VGLL3-Rearranged Spindle Cell Rhabdomyoblastic Tumor: A Clinicopathologic and Molecular Genetic Study of 18 Cases With Consistently Indolent Behavior

A rare spindle cell tumor with a skeletal muscle phenotype, male predilection, exclusive involvement of the head and neck region, particularly the tongue, and a suggested indolent course has been previously reported as vestigial-like 3 (VGLL3)-rearranged spindle cell rhabdomyosarcoma (SRMS). We report 18 cases with extended clinical follow-up, detailed molecular results, and methylation profiling. Tumors occurred in 5 females, 12 males, and 1 patient of unknown sex with a median age of 58 years (range, 22-71). Tumors involved the tongue (n = 13), lower lip (2), retropharyngeal region (n = 1), thyroid/parathyroid (n = 1), and palatine tonsil (1), with a median size of 1.2 cm. Treatment details (15 patients) revealed that 13 patients underwent excision only, whereas 1 patient underwent adjuvant chemotherapy and 1 patient underwent adjuvant radiation therapy. Follow-up (11 patients) showed no local recurrence or metastases. At the last follow-up (median, 45 months; range, 1-326 months), all patients were alive without evidence of disease. Histologically, tumors showed spindled to histiocytoid cells arranged in a fascicular, storiform, or haphazard architecture with variably collagenous stroma, rounded to infiltrative borders, and often diffusely growing through skeletal muscle, adipose tissue, and entrapped nerves. Necrosis was consistently absent with a median mitotic rate of 1/10 high-power fields (range, 0-7/10). By immunohistochemistry, tumors diffusely expressed desmin (n = 18), multifocal MyoD1 (n = 15), and/or myogenin (n = 12), and sometimes smooth muscle actin (n = 7). Molecular testing revealed EP300::VGLL3 (n = 6), TCF12::VGLL3 (n = 5), and PPARGC1A::VGLL3 (n = 1) fusions with VGLL3 rearrangement by fluorescence in situ hybridization in 3 cases. One archival tumor failed molecular and methylation testing despite multiple attempts, likely due to decreased DNA/RNA integrity, yet was included given classic morphologic features. Methylation data (n = 12) revealed that all but 1 tumor formed a distinct group separate from other fusion-driven rhabdomyosarcomas, including 5 infantile/congenital SRMS. We describe a well-characterized series of these rare tumors with extended follow-up data confirming lack of progression or recurrence. Furthermore, our DNA methylation profiling data support the view that these tumors form a distinct cluster, regardless of VGLL3 fusion partner and are separate from morphologic mimics and other fusion-driven SRMS, including 5 cases of congenital SRMS. We propose that these neoplasms may be better classified as VGLL3-rearranged spindle cell rhabdomyoblastic tumors to reflect their indolent behavior and to prevent overtreatment.