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Ewing sarcoma (ES) is the second
most common bone tumor in children and adolescents. It was named
for James Ewing, a pathologist who first described the tumor in
1921, emphasizing its distinction from osteosarcoma based upon enhanced
radiosensitivity and a propensity to involve flat bones of the axial
skeleton.1 In the early 1980s, both Ewing sarcoma
and peripheral primitive neuroectodermal tumor (PNET) were found
to contain identical t(11;22)(q24;q12) translocations.2,3 Based
upon the shared translocation, and similar clinical behaviors, Ewing
Sarcoma Family of Tumors (ESFT) is now considered one disease entity
that includes classical ES, atypical ES, peripheral primitive neuroectodermal
tumor, neuroepithelioma, and Askin tumor (an ESFT of the chest wall).
It should be emphasized that peripheral PNETs are entirely different
from PNETs arising in the central nervous system which do not bear
the t(11;22) translocation and are not considered part of the ESFT
category.
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Epidemiology,
Pathophysiology, and Genetics
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ESFTs occur in approximately 2 to 3 per million/year
in persons less than 20 years4 with a peak in the
second decade of life, although they have been reported in infants
and occur with a substantial incidence in adults, especially prior
to age 40. For unknown reasons, ESFT are extremely rare among individuals
of African and Asian heritage. This is in contrast to osteogenic
sarcoma, which has a relatively equal race distribution.4 Despite
this dramatic ethnic predilection, neither specific genetic nor
environmental risk factors for the development of ESFT have been
identified. For instance, unlike osteosarcoma, which occurs more commonly
following irradiation, there is no evidence for an increased incidence
of ESFT following irradiation, and there is no evidence that ESFT
occurs more frequently in patients with defined cancer predisposition
syndromes. Importantly, however, family members of ESFT patients
have an increased incidence of neuroectodermal, stomach, and breast
malignancies, and survivors of ESFT show a high rate of second malignant
neoplasms, suggesting that as yet undefined genetic factors may
predispose to ESFT.5
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The cell of origin that gives rise to ESFT is also unknown, with
primitive neural cells implicated historically, and recent studies
suggesting that mesenchymal stem cells may give rise to the disease.6,7 The
classic translocation t(11;22)(q24;q12), or another related translocation,
occurs in greater than 95% of ESFT.8 ESFT-associated
translocations join the Ewing sarcoma (EWS) gene
located on chromosome 22 to an ets-family gene,
most commonly FLI1 (Friend Leukemia Insertion),
located on chromosome 11.9 The 68-kDa protein produced
by the EWS-FLI1 fusion transcript functions as an aberrant transcription
factor and plays a critical role in initiating and sustaining ESFT.
Expression of this molecule can transform mouse fibroblasts,10 and
reduction of EWS-FLI1 expression induces death of ESFT cell lines.11-13 Such
studies have established the EWS-ets translocation
as a compelling therapeutic target. However, clinically applicable
therapies to successfully prevent expression of EWS-ets or
interfere with downstream oncogenic events induced by the ...