Abstract
Spindle cell rhabdomyosarcomas (SCRMS), recognized by the 2020 WHO Classification of Tumors of Soft Tissue and Bone as a distinct entity, comprise a family of malignant skeletal muscle tumors sharing spindle cell morphology. To date, members of this family include 1) MyoD1-mutated spindle cell/sclerosing RMS (SCRMS/SRMS), 2) intraosseous SCRMS with FET::TFCP2 or MEIS1::NCOA2 fusions and 3) infantile congenital SCRMS harboring NCOA1/2 or VGLL3 rearrangements. A rare, emerging subtype of SCRMS has been reported to harbor recurrent ZFP64::NCOA3 fusions. We studied 14 cases of this rare SCRMS subtype. The tumors presented in 11 men and 3 women (median age: 39.5 years; range: 22-69) and involved the thigh (4), lower leg (2), gluteal soft tissues (2), abdominal wall (1), mediastinum (1), subperiosteal surface of 3rd rib (1), glottis (1), prostate (1), and pelvis (1). Morphologically, 11 tumors showed uniform spindle cell morphology with a fascicular architecture, while the remaining 3 tumors demonstrated focal or predominant round cell morphology. Extensive chondro-osseous differentiation was seen in 2 cases. By immunohistochemistry, tumors were variably positive for both desmin and MyoD1 (6 tumors), desmin, MyoD1 and myogenin (1 tumor), desmin alone (3 tumors of which only one was also tested for MyoD1), or MyoD1 alone (3 tumors). Smooth muscle actin was noted in 6 of 10 tested cases, and 2 of 5 tested cases showed ALK expression. A ZFP64::NCOA3 fusion was detected in 8 tumors, and a ZFP64::NCOA2 fusion in 6. Methylation studies showed all but one tested tumor to form a tight cluster, clearly separate from other RMS subtypes and non-RMS morphologic mimics. Clinical follow-up (10 of 14 cases; median: 35 months; range: 3-108 months) demonstrated local recurrence in 2 patients and distant metastases in 5 (median: 12 months; range: at presentation – 106 months). At the time of last follow-up, 5 patients were alive without evidence of disease, 3 patients were alive with disease, and 2 patients died of disease at 34 and 108 months. We conclude that SCRMS with ZFP64::NCOA2/3 fusions represent a distinct, clinically aggressive sarcoma, characterized by fascicular and sometimes round cell morphology, occasional chondro-osseous differentiation and variable skeletal muscle marker expression. Recognition of this emerging subtype of SCRMS may have prognostic and therapeutic implications.

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