Symptoms, Types, Causes and Treatment

Clear cell sarcoma is an uncommon and aggressive cancer that can be challenging to diagnose and treat. Despite its rarity, understanding its symptoms, forms, underlying causes, and treatment options is crucial for patients, families, and clinicians. This article provides a comprehensive, evidence-based overview of clear cell sarcoma, synthesizing research from peer-reviewed sources to ensure up-to-date and reliable information.

Symptoms of Clear Cell Sarcoma

Clear cell sarcoma often presents subtly, with symptoms that overlap with other, more common conditions. Recognizing these early signs is vital, as early detection can improve treatment outcomes.

Symptom	Description	Patient Group	Source(s)
Mass	Painless, slow-growing lump	Adults, Children	1, 3, 5, 9
Pain	Discomfort or pain near tumor site	Adults, Children	1, 3, 5, 9
Hematuria	Blood in urine (renal sarcoma only)	Children (CCSK)	1
Neurological	Symptoms if brain metastasis occurs	Relapsed patients	8

Table 1: Key Symptoms

Recognizing the Signs

Clear cell sarcoma can be insidious in its onset. The most common presentation is a painless, slow-growing mass, typically on the tendons or aponeuroses of the arms or legs in young adults or older children 3, 5, 9. In children, particularly with clear cell sarcoma of the kidney (CCSK), symptoms may mimic other kidney tumors—such as Wilms tumor—making diagnosis even more difficult 1.

Pain may develop as the tumor grows or invades nearby tissues 1, 5. Hematuria (blood in the urine) is specifically observed in cases involving the kidney (CCSK) 1. In advanced or relapsed cases, clear cell sarcoma may spread to the brain, lungs, or bones—leading to neurological symptoms, respiratory issues, or bone pain 8.

Key Symptom Patterns

• Soft Tissue Sarcoma: Most commonly manifests as a lump or swelling, often painless at first.
• Renal Sarcoma (CCSK): May present with abdominal mass, pain, or hematuria in children.
• Metastatic Disease: Symptoms depend on the spread, such as headaches or seizures with brain metastases 8.

When to Seek Medical Advice

Because the initial symptoms can be mistaken for benign conditions, persistent or unusual lumps, especially in the extremities or abdomen, should always be evaluated by a healthcare professional—particularly if they increase in size or are accompanied by pain.

Types of Clear Cell Sarcoma

There is more than one form of clear cell sarcoma, each with unique clinical and pathological characteristics. Understanding these distinctions is important for diagnosis and treatment planning.

Type	Location	Age Group	Source(s)
Soft Tissue CCS	Tendons, aponeuroses	Young adults	3, 5, 9, 11
Clear Cell Sarcoma of Kidney	Kidney	Children	1, 2, 8
GI Tract Variant	Gastrointestinal tract	Rare, all ages	3

Table 2: Main Types of Clear Cell Sarcoma

Major Forms and Distinctions

Clear Cell Sarcoma of Soft Tissue

The classic form occurs in the soft tissues, especially tendons and aponeuroses of the limbs. This type mainly affects adolescents and young adults, with a slight female predominance 3, 5, 9. It is characterized by slow growth but has a high propensity for metastasis.

Clear Cell Sarcoma of the Kidney (CCSK)

A distinct entity, CCSK is a rare but aggressive kidney tumor found almost exclusively in children. Its symptoms and clinical course are often similar to Wilms tumor, but with unique genetic and histologic features 1, 2, 8. CCSK is notorious for its tendency to relapse and metastasize, especially to the brain, lungs, and bones.

Gastrointestinal Variant

An extremely rare form mimics characteristics of soft tissue CCS but arises in the gastrointestinal tract. While there are only a handful of reported cases, it underscores the heterogeneity of clear cell sarcoma as a disease family 3.

Histological and Genetic Differences

• Soft tissue CCS is usually positive for melanocytic markers and can contain melanin pigment, sometimes complicating diagnosis due to similarity with melanoma 4, 5.
• CCSK is defined by specific gene alterations, such as BCOR gene abnormalities or YWHAE–NUTM2 fusion 2.

Diagnostic Challenges

Distinguishing between these types is critical, as treatment and prognosis differ. Diagnosis relies on a combination of imaging, histopathology, immunohistochemistry, and increasingly, molecular genetic testing 1, 2, 3.

Causes of Clear Cell Sarcoma

The underlying causes of clear cell sarcoma are rooted in genetic changes rather than environmental or lifestyle factors. Recent research has shed light on the genes and molecular pathways involved.

Cause	Genetic Mechanism	Frequency	Source(s)
EWSR1/ATF1 Fusion	t(12;22) translocation	Most soft tissue CCS	6, 7, 10
MET Overexpression	Downstream of EWSR1 rearrangement	Most soft tissue CCS	7, 10
BCOR Alterations	ITDs or gene fusion (CCSK)	Most pediatric CCSK	2
YWHAE–NUTM2 Fusion	Alternative fusion in CCSK	Minority of CCSK cases	2

Table 3: Genetic Causes of Clear Cell Sarcoma

Genetic Drivers

Clear cell sarcoma is primarily driven by specific chromosomal translocations or genetic mutations:

EWSR1/ATF1 Fusion (Soft Tissue CCS)

• The hallmark genetic event in soft tissue CCS is a translocation between chromosomes 12 and 22, producing the EWSR1/ATF1 fusion gene 6, 7, 10.
• This fusion alters gene expression and is believed to originate in Tppp3-expressing cells of peripheral nerves, explaining the tumor’s predilection for tendons and aponeuroses 6.

MET Overexpression

• The EWSR1 rearrangement leads to overexpression of the MET proto-oncogene—a key driver of tumor cell proliferation and survival 7, 10.
• This pathway is a target for new therapies, such as MET inhibitors.

BCOR and YWHAE–NUTM2 Gene Fusions (CCSK)

• In clear cell sarcoma of the kidney, most cases involve internal tandem duplications (ITDs) of the BCOR gene, while a minority harbor a YWHAE–NUTM2 gene fusion 2.
• These genetic alterations are distinct from the EWSR1/ATF1 fusion found in soft tissue CCS, highlighting the separate developmental pathways for these sarcomas.

Not Linked to Lifestyle or Environment

There is no evidence linking clear cell sarcoma to environmental exposures, lifestyle choices, or inherited risk factors. Rather, the disease arises from spontaneous, somatic genetic events.

Treatment of Clear Cell Sarcoma

Treating clear cell sarcoma is challenging due to its aggressive nature and resistance to conventional therapies. Management strategies differ based on tumor location, stage, and genetic makeup.

Treatment	Purpose/Indication	Effectiveness/Notes	Source(s)
Surgical Excision	Remove primary tumor	Mainstay; wide excision best	9, 11
Radiotherapy	Local control, margins <1mm	Adjuvant; may improve outcomes	11
Chemotherapy	Metastatic/relapsed disease, CCSK	Limited, more used in CCSK	8
High-dose Chemo + ABMT	Relapsed CCSK	Some benefit, high toxicity	8
Targeted Therapy	MET+ disease (crizotinib)	Variable, ongoing research	7, 10

Table 4: Treatment Options for Clear Cell Sarcoma

Standard Approaches

Surgery

• Wide local excision is the cornerstone of treatment for clear cell sarcoma of soft tissue. Radical excision or, rarely, amputation may be required for optimal local control, especially for larger tumors 9, 11.
• In kidney sarcomas (CCSK), radical nephrectomy is standard 1.

Radiotherapy

• Adjuvant radiotherapy is recommended, particularly if surgical margins are close (<1 mm), to reduce the risk of local recurrence 11.

Chemotherapy

• The role of chemotherapy in soft tissue CCS is limited, as these tumors tend to be resistant.
• In CCSK, chemotherapy is more commonly used, especially for metastatic or relapsed disease 8. Combination chemotherapy protocols are applied, often similar to those used for Wilms tumor.

High-dose Chemotherapy and Autologous Bone Marrow Transplant (ABMT)

• For relapsed CCSK, high-dose chemotherapy followed by ABMT has shown some benefit in achieving remission, though long-term survival remains low 8.

Targeted Therapy

• MET inhibitors (e.g., crizotinib) are under investigation for MET-positive clear cell sarcoma. While some patients achieve stable disease, response rates are modest, and this approach is not yet standard of care 7, 10.
• The need for novel targeted therapies is urgent, especially for relapsed or metastatic disease, where prognosis is poor 8.

Prognosis and Outcomes

• Overall, clear cell sarcoma carries a guarded prognosis due to its high risk of local recurrence and distant metastasis—even years after initial treatment 9, 11.
• In CCSK, the five-year event-free survival after relapse is only 18%, underscoring the need for better therapies 8.

Conclusion

Clear cell sarcoma remains one of the most challenging soft tissue and pediatric kidney cancers to diagnose and treat. Early recognition, accurate classification, and advances in genetic understanding are vital for improving patient outcomes. Key points include:

• Symptoms are often non-specific, most commonly presenting as a painless mass, pain, or—rarely—hematuria.
• Types include soft tissue CCS, CCSK, and rare gastrointestinal variants, each with unique clinical and genetic features.
• Causes are rooted in specific genetic alterations (EWSR1/ATF1 fusion, BCOR and YWHAE–NUTM2 fusions), not lifestyle or environmental factors.
• Treatment relies on surgery with wide margins, adjuvant radiotherapy, and, for CCSK, chemotherapy and ABMT—though new targeted therapies are under investigation.

In summary:

• Early detection and expert diagnosis are crucial.
• Treatments are evolving, but prognosis remains guarded, especially for relapsed cases.
• Ongoing research into genetics and targeted therapies offers hope for more effective, less toxic treatments in the future.

If you or a loved one is affected by clear cell sarcoma, consultation with a multidisciplinary sarcoma team and access to clinical trials are strongly recommended.