Fusion-driven Spindle Cell Rhabdomyosarcomas of Bone and Soft Tissue: A Clinicopathologic and Molecular Genetic Study of 25 Cases

Carina A Dehner; Stephen M Broski; Jeanne M Meis; Paari Murugan; John S A Chrisinger; Carlos Sosa; Matthew Petersen; Kevin C Halling; Sounak Gupta; Andrew L Folpe

doi:10.1016/j.modpat.2023.100271

Fusion-driven Spindle Cell Rhabdomyosarcomas of Bone and Soft Tissue: A Clinicopathologic and Molecular Genetic Study of 25 Cases

Mod Pathol. 2023 Oct;36(10):100271. doi: 10.1016/j.modpat.2023.100271. Epub 2023 Jul 7.

Authors

Affiliations

¹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
² Department of Radiology, Mayo Clinic, Rochester, Minnesota.
³ Department of Pathology and Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
⁴ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.
⁵ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
⁶ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Electronic address: folpe.andrew@mayo.edu.

PMID: 37422156
DOI: 10.1016/j.modpat.2023.100271

Abstract

The evolving classification of rhabdomyosarcoma (RMS) now includes spindle cell RMS (SRMS). Bone/soft tissue SRMS often harbor TFCP2, or less often MEIS1 rearrangements. We studied 25 fusion-driven SRMS involving bone (n = 19) and soft tissue (n = 6). Osseous SRMS occurred in 13 women and 6 men (median age: 41 years) and involved the pelvis (5), sacrum (2), spine (4), maxilla (4), mandible (1), skull (1), and femur (2). Follow-up (median: 5 months) demonstrated local recurrence in 2/16 and distant metastases in 8/17 patients (median time to metastasis: 1 month). Eight patients died of disease; 9 were alive with disease. Soft tissue SRMS occurred in 4 men and 2 women (median: 50 years). Follow-up (median: 10 months) revealed distant metastasis at diagnosis (1), alive with unresected tumor (1), and no evidence of disease (4). Next-generation sequencing demonstrated FUS::TFCP2 (12), EWSR1::TFCP2 (3) and MEIS1::NCOA2 (2); FISH identified EWSR1 (2) rearrangements. Most TFCP2-rearranged SRMS (13/17) showed spindled/epithelioid morphology, rarely with rhabdomyoblasts. The bone tumors were diffusely desmin and MyoD1 positive with limited myogenin; 10/13 were ALK -positive and 6/15 were keratin positive. Soft tissue SRMS harbored EWSR1::TFCP2, MEIS1::NCOA2, ZFP64::NCOA2, MEIS1::FOXO1, TCF12::VGLL3 and DCTN1::ALK, and displayed spindled/epithelioid, leiomyomatous, and myxofibrosarcoma-like morphologies. Immunohistochemistry (IHC) was positive for MyoD1 (6/6), focal desmin (5/6), myogenin (3/6), and keratin (1/6). We conclude that TFCP2-rearranged SRMS of bone and soft tissue show consistent morphologic and IHC features, likely representing a distinct subset of RMS. Non-TFCP2 fusion-positive SRMS could represent a single RMS subset, multiple subtypes of RMS, or "fusion-defined" sarcomas with rhabdomyoblastic differentiation.

Keywords: bone tumors; immunohistochemistry; molecular genetics; rhabdomyosarcoma; soft tissue tumors.