EP300::VGLL3 fused rhabdomyoblastic tumor revisited: Is the label “rhabdomyosarcoma” justified?

VGLL3 (encoding the mammalian Vestigial-like 3 transcriptional cofactor) has emerged as a fusion partner in hybrid nerve sheath tumors and in rare spindle cell rhabdomyosarcomas (RMS) of the head and neck. We herein describe a new EP300::VGLL3 RMS and review/update reported cases (total: 6) to reappraise their outcome. All six reported EP300::VGLL3 fusion RMS cases originated exclusively in the tongue musculature of adult males at a median age of 48 years (range, 36-59). Nonradical surgery was the initial treatment in most cases, followed by variable re-excisions in most. Incomplete adjuvant chemotherapy was given to one patient. No metastases were recorded, and all patients with follow-up were disease-free at last follow-up (12, 34, 36, and 48 months). Histologically, all tumors displayed bland spindled to ovoid plump cells lacking clear-cut rhabdomyoblastic features and disposed into fascicular and storiform patterns. The tumor margins were infiltrating with entrapment of skeletal muscle fibers. Overtly malignant cytology, brisk mitotic activity, necrosis, lymphovascular, and perineural invasion were absent. Immunohistochemistry was consistently positive for desmin (6/6), and variably myogenin (6/6), myoD1 (4/4), and SMA (5/6). Fusion breakpoints were identical among all cases (EP300ex31::VGLL3ex2). Given their indolent course after local excision alone, the noncommitted term EP300::VGLL3-fused rhabdomyoblastic tumor might be more appropriate for these tumors than the original RMS terminology to avoid overprognostication/overtreatment that the "rhabdomyosarcoma" label would imply. Reporting more cases is mandatory to elucidate the full anatomic and biological spectrum of this morphologically, anatomically, and genetically unique entity.