Novel EPS15 :: KLF17 and EPS15L1 :: KLF17 Fusions Define a Distinctive Group of MUC4-Positive Spindled to Epithelioid...

A subset of epithelioid-to-spindle cell sarcomas remains difficult to classify due to lack of defining molecular alterations or pathologic features that do not fit neatly into a single tumor class. After identification of a primary mesenchymal neoplasm with EPS15L1::KLF17 gene fusion, we retrospectively collected 4 additional soft tissue tumors with EPS15L1 :: KLF17 or EPS15 :: KLF17 fusions. The cohort comprised 4 males and one female with age range of 5 to 64 years. The tumors arose in soft tissue of the extremities, head/neck, paraspinal region, and intra-abdominal mesentery. Two patients developed metastatic disease with one death from disease at 62 months; one showed late metastases at 5 and 11 years. Histologically, these were cellular neoplasms composed of epithelioid and spindled tumor cells with prominent cystic spaces and focal stromal sclerosis. All tumors demonstrated diffuse, strong MUC4 positivity (5/5) with cytokeratin (3/3), EMA (4/4), and S100 (3/4) expression. Whole transcriptome RNA sequencing identified EPS15L1 :: KLF17 fusions in 2 cases and EPS15 :: KLF17 fusions in 3 cases. RNA expression profiles, available in 2 cases, showed high expression of MUC4 and CD24. DNA methylation profiling revealed distinct epigenetic clustering, separate from EWSR1 :: KLF15 -rearranged soft tissue myoepithelial tumor, sclerosing epithelioid fibrosarcoma, low-grade fibromyxoid sarcoma, and other mesenchymal neoplasms. EPS15/EPS15L1 :: KLF17 -rearranged sarcoma has distinctive histologic findings, including diffuse MUC4 expression. Recognition is clinically important given its potential for late recurrence and metastasis.