Epithelioid Sarcoma: Symptoms, Types, Causes and Treatment

Epithelioid sarcoma is a rare and aggressive type of soft tissue cancer that can present significant challenges in diagnosis and treatment. Unlike more common cancers, it often affects younger adults and has a high risk of recurrence and metastasis. Understanding its symptoms, the types that exist, what causes the disease, and how it is treated is crucial for patients, families, and clinicians alike. This detailed article will guide you through the latest knowledge on epithelioid sarcoma, synthesizing evidence from recent clinical research.

Symptoms of Epithelioid Sarcoma

Epithelioid sarcoma often sneaks up quietly, with subtle symptoms that can easily be mistaken for less serious conditions. This makes early diagnosis difficult. Many patients first notice a painless lump, usually in the skin or soft tissues of their hands, forearms, feet, or other extremities. Over time, the tumor may grow, become tender, or cause functional problems. Because the symptoms are so subtle, the disease is often advanced by the time it’s diagnosed.

Symptom	Description	Frequency/Occurrence	Source(s)
Mass/Lump	Painless, firm, slow-growing	Most common, initial sign	1 2 4 5
Tenderness	Mild discomfort or pain	Occasional, progressive	2
Functional Impairment	Difficulty moving fingers/limbs	When tumor involves tendons or nerves	2
Skin Changes	Usually absent	Rare	2
Recurrence	Return after removal	High recurrence rate	2 4 6

Table 1: Key Symptoms

Common Presentations

The classic presentation is a painless, firm mass beneath the skin, usually in the distal extremities such as fingers, hands, or feet. In some cases, particularly in teenagers and young adults, the lump may make it difficult to extend or flex fingers or toes, especially if the tumor is near tendons or nerves 2 4 5. The lump often feels hard and may be fixed to underlying tissues.

Progression of Symptoms

• Early Stage: Typically, there are no significant skin changes. The lump may be noticed incidentally or cause mild tenderness.
• Advanced Stage: As the tumor grows, it can invade deeper tissues, causing pain, swelling, or deformity. Involvement of nerves or blood vessels may lead to numbness, tingling, or loss of function 2.
• Recurrence: One of the hallmark features of epithelioid sarcoma is its tendency to recur locally after surgical removal. Recurrent tumors may be more aggressive 2 4 6.

Metastatic Symptoms

If the cancer spreads, symptoms can vary depending on the location:

• Lymph Nodes: Swelling in the regional lymph nodes is common 4 6.
• Lungs: Shortness of breath, cough, or chest pain if lung metastases develop 4.
• Other Organs: Less commonly, the disease may metastasize to bone, scalp, or other organs 4 6.

Types of Epithelioid Sarcoma

Epithelioid sarcoma is not a single disease but exists in two major forms, each with distinct features and outcomes. Knowing the type is crucial, as it affects prognosis and treatment strategies.

Type	Usual Location	Cell Features	Prognosis	Source(s)
Classic (Distal)	Hands, forearms, feet	Nodular, uniform cells	Better	4 5 6
Proximal	Trunk, pelvis, thighs	Larger, atypical, rhabdoid cells	Worse	1 3 4 5 6

Table 2: Types of Epithelioid Sarcoma

Classic (Distal-Type) Epithelioid Sarcoma

• Location: Most commonly occurs in the distal parts of limbs—hands, forearms, and feet—often in young adults, especially males 4 5.
• Appearance: Tumors are usually composed of nodules of relatively uniform epithelioid cells, sometimes with central necrosis. The cells tend to be less atypical, and there may be a granuloma-like pattern 4 5.
• Behavior: This type is indolent but still carries a significant risk of recurrence and metastasis, particularly to regional lymph nodes and lungs 4 6.

Proximal-Type Epithelioid Sarcoma

• Location: Arises in proximal limbs (shoulders, thighs), pelvis, perineum, trunk, and even the vulva. Patients tend to be slightly older, but the age range is broad 1 3 5 6.
• Appearance: The tumors feature larger, more atypical, and sometimes rhabdoid (eccentric nuclei, prominent nucleoli) cells, often in sheets rather than nodules. The classic granuloma-like pattern is absent in most cases 1 3 5.
• Behavior: More aggressive, with higher rates of local recurrence, early metastasis (especially to lymph nodes), and poorer overall survival 1 3 6.

Grading and Prognosis

• Classic-Type Grading: Classic-type can be further split into high-grade and low-grade forms, based on the number of mitoses, amount of necrosis, and nuclear atypia. High-grade classic-type tumors behave more like the proximal type, with worse outcomes 6.
• Prognosis: Proximal-type and high-grade classic-type have the worst outcomes, with 5- and 10-year survival rates significantly lower than low-grade classic-type 6.

Causes of Epithelioid Sarcoma

The underlying causes of epithelioid sarcoma are still being unraveled. Unlike many cancers, there are no known environmental or lifestyle risk factors. Instead, research points to a unique genetic event as the major driver.

Cause	Details	Relevance	Source(s)
SMARCB1 Loss	Inactivation or deletion of SMARCB1/INI1 gene	Defining feature	5 7 8 9 10
Chromosomal Abnormalities	Some cases show 22q region changes	Occasional	4
Other Molecular Defects	Disruption of SWI/SNF chromatin remodeling	Under study	8 9
No Environmental Risk	No known exposures linked	N/A	4 5 8

Table 3: Causes and Molecular Features

SMARCB1/INI1 Gene Inactivation

• Key Event: Nearly all epithelioid sarcomas show loss of the SMARCB1 (also called INI1) gene—a critical component of the SWI/SNF chromatin remodeling complex 5 7 8 9 10.
• Role: SMARCB1 acts as a tumor suppressor. Its loss leads to uncontrolled cell growth, altered gene expression, and cellular features typical of epithelioid sarcoma 7 9.
• Detection: Loss of SMARCB1/INI1 is often confirmed by immunohistochemistry and genetic testing 5 7 10.

Other Molecular Pathways

• Chromatin Remodeling: Disruption of other SWI/SNF complex components may play a role, but SMARCB1 loss is the defining molecular signature 9.
• Signaling Pathways: Research has identified additional changes, such as activation of the ERBB1/EGFR and MET pathways, which may contribute to tumor growth and could serve as targets for future therapies 7 9.

Chromosomal Abnormalities

• A minority of cases show chromosomal changes in the 22q region, but no single genetic alteration besides SMARCB1 loss is consistently found 4.

Lack of Environmental or Lifestyle Risk Factors

• Unlike many cancers, there are no known associations with chemical exposures, viral infections, or inherited syndromes 4 5 8.

Treatment of Epithelioid Sarcoma

Treating epithelioid sarcoma is complex and depends on the tumor’s size, location, type, and extent of spread. Localized disease is approached differently from advanced or metastatic disease. New targeted therapies are offering hope, but challenges remain.

Treatment	Approach/Details	Suitability/Outcome	Source(s)
Surgery	Wide resection with clear margins	Mainstay for local disease; lowers recurrence	2 4 5 6 8 13
Radiotherapy	Often adjuvant or neoadjuvant	Reduces local recurrence; preserves function	8 13
Chemotherapy	Doxorubicin-based, ifosfamide, others	Used in advanced/metastatic cases; modest benefit	8 10 12
Targeted Therapy	Tazemetostat (EZH2 inhibitor)	For SMARCB1-loss tumors; FDA-approved; promising results	8 10 14
Lymph Node Management	Sentinel node biopsy, dissection	Consider due to high nodal metastasis risk	8

Table 4: Treatment Strategies

Surgery: The Mainstay

• Wide Local Excision: The primary treatment for localized epithelioid sarcoma is surgical removal with wide margins to reduce the risk of recurrence 2 4 5 6 8.
• Marginal vs. Radical Resection: Marginal excision carries a high risk of recurrence; more extensive surgery (radical resection) is often preferred, especially internationally 2.
• Amputation: Reserved for recurrent or extensive disease where limb preservation is not feasible 2 13.
• Recurrence Management: Recurrent tumors may require further surgery, sometimes including amputation 2 4.

Radiotherapy

• Role: Often used before (neoadjuvant) or after (adjuvant) surgery to lower the risk of local recurrence, particularly when margins are close or positive 8 13.
• Outcome: Combined surgery and radiotherapy can achieve good local control and limb preservation 13.

Chemotherapy

• Agents: Doxorubicin-based regimens are standard for advanced cases; other agents include ifosfamide, pazopanib, trabectedin 8 10 12.
• Efficacy: Response rates are modest, with median progression-free survival under 6 months and overall survival around 11 months for metastatic disease 10 12.
• Metastatic Disease: Chemotherapy is the main option, but most patients eventually progress 10 12.

Targeted Therapies

• Tazemetostat: An oral EZH2 inhibitor, tazemetostat, is FDA-approved for advanced or metastatic epithelioid sarcoma with SMARCB1 loss 10 14.
  • Benefits: In a phase II trial, 15% of patients had an objective response, and responses were durable (over 6 months in two-thirds of cases) 10 14.
  • Tolerability: Well-tolerated with manageable side effects 10.
  • Future: Ongoing trials are testing it with other agents such as doxorubicin 10.

Lymph Node Management

• Sentinel Lymph Node Biopsy: Considered in patients due to high risk of nodal metastasis 8.
• Lymphadenectomy: May be necessary if nodes are involved 8.

Experimental and Future Treatments

• Immunotherapy: Still under investigation; not yet standard of care 8.
• Other Targets: Research into EGFR, MET, and other pathways could lead to additional therapies 7 9.

Prognosis and Follow-Up

• Recurrence: High risk, especially in proximal-type and high-grade tumors 4 6.
• Metastasis: Common sites include lymph nodes and lungs 4 6 8.
• Survival: 5- and 10-year overall survival rates range from 37% to 77%, depending on type and grade 6.
• Long-Term Care: Lifelong follow-up is recommended due to late recurrences and metastases 6.

Conclusion

Epithelioid sarcoma is a rare, aggressive cancer that requires vigilance, prompt diagnosis, and multidisciplinary care. While classic and proximal types differ in location, cellular features, and prognosis, both are united by the hallmark loss of SMARCB1/INI1. Surgery remains the cornerstone of treatment for localized disease, with radiotherapy and newer targeted agents like tazemetostat offering valuable options, especially in advanced cases. Ongoing research into the molecular underpinnings of this disease is paving the way for better, more personalized therapies.

Key Points:

• Epithelioid sarcoma typically presents as a painless lump in a limb, often without alarming symptoms.
• Two main types exist: classic (distal) and proximal, with the proximal type being more aggressive.
• The disease is defined by the loss of the SMARCB1/INI1 tumor suppressor gene.
• Treatment relies on surgery with wide margins, often supplemented by radiotherapy.
• Advanced or metastatic disease has a poor prognosis, but targeted therapies like tazemetostat are showing promise.
• Lifelong follow-up is essential due to the risk of recurrence and metastasis.
• There are no known lifestyle or environmental risk factors, making awareness and early detection vital.

Epithelioid sarcoma remains a challenging malignancy, but advances in molecular diagnostics and targeted treatment offer new hope for patients facing this rare disease.