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 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 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 median age of 58 years (range: 22-71). Tumors involved tongue (n=13), lower lip (2), retropharyngeal region (n=1), thyroid/parathyroid (n=1), and palatine tonsil (1) with median size of 1.2 cm. Treatment details (15 patients) revealed that 13 patients underwent excision only, while 1 patient underwent adjuvant chemotherapy and 1 adjuvant radiation therapy. Follow-up (11 patients) showed no local recurrence or metastases. At 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 HPFs (range: 0-7/10). By immunohistochemistry, tumors diffusely expressed desmin (n=18), multifocal MyoD1 (n=15) and/or myogenin (n=12), and sometimes SMA (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 (FISH) 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 morphological features. Methylation data (n=12) revealed all but 1 tumor to form 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. Further, our DNA methylation profiling data supports these tumors to form a distinct cluster, regardless of VGLL3 fusion partner, and 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.