Abstract

Distinguishing between melanocytic and nerve sheath tumors can be challenging, particularly with desmoplastic/spindle cell melanoma and malignant peripheral nerve sheath tumors (MPNST). A 56-year-old man presented with a 6.5 cm cutaneous/subcutaneous mass in the left upper abdominal quadrant. Histologic examination showed a variably cellular proliferation of spindled cells in the dermis, with scattered lymphoid aggregates and an area of nodular epithelioid growth. Most cells were arranged in thin fascicles or singly in a collagenous stroma, featuring ill-defined cytoplasm, wavy nuclei with tapered ends, open chromatin, and absent to pinpoint nucleoli. An epithelioid schwannian-like nodular area displayed sheets and thin, loose fascicles of cells with distinct cytoplasmic membranes, eosinophilic cytoplasm, enlarged ovoid to irregular nuclei with clumped chromatin, frequent multinucleation, and prominent but small nucleoli, similar to spitzoid or BAP1-inactivated melanocytic tumors. Mitoses were inconspicuous, and necrosis was not present. All tumor cells were positive for S100, SOX-10, and CD34, and negative for EMA, MART1, PRAME, myoD1, and desmin. Targeted NGS identified a PWWP2A exon 1::ROS1 exon 36 fusion and a PIK3R2 p.G92fs mutation, with a TMB of 3.4 mutations/megabase. These findings argued against a low-grade MPNST or spindle cell melanoma and supported a diagnosis of hybrid nerve sheath tumor with PWWP2A::ROS1. PWWP2A::ROS1 has previously only been reported in one Spitz tumor. Hybrid nerve sheath tumors, typically seen in NF2 patients, are rare, and have not been reported to show gene fusions.  This case highlights a potentially novel entity, suggesting alternative molecular mechanisms in nerve sheath tumors and warranting further investigation.