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Distal and proximal epithelioid sarcoma — differences in diagnosis and similarities in treatment

Maria Krotewicz1, Anna M. Czarnecka1, Piotr Błoński12, Jakub Śledź13, Bartłomiej Szostakowski1, Anna Szumera-Ciećkiewicz4, Ewa Bartnik56, Piotr Rutkowski1

Abstract

Epithelioid sarcoma (ES) comprises two subtypes, distal and proximal. Initially, the distinction between these variants was based on tumor location, but subsequent research highlighted numerous functional differences between them. Proximal ES is distinguished by the molecular deletion of INI1, while classic ES is characterized by retained dysfunctional INI1 expression. Classic ES features elevated expression of GLI3, FYN, and CXCL12, along with overactive Notch/Hedgehog pathways and class 1 human leukocyte antigens (HLA). In contrast, proximal ES demonstrates MYC overexpression and upregulation of genes associated with the cell cycle, chromatin metabolism, and protein synthesis. The differences in clinical presentation underscore the necessity for tailored treatment approaches for each ES subtype. New therapeutic strategies are crucial, especially for the aggressive proximal variant. Tazemetostat, an oral selective inhibitor of the histone methyltransferase enhancer of zeste homolog 2 (EZH2), has recently gained FDA approval as a first-line treatment for ES patients.

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