malignant tumors thought to be derived from mesenchymal cells and contain cells
that resemble those of connective tissues in the body.
(RMS) are sarcomas resembling developing skeletal muscle and consist of cells
showing specific stages of skeletal muscle development (myogenesis). They are a
heterogeneous group of tumors and although rare, they are more prevalent in childhood
than later life. Historically, they are broadly divided into two major
Alveolar RMS (ARMS) – cellular architecture resembling the alveolar spaces of the
lungs. Based on molecular evidence, a solid variant of ARMS has been described
that does not show alveolar-like spaces.
Embryonal RMS (ERMS) – more frequent group and classical ERMS are seen predominantly
in young children. Variants include botryoid and spindle cell.
In addition, a
rarer pleomorphic subtype exists that is predominant in adults and most often
found in the extremities and the trunk.
(RMS) is the most common soft tissue sarcoma of childhood (Childhood Cancer)
and accounts for 4–8% of all childhood cancer cases.
Males are more
commonly affected, with an approximate ratio 1.3:1. The embryonal subtype
accounts for around 70% of RMS cases and most frequently affects young children.
The alveolar subtype is more prevalent in older children. Although RMS can
arise anywhere in the body, they occur most commonly in three regions: (1) the
head and neck (mainly ERMS), (2) the genitourinary tract (botryoid) and
retroperitoneum (ARMS), and (3) the upper and lower extremities (ARMS).
than 70% of RMS patients survive long term. Treatment of RMS usually involves
two or more modalities (multimodal therapy can include surgery, chemotherapy,
or radiotherapy). The survival rate depends significantly on tumor size,
location, histology, and whether metastasis has occurred. The outcome for the
alveolar subtype is generally worse than for the embryonal cases. Accurate
diagnosis of more undifferentiated RMS and tumors without distinct histological
features may be difficult. ARMS are characterized by small round cells that may
be difficult to distinguish from other so-called small round cell tumors,
including neuroblastoma and the Ewing sarcoma family tumors. ARMS and
especially the solid variant may also be difficult to distinguish from ERMS.
Development of improved disease-specific therapeutic strategies, with
concomitant improvements in outcome, has rendered accurate diagnosis of
paramount importance. Distinctive cytogenetic and corresponding molecular
changes associated with the various small round cell tumors can be useful
diagnostic markers in addition to standard immunohistochemical and
of the muscle related factor family of transcription factors and the expression
of the PAX3 and PAX7 genes in RMS is
consistent with their morphological resemblance to developing skeletal muscle.
The PAX genes are also involved
in ARMS through specific translocations; t(2;13)(q35;q14) and variant t(1;13)(p36;q14)
result in PAX3-FKHR and PAX7-FKHR fusion genes, respectively. The fusion genes encode chimeric
transcription factors with the DNA binding domain from PAX3/PAX7 fused to the
potent transactivation domain of FKHR (also called FOXO1a). The fusion proteins
are more potent transcription factors than the wild type PAX3 or PAX7 gene
products. The PAX3-FKHR fusion gene is associated with cases that have a poorer prognosis than those
with PAX7-FKHR. Although the fusion
proteins can transform NIH3T3 cells mice very rarely developed tumors in a
knock-in PAX3-FOXO1a mouse model. The prevalence of tumors increased when crossed with an INK4a/Arf/p53 deficient background. This
indicates that the fusion product alone may not be sufficient to induce
malignancy or that the animal models to date do not recapitulate the necessary conditions.
A number of
downstream targets of the PAX3-FKHR fusion protein have been indicated through expression
profiling analyses such as EN2, BVES, FLT1 Itam2A, and MET. MET encodes the HGF/SF receptor (hepatocyte growth factor/scatter factor)
and silencing MET expression in both ARMS and ERMS cell lines impaired cell
replication, survival, invasiveness, and anchorage independent growth.
Furthermore, RMS were induced in mice at a very high frequency, and with short
latency, through simultaneous loss of INK4a/ARF function and disruption of MET.
expression of genes such as MYCN, MDM2, CDK4, and GPC5 are also features of RMS. In addition, disruption of genes such as ATR, PTC, P16, and TP53 have been implicated in
RMS development. In contrast to the PAXFKHR fusion genes associated with alveolar subtype, the hallmark of ERMS is
recurrent loss of heterozygosity, loss of imprinting, or paternal disomy at the
11p15 locus. This loss leads to overexpression of the IGFII gene and is consistent with a role for the IGF
pathway in ERMS development.
syndrome is associated with fetal overgrowth and development of embryonal tumors
including RMS and is also linked to the involvement of the 11p15.5 region. Costello
syndrome is caused by mutation of the HRAS gene at 11p15.5 and children with Costello syndrome have a high incidence
of ERMS. However, although sporadic ERMS show uniparental disomy at 11p15.5,
this is not driven by HRAS mutations. Li–Fraumeni syndrome involves germ line TP53 mutations and is
associated with increased risk of several tumor types including RMS.
understanding of RMS tumorigenesis, and in particular determining the key genes
and molecular pathways involved, is resulting in novel targeted therapeutic strategies.
This should lead to increased cure rates and reduce treatment associated
toxicity for children with these tumors.