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Epithelioid Sarcoma: Opportunities for Biology-Driven Targeted Therapy.

Noujaim J, Thway K, Bajwa Z, Bajwa A, Maki RG, Jones RL, Keller C - Front Oncol (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Royal Marsden Hospital , London , UK.

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.

No MeSH data available.


Related in: MedlinePlus

(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  tumors, the misassembled SWI/SNF complex has the potential to dysregulate target loci that may be co-regulated by other transcription factors (36, 38–40, 43) and thereby present indirect ways to drug target the misassembled complex.
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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 tumors, the misassembled SWI/SNF complex has the potential to dysregulate target loci that may be co-regulated by other transcription factors (36, 38–40, 43) and thereby present indirect ways to drug target the misassembled complex.

Mentions: Epithelioid sarcoma (ES), first described by Enzinger over half a century ago (1), is a rare neoplasm accounting for <1% of adult soft tissue sarcomas and between 4 and 8% of pediatric non-rhabdomyosarcomatous sarcomas (2, 3). ES is presumed to be a mesenchymal malignancy, but ES characteristically exhibits both mesenchymal and epithelial markers. The cell of origin and molecular drivers are still a matter of debate. ES is divided into two recognizable clinicopathological entities, classic ES (also called distal-type ES), and proximal-type ES (Figures 1A–E). These two subtypes are thought be a continuum of disease rather than distinct entities (4). Distal-type ES is histologically identifiable by tumor nodules with central necrosis surrounded by large polygonal cells and spindle cells merging in the periphery (5) (Figures 1A,B). Described variants include angiomatoid variant, fibroma-like variant, and myxoid variant. Proximal-type ES is characterized by a multinodular pattern and sheet-like growth of large polygonal cells, often accompanied by a focal or predominant rhabdoid morphology (6) (Figures 1C,D). A specific marker has not yet been identified in ES. On immunohistochemistry (IHC), virtually all cases are positive for cytokeratin (CK) and epithelial membrane antigen (EMA) and most cases co-express vimentin. The marker CD34 is expressed in 60–70% of cases. IHC studies are typically negative for S-100, neurofilament protein, carcinoembryonic antigen, factor VIII-related antigen and CD-31, and INI-1 (SMARCB1) whose expression is lost in tumor nuclei (7). Establishing a diagnosis of ES can be difficult as tumors can present with a wide range of appearances and immunophenotypes. The differential diagnosis include fibrous histiocytoma, nodular fasciitis, other reactive proliferations, fibromatosis, giant cell tumor of tendon sheath, sclerosing epithelioid fibrosarcoma, and even some carcinomas and melanomas (7). IHC is helpful in differentiating these entities. Epithelioid vascular tumors can resemble ES and efforts must be made to exclude a diagnosis of epithelioid hemangioendothelioma. In epithelioid hemangioendothelioma, the unique translocation t(1;3)(p36;q25), resulting in the fusion of WWTR1 with CAMTA1I establishes a firm diagnosis (8).


Epithelioid Sarcoma: Opportunities for Biology-Driven Targeted Therapy.

Noujaim J, Thway K, Bajwa Z, Bajwa A, Maki RG, Jones RL, Keller C - Front Oncol (2015)

(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  tumors, the misassembled SWI/SNF complex has the potential to dysregulate target loci that may be co-regulated by other transcription factors (36, 38–40, 43) and thereby present indirect ways to drug target the misassembled complex.
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Related In: Results  -  Collection

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Show All Figures
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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 tumors, the misassembled SWI/SNF complex has the potential to dysregulate target loci that may be co-regulated by other transcription factors (36, 38–40, 43) and thereby present indirect ways to drug target the misassembled complex.
Mentions: Epithelioid sarcoma (ES), first described by Enzinger over half a century ago (1), is a rare neoplasm accounting for <1% of adult soft tissue sarcomas and between 4 and 8% of pediatric non-rhabdomyosarcomatous sarcomas (2, 3). ES is presumed to be a mesenchymal malignancy, but ES characteristically exhibits both mesenchymal and epithelial markers. The cell of origin and molecular drivers are still a matter of debate. ES is divided into two recognizable clinicopathological entities, classic ES (also called distal-type ES), and proximal-type ES (Figures 1A–E). These two subtypes are thought be a continuum of disease rather than distinct entities (4). Distal-type ES is histologically identifiable by tumor nodules with central necrosis surrounded by large polygonal cells and spindle cells merging in the periphery (5) (Figures 1A,B). Described variants include angiomatoid variant, fibroma-like variant, and myxoid variant. Proximal-type ES is characterized by a multinodular pattern and sheet-like growth of large polygonal cells, often accompanied by a focal or predominant rhabdoid morphology (6) (Figures 1C,D). A specific marker has not yet been identified in ES. On immunohistochemistry (IHC), virtually all cases are positive for cytokeratin (CK) and epithelial membrane antigen (EMA) and most cases co-express vimentin. The marker CD34 is expressed in 60–70% of cases. IHC studies are typically negative for S-100, neurofilament protein, carcinoembryonic antigen, factor VIII-related antigen and CD-31, and INI-1 (SMARCB1) whose expression is lost in tumor nuclei (7). Establishing a diagnosis of ES can be difficult as tumors can present with a wide range of appearances and immunophenotypes. The differential diagnosis include fibrous histiocytoma, nodular fasciitis, other reactive proliferations, fibromatosis, giant cell tumor of tendon sheath, sclerosing epithelioid fibrosarcoma, and even some carcinomas and melanomas (7). IHC is helpful in differentiating these entities. Epithelioid vascular tumors can resemble ES and efforts must be made to exclude a diagnosis of epithelioid hemangioendothelioma. In epithelioid hemangioendothelioma, the unique translocation t(1;3)(p36;q25), resulting in the fusion of WWTR1 with CAMTA1I establishes a firm diagnosis (8).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Royal Marsden Hospital , London , UK.

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.

No MeSH data available.


Related in: MedlinePlus