A novel BRD4-LEUTX fusion in a pediatric sarcoma with epithelioid morphology and diffuse S100 expression

Malignant epithelioid soft tissue tumors encompass a wide spectrum of lesions. Among them, Epithelioid Malignant Peripheral Nerve Sheath Tumors (MPNST) constitute a distinct subgroup, accounting for <5% of all MPNST. Epithelioid MPNST are infrequently associated with neurofibromatosis type 1, occasionally arise in a schwannoma and show diffuse S100 and CD34 expression, often combined with INI-1 loss. However, the molecular mechanisms underlying the tumorigenesis of epithelioid MPNST remain largely unknown. We describe a case of a 10-year-old girl with an epithelioid malignancy of the orbit. The tumor proved positive for S100, CD34 and SOX10, and, although INI-1 expression was maintained, the overall features suggested the possibility of an epithelioid MPNST, arising in an unusual location. NGS analysis revealed a novel in-frame BRD4-LEUTX fusion gene. LEUTX plays an important role in embryonal genome activation and its expression is mostly suppressed postnatally. We were able to detect increased levels of LEUTX transcript in the tumor, indicating that BRD4-LEUTX fusion leads to LEUTX re-activation. To our knowledge, this fusion has never been reported previously. Whether the current case represents an example of epithelioid MPNST or a distinct tumor entity remains to be determined.

Automated summary

Epithelioid malignant peripheral nerve sheath tumors (MPNST) are a rare subgroup characterized by diffuse S100 and CD34 expression, often combined with INI-1 loss. This study describes a case of an epithelioid malignancy of the orbit in a 10-year-old girl, with NGS analysis revealing a novel BRD4-LEUTX fusion gene. The fusion gene leads to the re-activation of LEUTX, which has not been reported previously, raising questions about the classification of this tumor entity.