Epithelioid sarcoma is a rare soft tissue sarcoma arising from mesenchymal tissue and characterized by epithelioid-like features. It accounts for less than 1% of all soft tissue sarcomas. It was first definitively characterized by F.M. Enzinger in 1970. 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. A proximal version has also been described, frequently occurring in the upper extremities. Less commonly, cases are reported in the pelvis, vulva, penis, and spine.
Histologically, epithelioid sarcoma forms nodules with central necrosis surrounded by bland, polygonal cells with eosinophilic cytoplasm and peripheral spindling. Epithelioid sarcomas typically express vimentin, cytokeratins, epithelial membrane antigen, and CD34, whereas they are usually negative for S100, desmin, and FLI1 (FLI-1). They characteristically lack the protein INI1 (see below). Epithelioid sarcomas typically stain positive for CA125.
Epithelioid sarcoma most commonly strikes young adults, yet no age group is immune. The disease has a tendency to develop local recurrences and metastasis thereafter to regional lymph nodes, lung, bone, brain, and other locations. 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). Epithelioid sarcoma also demonstrates lymphatic spread (in 22-48% of cases), and metastasis (in 21-63% of cases). These events, as well as advanced stage (progression) and grade (aggressiveness), are predictive of an overall worse outcome. Associated with a more positive outcome are younger age, female vs. male sex, distal vs. proximal location, smaller tumor size, and negative margins upon tumor resection.
Signs and symptoms Epithelioid sarcoma is a slow-growing and relatively painless tumor, often resulting in a lengthy period of time between presentation and diagnosis. Due to the difficulty of discerning this cancer as different from more common cancers, such as cancers of the skin (squamous cell carcinoma or basal cell carcinoma), it is often misdiagnosed, mistaken as a persistent wart or cyst. It most commonly presents itself in the distal limbs (fingers, hands, forearms, or feet) as a small, soft mass or a cluster of nodules. It is most often described as a firm-to-hard palpable mass, either in the deep soft tissue or in the dermis. These cancers can form a crater or ulcer, leading to a mistaken diagnosis of a poorly healing traumatic wound or wart. About 13% of patients present with multifocal tumors, and about 13% of patients present with metastatic disease.
Genetics The most common genetic mutation (found in 80-90% of epithelioid sarcomas) is the inactivation of the SMARCB1 gene, or the loss of protein INI1 function,. Epithelioid sarcoma typically contains chromosome 22q11.2 mutations or deletions and 8q gains. Aberrations of 18q as well as recurrent gains at 11q13, have also been observed.
The SMARCB1 gene (whose protein product is termed BAF47, INI1, or hSNF5) is located on chromosome 22q11.2. It codes for a member of the SWI/SNF chromatin remodeling complex. 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. SMARCB1 is a core protein subunit of the 15 subunit SWI/SNF (or BAF) complex involved in regulating the packaging of DNA in the cell nucleus. It has been shown to be a potent tumor suppressor gene, meaning that its primary role is to control cell division. Since this tumor suppressor is commonly inactivated in epithelioid sarcoma, cell division can fail to appropriately stop, resulting in uncontrolled cancer growth. Research teams are trying to develop ways to reverse this loss of genetic function characteristic of epithelioid sarcoma.
Molecular biology A number of important proteins appear to be active in epithelioid sarcoma. Some of these are described below.
VEGF VEGF (vascular endothelial growth factor) is often over-expressed in epithelioid sarcoma. This is a critical pathway in angiogenesis, a process that cancer cells use to form new blood vessels, which provide necessary elements to the tumor for tumor survival. Anti-VEGF agents such as pazopanib are approved for use in carcinomas and in soft tissue sarcomas such as epithelioid sarcoma, though access to these medications varies from country to country.
MET MET (mesenchymal to epithelial transition) is a biological pathway that appears to be important for the development and progression of epithelioid sarcoma. MET is a tyrosine kinase oncogene, and its signaling pathway has been implicated in a variety of malignancies, including many cancers.
Sonic hedgehog and Notch The Sonic hedgehog (SHH) and Notch signaling pathways appear to be active in epithelioid sarcoma. These cell signaling pathways control cellular proliferation and differentiation. They are also involved in cancer stem cell coordination and disease invasiveness and metastasis. Hhat inhibitors (such as RU-SKI 43) block the SHH pathway by inhibiting hedgehog palmitoyl acytl-transferase. Trials have investigated Notch inhibitors in sarcomas such as epithelioid sarcoma.
mTOR The frequent overactivation of mTOR (mammalian target of rapamycin) signaling has also been observed in epithelioid sarcoma. The mTOR pathway has been described as a "master switch" for cellular catabolism and anabolism, and it can enhance cell cycle progression, cell survival, and block normal cell death (apoptosis). It has been demonstrated that simply blocking mTOR signaling can result in the reactivation of the AKT pathway, negating much of mTOR blockade. Reactivation of AKT has been shown to be MET-dependent, resulting in the rationale that blocking both mTOR and MET concurrently should be a useful approach to treat epithelioid sarcoma.
EGFR The over-expression of epidermal growth factor receptor (EGFR) has been reported in a majority of epithelioid sarcomas. EGFR is a member of the HER receptor family. Upon ligand binding, EGFR phosphorylation triggers the activation of downstream signaling pathways involved in critical cellular functions such as proliferation, survival, and angiogenesis. 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. 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.
CD109 CD109, usually found on lymphocytes, is also expressed in epithelioid sarcoma, and is thought to mark the cancer stem cell (or cancer initiating cell) of the disease. Its expression has also been shown to be predictive of outcome. Cancer stem cells are a small population of tumor cells characterized by general chemo-resistance, the ability to self-renew, multi-differentiation potential, dormancy capabilities, and tumorigenesis. In this way, cancer stem cells are thought to play key roles in the progression and relapse of cancer.
Cyclin D1 Cyclin D1 is a protein requisite for cell cycle progression and has been shown to be up-regulated in epithelioid sarcoma. Cyclin D1 is a regulator of cyclin-dependent kinases (specifically, CDK4 and CDK6). It has been shown to interact with the retinoblastoma protein (a tumor suppressor gene), CDK4 and CDK6, thyroid hormone receptor beta, and nuclear receptor coactivator 1, among others. Cyclin D and CDKs promote cell cycle progression by releasing transcription factors that are important for the initiation of DNA replication. Abnormal levels of cyclin D1 may be associated with more rapid cell division in epithelioid sarcoma.
Diagnosis Tissue biopsy is the diagnostic modality of choice. Due to a high incidence of lymph node involvement, a sentinel lymph node biopsy may be performed. Histopathologically, epithelioid sarcoma presents in two primary types: distal (classical) and proximal. The distal types manifests as dermal or subcutaneous nodules of fairly uniform plump cells mimicking granulomas, often with spindle cells, inflammation and calcification. The proximal type exhibits larger, infiltrative polygonal cells with rhabdoid features, prominent nucleoli, mitosis and necrosis. 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). Immunohistochemical staining of INI1 is available and helps to diagnose of epithelioid sarcoma. MRI is the diagnostic modality of choice for imaging prior to biopsy and pathologic diagnosis for most patients.
Staging 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)
Treatment Surgery, radiation, and systemic therapy such as chemotherapy are all used at various times in the treatment of patients who have epitheloid sarcoma. Since sarcomas are considered very rare, it is not surprising that outcomes for patients with this type of cancer are better when patients are evaluated in expert centers, and when possible, treated there.
Surgical resection of epithelioid sarcoma with wide margins remains the preferred method of treatment, and as of 2023, remains the only curative approach for the cancer, sometimes in concert with radiation or chemotherapy. Limb-sparing surgery is the standard of care for treating all sarcomas, and is used wherever possible for treatment of epithelioid sarcoma as well.
In cases of advanced, recurrent, or metastasized disease, or if the tumor is inoperable, chemotherapy and radiation are the standard of care. The benefit for standard medications such as doxorubicin, ifosfamide, and combinations involving gemcitabine is generally measured in months, not years.
In January 2020, The U.S. Food and Drug Administration approved the oral medication tazemetostat (trade name Tazverik), a drug that blocks the EZH2 methyltransferase, for the treatment of epithelioid sarcoma in patients aged 16 years and older with either metastatic or locally advanced (unable to be completely removed surgically) disease. The data that led to the drug's authorization have been supported by post-marketing studies. 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.
Prognosis The 5-year survival rate for epithelioid sarcoma patients is usually quoted as 50-70%, with the 10-year survival rate is 42-55%. Children with epithelioid sarcoma may have somewhat better outcomes than adults, with 5 year survival rates around 65%. Pediatric patients also less often demonstrate lymphatic spread and metastasis than adults with this diagnosis. In addition to stage and grade of the tumor, gender, site, age at diagnosis, tumor size and microscopic pathology all have been shown to affect prognosis. Unsurprisingly, advanced stage and grade are associated with worse outcomes. Females tend to have more favorable outcomes than males, proximal cases show worse outcomes than distal cases. Tumors more than 2 cm in diameter and tumors with necrosis and vascular invasion also have been correlated with a worse outcome.