Recurrent Fusions Between YAP1 and KMT2A in Morphologically Distinct Neoplasms Within the Spectrum of Low-grade Fibromyxoid Sarcoma and Sclerosing Epithelioid Fibrosarcoma

Am J Surg Pathol. 2020 May;44(5):594-606. doi: 10.1097/PAS.0000000000001423.


Sclerosing epithelioid fibrosarcoma (SEF) is an aggressive soft tissue sarcoma. In the majority of cases, there is overexpression of MUC4, and most cases show EWSR1-CREB3L1 gene fusions. A subset of SEF displays composite histologic features of SEF and low-grade fibromyxoid sarcoma (LGFMS). These "hybrid" tumors are more likely to harbor the FUS-CREB3L2 fusion, which is also seen in most LGFMS. We, here, characterize a series of 8 soft tissue neoplasms with morphologic features highly overlapping with LGFMS and SEF but lacking MUC4 expression and EWSR1/FUS-CREB3L gene fusions. Seven tumors showed fusions of the YAP1 and KMT2A genes, and 1 had a fusion of PRRX1 and KMT2D; all but 1 case displayed reciprocal gene fusions. At gene expression profiling, YAP1 and KMT2A/PRRX1 and KMT2D tumors were distinct from LGFMS/SEF. The patients were 4 female individuals and 4 male individuals aged 11 to 91 years. Tumors with known locations were in the lower extremity (5), trunk (2), and upper extremity (1); 3 originated in acral locations. Tumor size ranged from 2.5 to 13 cm. Proportions of SEF-like and LGFMS-like areas varied considerably among tumors. All tumors that showed infiltrative growth and mitotic figures per 10 HPFs ranged from 0 to 18. Tumor necrosis was present in 1 case. Follow-up was available for 5 patients (11 to 321 mo), 2 of whom developed local recurrences, and 1 died of metastatic disease. The clinical behavior of these soft tissue sarcomas remains to be further delineated in larger series with extended follow-up; however, our limited clinical data indicate that they are potentially aggressive.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics*
  • Child
  • Diagnosis, Differential
  • Disease Progression
  • Epithelioid Cells / pathology
  • Europe
  • Female
  • Fibrosarcoma / genetics*
  • Fibrosarcoma / mortality
  • Fibrosarcoma / secondary
  • Fibrosarcoma / therapy
  • Gene Fusion*
  • Genetic Predisposition to Disease
  • Histone-Lysine N-Methyltransferase / genetics*
  • Homeodomain Proteins / genetics
  • Humans
  • In Situ Hybridization, Fluorescence
  • Male
  • Middle Aged
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Neoplasm Grading
  • Neoplasm Recurrence, Local
  • Phenotype
  • Predictive Value of Tests
  • RNA-Seq
  • Sclerosis
  • Soft Tissue Neoplasms / genetics*
  • Soft Tissue Neoplasms / mortality
  • Soft Tissue Neoplasms / pathology
  • Soft Tissue Neoplasms / therapy
  • Transcription Factors / genetics*
  • Treatment Outcome
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Biomarkers, Tumor
  • Homeodomain Proteins
  • KMT2A protein, human
  • PRRX1 protein, human
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase