Dermal Nerve Sheath Myxomas Harbor Recurrent DPYSL2::CDX1 Fusions and Expand the Spectrum of CDX1-Rearranged Soft Tissue Tumors.

Abstract

Dermal nerve sheath myxoma (DNSM) is a rare benign mesenchymal tumor with presumed nerve sheath differentiation with distinctive morphologic and immunophenotypic features; however, its molecular pathogenesis remains poorly understood. We investigated a series of nine morphologically classic DNSMs and performed molecular testing to identify recurrent genetic alterations. The cohort included five female and four male patients (median age: 56 years; range: 23-75 years). Tumors arose predominantly on the extremities and presented as multinodular dermal-based myxoid neoplasms composed of uniform spindled to epithelioid cells arranged in reticular cords within abundant myxoid stroma. Vacuolated "signet ring-like" cells were identified in all tumors. Immunohistochemically, all tested tumors showed diffuse S100, SOX10 and GFAP expression, and a subset focally expressed EMA, keratin AE1/AE3, and GLUT1. RNA-based sequencing identified an identical in-frame DPYSL2::CDX1 fusion in 7 of 9 cases. Fluorescence in situ hybridization testing using CDX1 and DPYSL2 break apart probes as well as DPYSL2/CDX1 dual-fusion probe confirmed rearrangement in 6/7 tested tumors. We herein demonstrate that most DNSM are characterized by recurrent DPYSL2::CDX1 fusions, representing the first recurrent molecular alteration identified in this tumor type. These findings further support the classification of DNSM as a distinct neoplastic entity and highlight the potential utility of molecular testing as a diagnostic adjunct in morphologically challenging cases. Further studies are warranted to clarify the biologic role of CDX1-related fusions and their relationship to other fusion-driven soft tissue neoplasms, particularly those with CDX1/CDX2 fusions.