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

Baranov E, Ameline B, Berthold R, Perry KD, Torres-Mora J, Maclean F, Abrahao-Machado LF, Michal M, Kerr DA, Lu L, Hou T, Malik F, Goldfaden JS, Prasad JL, Gestrich C, Stelow E, Fanburg-Smith JC, LeGallo R, Zadeh S, Haglund de Flon F, Zhang PJ, Hartmann W, Miele E, Stejskal V, Alaggio R, Agaimy A, Nielsen GP, Demicco EG, Baumhoer D, Dehner CA (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 39

Article Number: 101014

Journal Issue: 7

DOI: 10.1016/j.modpat.2026.101014

Abstract

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.

Authors with CRIS profile

Involved external institutions

Karolinska Institute Sweden (SE) University of Virginia (UVA) United States (USA) (US) Hospital of the University of Pennsylvania (HUP) United States (USA) (US) Universitätsspital Basel Switzerland (CH) Universitätsklinikum Münster Germany (DE) University of Michigan United States (USA) (US) Mayo Clinic United States (USA) (US) Sonic Healthcare Limited Australia (AU) Laboratório Bacchi Consultoria em Patologia Brazil (BR) Biopticka laborator s.r.o. Czech Republic (CZ) Dartmouth-Hitchcock Medical Center (DHMC) United States (USA) (US) Indiana University – Purdue University Indianapolis United States (USA) (US) St. Jude Children’s Research Hospital United States (USA) (US) Ospedale Pediatrico Bambino Gesu Italy (IT) University Hospital Hradec Králové / Fakultní Nemocnice Hradec Králové Czech Republic (CZ) Harvard University United States (USA) (US) University of Pittsburgh United States (USA) (US) University of Pittsburgh Medical Center (UPMC) United States (USA) (US)

How to cite

APA:

Baranov, E., Ameline, B., Berthold, R., Perry, K.D., Torres-Mora, J., Maclean, F.,... Dehner, C.A. (2026). VGLL3-Rearranged Spindle Cell Rhabdomyoblastic Tumor: A Clinicopathologic and Molecular Genetic Study of 18 Cases With Consistently Indolent Behavior. Modern Pathology, 39(7). https://doi.org/10.1016/j.modpat.2026.101014

MLA:

Baranov, Esther, et al. "VGLL3-Rearranged Spindle Cell Rhabdomyoblastic Tumor: A Clinicopathologic and Molecular Genetic Study of 18 Cases With Consistently Indolent Behavior." Modern Pathology 39.7 (2026).

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