What is the pathophysiology of pediatric rhabdomyosarcoma (RMS)?

Updated: Mar 28, 2019
  • Author: Roshni Dasgupta, MD, MPH; Chief Editor: Eugene S Kim, MD, FACS, FAAP  more...
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Answer

The pathogenesis of RMS is not well elucidated, though it is believed to involve disruption of mesenchymal cell growth.

Five variants of rhabdomyosarcoma are described in the international classification of RMS. [12]  Most cases, however, fall into one of the two major subtypes: embryonal and alveolar. Treatment and prognosis are dependent on histologic subtype and tumor location.

The embryonal subtype is most common, accounting for 55% of all RMS. It is usually found in the head and neck, genitourinary tract, or orbit in younger patients. This subtype is characterized by a loss of heterozygosity at the 11p15.5 locus, the region of the IGFII gene. Anaplasia, which may be a feature of this subtype, adversely affects the likelihood of failure-free survival.

Embryonal RMS (ERMS) has also been subclassified into botryoid and spindle cell variants. The botryoid variant, named after its gross resemblance to a cluster of grapes, arises within a hollow cavitary viscus (eg, vagina, biliary tract, or bladder) and is found more frequently in infants. The spindle cell variant is found most commonly in the paratesticular area.

Alveolar RMS (ARMS) is often seen in older patients, accounting for 20% of all tumors in older children. It usually affects the extremities, trunk, and perineum.

Another, albeit much less common, subtype is undifferentiated RMS.

A translocation involving the PAX3 locus, between the long arm of chromosome 2 and the long arm of chromosome 13, has been identified in RMS patients. This involves the PAX3 and FKHR genes. The FOXO transcription factor gene can fuse with either the PAX3 or the PAX7 transcription factor gene. These fusion proteins have been identified in patients with ARMS. [13, 14]

In these PAX/FOXO fusions, the DNA binding domain of PAX is combined with the regulatory domain of FOXO. [15] This results in increased PAX activity, leading to dedifferentiation and the proliferation of myogenic cells. [16]  PAX3-FOXO fusion is more common than PAX7-FOXO fusion (55% vs 23%) and is associated with worse overall survival. [17]

It has been demonstrated that approximately 25% of ARMS tumors are translocation-negative. By gene array analysis, these fusion-negative ARMS tumors more closely resemble ERMS and have a prognosis similar to that of ERMS. [18] ​ In future studies and treatment protocols, fusion status will replace tumor histology for the classification and stratification of RMS tumors.

For additional information, see Rhabdomyosarcoma.


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