Chapter 455

Rhabdomyosarcoma (RMS) is the most common soft tissue tumor in children, representing approximately 5% of all cancers among children and adolescents.1-5 Approximately 350 new cases are diagnosed each year in the United States, for an annual incidence of 4.3 per million children and adolescents younger than 20 years.1 Although RMS can occur in adolescents and adults, two thirds of patients are less than 10 years of age.1,4 The incidence of RMS is slightly higher in males.1 With current multimodal therapy (including chemotherapy, radiotherapy, and surgery), approximately 70% of children with RMS can be cured.2-6

### Genetics and Epidemiology

A small fraction of RMS cases occur as part of recognizable genetic syndromes, either as an inherited gene in an affected family or as a new germline mutation. These syndromes can be divided into those with only tumor susceptibility and those with both tumor susceptibility and nonneoplastic effects. The former category includes both Li Fraumeni and hereditary retinoblastoma syndromes, which are caused by mutations in the TP53 and RB1 tumor suppressor genes, respectively.7 In Li Fraumeni syndrome, which is characterized by susceptibility to a heterogeneous group of cancers, RMS occurs relatively frequently in addition to other soft tissue sarcomas, breast cancer, brain tumors, and acute leukemia.8 In contrast, RMS occurs less frequently as a secondary tumor in hereditary retinoblastoma syndrome, typically presenting in or near the radiation field following treatment of the primary retinoblastomas.9

Costello syndrome and neurofibromatosis type-1 are syndromes with tumor susceptibility and nonneoplastic effects that are caused by mutations of genes in the RAS signaling pathway—HRAS and NF1, respectively.10 In addition to developmental effects involving the skin and brain, these two syndromes are characterized by a high incidence of benign tumors (skin papillomata and neurofibromas, respectively) and a lower incidence of malignant tumors. RMS is the most common cancer in Costello syndrome, whereas RMS occurs less commonly than malignant peripheral nerve sheath tumors in neurofibromatosis type-1.

In a final group of other tumor susceptibility syndromes with nonneoplastic effects, there are only a few reported RMS cases. These conditions include Beckwith-Wiedemann, Gorlin, and Rubinstein-Taybi syndromes, which are linked to dysregulated imprinted genes in the 11p15 chromosomal region, PTCH mutations, and CREBBP mutations, respectively.7,11,12 In the first two conditions, RMS occurs infrequently relative to a frequent cancer type (Wilms tumor and basal cell carcinoma, respectively), but in the latter, RMS and all other tumors occur infrequently.10,13,14

### Pathology and Genetics

The tumors of the RMS family have in common a poorly understood relationship to the skeletal muscle lineage and often can be diagnosed based on evidence of this differentiated phenotype. RMS is then further subclassified into two main histopathologic subtypes—alveolar (ARMS) and embryonal (ERMS).15 ARMS is characterized by small cells with round nuclei and scant cytoplasm. Aggregates of ...

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