[1] It commonly presents itself in the distal limbs (fingers, hands, forearms, or feet) of young adults as a small, soft mass or a cluster of bumps.

Histologically, epithelioid sarcoma forms nodules with central necrosis surrounded by bland, polygonal cells with eosinophilic cytoplasm and peripheral spindling.

The disease has a tendency to develop local recurrences and metastasis thereafter to regional lymph nodes, lung, bone, brain, and other locations.

[3] Generally speaking, epithelioid sarcoma has a high rate of relapse after initial treatment and tends to recur locally or regionally (at or near the original tumor site).

It most commonly presents itself in the distal limbs (fingers, hands, forearms, or feet) as a small, soft mass or a cluster of nodules.

Loss of SMARCB1 function is the most common genetic mutation observed in epithelioid sarcoma, and this dysfunction is likely a major driver of disease progression.

Since this tumor suppressor is commonly inactivated in epithelioid sarcoma, cell division can fail to appropriately stop, resulting in uncontrolled cancer growth.

[17] MET (mesenchymal to epithelial transition) is a biological pathway that appears to be important for the development and progression of epithelioid sarcoma.

[19] Reactivation of AKT has been shown to be MET-dependent,[19] resulting in the rationale that blocking both mTOR and MET concurrently should be a useful approach to treat epithelioid sarcoma.

Upon ligand binding, EGFR phosphorylation triggers the activation of downstream signaling pathways involved in critical cellular functions such as proliferation, survival, and angiogenesis.

[24] In-vitro and in-vivo laboratory experiments have demonstrated that the blockade of EGFR in epithelioid sarcoma results in decreased cell proliferation, increased apoptosis, and abrogated invasion and migration capacities.

[22] While the blockade of EGFR with a medication has shown limited results in the clinical setting, when used as part of a combination with another drugs, such as an mTOR inhibitor, synergy has been observed, and superior tumor growth inhibition has been demonstrated.

[14] Cyclin D and CDKs promote cell cycle progression by releasing transcription factors that are important for the initiation of DNA replication.

A common characteristic of epithelioid sarcoma (observed in 80% of all cases) is the loss of function of the SMARCB1 gene (whose protein product is termed BAF47, INI1, or hSNF5).

The staging for epithelioid sarcoma takes into account size and location of the primary tumor, lymph node involvement, presence and location of metastasis, and histologic grade (a measure of disease aggressiveness)[26] Surgery, radiation, and systemic therapy such as chemotherapy are all used at various times in the treatment of patients who have epitheloid sarcoma.

[32] The benefit for standard medications such as doxorubicin, ifosfamide, and combinations involving gemcitabine is generally measured in months, not years.

As with standard chemotherapy, the effectiveness of tazemetostat is generally measured in months, though some patients will fare better for a longer period of time.

[citation needed] Epithelioid sarcoma (especially advanced stage, recurrent, or metastasized disease) has been shown to become resistant to traditional cancer therapies, necessitating further exploration of novel treatment methods and techniques.

New chemotherapies are being explored in current clinical trials for epithelioid sarcoma, although, thus far, none has shown significant improvement over the efficacy of doxorubicin and/or ifosfamide.

[41] Multiple techniques and treatment strategies are currently being studied in many cancers in an effort to improve the usefulness of vaccine therapy.

[40][42] In one case, a patient with advanced epithelioid sarcoma who had failed multiple therapies showed a strong response to expanded lymphocytes and natural killer cells.

Several anti-angiogenic agents are being explored in epithelioid sarcoma,[citation needed] a cancer that likely relies on angiogenesis for survival and progression.

Given the multiple genetic abnormalities and disrupted biological pathways observed in epithelioid sarcoma, drugs targeting unique tumor characteristics are being examine for more effective treatments.

Tyrosine kinase inhibitors (such as sunitinib, pazopanib, and dasatinib) have shown some effect against several cancer types, one example among sarcomas being Imatinib in gastrointestinal stromal tumors (GISTs).

Tyrosine kinases can contain mutations that cause them to become constitutively active,[49] or stuck in the “on” position, resulting in unregulated cell division (a hallmark of cancer).

Tyrosine kinase inhibitors have been shown to inhibit the VEGF, EGFR, and MET,[48] pathways that are frequently over-expressed in epithelioid sarcoma.

[22] Selective inhibitors of nuclear export (SINE) compounds, such as selinexor and CBS9106, are being investigated in several sarcomas and have shown promising results in both hematological malignancies and solid tumors.

[17][54] It has been noted that the therapeutic potential of oncolytic virotherapy is not a simple consequence of the cytopathic effect but strongly relies on the activation of the body's own immune response against infected cells.

OBP-301 is not approved for use in cancer patients, but it has been studied in epithelioid sarcoma and shown to promote apoptosis and cell death in the laboratory.

While CGTG-102 has shown efficacy as a single agent against several soft tissue sarcomas in the laboratory, as of 2023, clinical research on it appears to have come to a halt.