Le Loarer F, Cleven AHG, Bouvier C, et al. - Cases were retrospectively and prospectively enrolled and analyzed by immunohistochemistry, fluorescence in situ hybridization with TFCP2 break-apart probe (n = 10/14), array comparative genomic hybridization, whole RNA-sequencing, or anchored multiplex PCR-based targeted next-generation sequencing by the researchers in order to report the clinicopathological, transcriptional, and genomic characteristics of a series of 14 cases. Most tumors exhibited a mixed spindle cell and epithelioid pattern with frequent vesicular nuclei. All tumors expressed keratins and demonstrated a rhabdomyogenic phenotype. In all, ALK was overexpressed but three cases without underlying ALK fusion on break-apart FISH (n = 5) nor next-generation sequencing (n = 14). At the genomic level, ALK upregulation was frequently related to an internal deletion. TFCP2 was fused in 5′ either to EWSR1 (n = 6) or FUS (n = 8). In both soft tissue cases, EWSR1 was involved. In all tested cases (n = 8), including one case with an unbalanced signal, FISH with TFCP2 break-apart probe was positive. All tested tumors revealed complex genetic profiles with genomic indexes ranging from 13 to 107.55 and recurrent CDKN2A deletions on array-CGH. FET-TFCP2 rhabdomyosarcomas clustered together and clearly from other rhabdomyosarcomas subgroups. Collectively, the spectrum of the new family of FET-TFCP2 rhabdomyosarcomas, which was correlated with a predilection for the craniofacial bones, an aggressive course, and recurrent pathological features, was validated and expanded. Their relationship with ALK overexpression might serve as a therapeutic vulnerability.