Epithelioid sarcoma

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 clearly 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 series of bumps. A proximal version has also been described, frequently occurring in the upper extremities. Rare cases have been reported in the pelvis, vulva, penis, and spine.Intermed. mag.High mag.High mag. (SMARCB1) 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 clearly 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 series of bumps. A proximal version has also been described, frequently occurring in the upper extremities. Rare cases have been 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 FLI-1. They 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, including the scalp. Generally speaking, epithelioid sarcoma has a high rate of relapse after initial treatment and tends to recur locally (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. The overall five-year survival rate for epithelioid sarcoma is anywhere from 25 to 78%. Importantly, the 10-year and 15-year survival rate drops off significantly. 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. In general, epithelioid sarcoma is a slow-growing and relatively painless tumor, often resulting in a lengthy period of time between presentation and diagnosis. Due to its ambiguity, 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 series of bumps. It is most often described as a firm-to-hard palpable mass, either in the deep soft tissue or in the dermis. Often, superficial lesions will ulcerate causing a mistaken diagnosis of a poorly healing traumatic wound or wart. About 13% of patients will present with multifocal tumors, and about 13% of patients will present with metastatic disease. The most common genetic mutation (found in 80-90% of epithelioid sarcomas) is the inactivation of the SMARCB1 gene, or the loss of INI-1 function, which is thought to be a major contributor to disease progression. Epithelioid sarcoma typically contains chromosome 22q11.2 mutations or deletions and 8q gains, particularly i(8) (>q10). Aberrations of 18q and 8q, as well as recurrent gains at 11q13, have also been observed. The SMARCB1 gene (also termed BAF47, INI1, or hSNF5) is located on chromosome 22q11.2 and 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 nucleosome architecture of our genome and has been shown to be a potent tumor suppressor gene, meaning that its primary role is to control cell division and to even halt division under appropriate circumstances (i.e. signals to over-replicate). As this tumor suppressor is commonly inactivated in epithelioid sarcoma, cell division can fail to appropriately halt, resulting in unregulated cellular growth and the formation of cancer tumors. Several research teams are currently developing techniques to reverse this loss of genetic function characteristic of epithelioid sarcoma. 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 have shown promise across several different carcinomas and in soft tissue sarcomas. In one case study, a patient with advanced metastatic vulvar epithelioid sarcoma showed a partial resolution of both lung and pleural metastases when pazopanib was administered, whereas all other therapies had failed MET (mesenchymal to epithelial transition) is another biological pathway that is likely involved in the development and progression of epithelioid sarcoma. c-MET is a tyrosine kinase oncogene, and its signaling pathway has been implicated in a variety of malignancies, including many cancers. The Sonic hedgehog and Notch signaling pathways are also suspected to be up-regulated 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 Sonic hedgehog signaling pathway by inhibiting hedgehog palmitoyl acytl-transferase. Current trials are investigating Notch inhibitors against epithelioid sarcoma.