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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
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Genetics and Epidemiology
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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
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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.
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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
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Pathology and Genetics
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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. ...