Epithelioid Sarcoma: Opportunities for Biology-Driven Targeted Therapy

Abstract

Epithelioid sarcoma (ES) is a soft tissue sarcoma of children and young adults for which the preferred treatment for localized disease is wide surgical resection. Medical management is to a great extent undefined, and therefore for patients with regional and distal metastases, the development of targeted therapies is greatly desired. In this review, we will summarize clinically relevant biomarkers (e.g., SMARCB1, CA125, dysadherin, and others) with respect to targeted therapeutic opportunities. We will also examine the role of EGFR, mTOR, and polykinase inhibitors (e.g., sunitinib) in the management of local and disseminated disease. Toward building a consortium of pharmaceutical, academic, and non-profit collaborators, we will discuss the state of resources for investigating ES with respect to cell line resources, tissue banks, and registries so that a roadmap can be developed toward effective biology-driven therapies.

Keywords: BAF47; INI1; SMARCB1; SWI/SNF complex; epithelioid sarcoma.

Figure 1

(A,B) Distal-type ES. (A) Low power histology shows a nodule of tumor present in the dermis and subcutis, comprising a large area of central geographic necrosis, surrounded by sheets of relatively uniform polygonal neoplastic cells (hematoxylin and eosin, ×40). Scale bar, 500 μM. (B) At higher power, these are medium-sized, rounded cells, with ovoid vesicular nuclei with even chromatin, and small nucleoli. This example is cellular, but more sparsely cellular neoplasms can appear subtle, and the neoplastic cells may be confused with inflammatory cells. The characteristic necrosis is seen abutting the tumor cells (bottom left of field) (hematoxylin and eosin, ×200). Scale bar, 50 μM. (C,D) Proximal-type ES. (C) At low power, proximal-type ES comprises sheets or lobules of medium-sized to large round cells, and is seen to lack the more defined architecture and geographic central necrosis of the distal-type variant (hematoxylin and eosin, ×40). Scale bar, 20 μM. (D) At higher power, this is characterized by a sheet-like growth of large polygonal cells, often with focal rhabdoid morphology, and which have ovoid vesicular nuclei, prominent large nucleoli, and relatively abundant eosinophilic cytoplasm. The cells are often more pleomorphic than those of the distal-type variant. On morphology alone, these cells are difficult to distinguish from other malignant epithelioid cells, such as those of carcinoma, melanoma, rhabdomyosarcoma, or epithelioid angiosarcoma, and therefore immunohistochemistry is crucial for establishing a correct diagnosis (hematoxylin and eosin, ×200). Scale bar, 50 μM. (E) Distributions of ES subytpes, adapted from the largest series reported by the French Sarcoma Group (9). (F) Vulnerabilities in the misassembled SWI\SNF complex when SMARCB1 is absent. Using epithelioid sarcoma as well as rhabdoid tumor as a basis for this model of SMARCB1 null tumors, the misassembled SWI/SNF complex has the potential to dysregulate target loci that may be co-regulated by other transcription factors (, –40, 43) and thereby present indirect ways to drug target the misassembled complex.