Pediatric Embryonal Rhabdomyosarcoma: An Integrated Study of Clinicopathological Features, Pan-cancer Targeted Next-generation Sequencing, and Chromosomal Microarray Analysis from a Single Institution

Rhabdomyosarcoma is the most common soft tissue sarcoma in children and adolescents, and embryonal rhabdomyosarcoma (ERMS) is the most common subtype. Previous reports have identified a wide range of genetic aberrations in ERMS. However, the clinicopathological significance of these genetic aberrations is not clear, and further integrated research is needed. To analyze correlations among clinicopathological features, molecular genetic aberrations, and prognosis, we collected 15 cases of pediatric ERMS, including complete data derived from clinicopathological features, pan-cancer targeted next-generation sequencing/OncoKids® panel, and chromosomal microarray. Patient ages ranged from 1 to 15 years (median, 6 years). Eight patients were boys, and 7 were girls. Clinical follow-up information was available for all 15 patients (follow-up duration range, 13-72 months; median, 41 months). Twelve (80.0%) patients were alive without evidence of recurrent or metastatic disease. Two (13.3%) patients were alive with evidence of recurrent or metastatic disease, and one patient (case 9) died with synchronous lung, iliac and sacral bone metastases, 15 months after treatment. We found recurrent mutations of NRAS, FGFR4, and CTNNB1 genes in 3 cases, and mutations of HRAS, MAP2K1, PPM1D, KRAS, PIK3CA, and TP53 genes in 1 case each. Case 1 had heterologous cartilaginous differentiation with germline mutation in CBL but no mutation in DICER1. Case 9 simultaneously showed homozygous loss of CDKN2A/B and TP53 with diffuse anaplastic tumor cells. Nine cases (9/14) exhibited gains of whole chromosome 2. Four cases (4/14) revealed loss of whole chromosome X. Three cases (3/14) contained loss of heterozygosity (LOH) for chromosome 4p16.3q35.2 (2 copies). Our results demonstrate new mutations in MAP2K1 and PPM1D, further expanding the mutation spectrum of ERMS. A germline mutation in CBL may be related to cartilage differentiation in ERMS. Gain of whole chromosome 2 is a frequent copy number alteration (64.3%) in pediatric ERMS. The concurrent homozygous loss of CDKN2A/B and TP53 in ERMS may be associated with diffuse anaplasia and portend a more adverse prognosis.