Review Article

Ewing Sarcoma Family of Tumors

Abstract
Aditya V. Maheshwari, MD
Edward Y. Cheng, MD

From the Department of

Orthopaedic Surgery, University of
Minnesota, Minneapolis, MN
(Dr. Maheshwari), and the
Department of Orthopaedic Surgery,
Masonic Cancer Center, University
of Minnesota (Dr. Cheng).
Dr. Cheng or an immediate family
member serves as a board member,
owner, officer, or committee member
of Musculoskeletal Tumor Society,
has received royalties from
Innomed, and has received research
or institutional support from Aastrom
Biosciences and Musculoskeletal
Transplant Foundation. Neither
Dr. Maheshwari nor an immediate
family member has received
anything of value from or owns
stock in a commercial company or
institution related directly or
indirectly to the subject of this
article.
J Am Acad Orthop Surg 2010;18:94107
Copyright 2010 by the American
Academy of Orthopaedic Surgeons.

94

The Ewing sarcoma family of tumors (ESFT) consists of a group of

tumors characterized by morphologically similar round-cell neoplasm and by the presence of a common chromosomal translocation. Although rare, such tumors constitute the third most frequent
primary sarcoma of bone after osteosarcoma and chondrosarcoma.
ESFT most commonly affects young children and adolescents. Because most patients with clinically apparent localized disease at
diagnosis may also have occult metastatic (ie, systemic) disease,
multidrug chemotherapy as well as local disease control with surgery and/or radiation therapy are indicated for all patients. Despite
marked improvements in survival during the past 40 years for patients with localized disease, lesser improvements have been seen
in patients with metastatic or recurrent disease. A better understanding of the complex biology of ESFT may lead to the successful development of biologically targeted therapies. As the regulatory
pathways responsible for transformation, growth, and metastasis of
ESFT become more refined, the number of potential therapeutic
targets will expand.

umors of the Ewing sarcoma family of tumors (ESFT) are characterized by morphologically similar roundcell neoplasms as well as by the presence
of common chromosomal translocation. In 1918, Stout1 reported a case
of an ulnar nerve tumor composed of
undifferentiated round cells that
formed rosettes; this lesion was subsequently defined as primitive neuroectodermal tumor (PNET) of soft tissue. In 1921, Ewing2 reported a case
of round-cell tumor in the radius of a
14-year-old girl as a diffuse endothelioma of bone, proposing an endothelial derivation (Ewing sarcoma
[ES]). Angervall and Enzinger3 reported the first case of an ES arising
in soft tissue (ie, extraskeletal ES) in
1975. In 1979, Askin et al4reported a
malignant small-cell tumor of the
thoracopulmonary region (ie, Askin
tumor) with histologic features similar to those in PNET. In 1984, Jaffe

et al5 described a neuroectodermal

tumor of bone, calling it a PNET of
bone.
Initially, ESFT were believed to be
biologically distinct. However, based
on their wide spectrum of neural differentiation (PNET being the most
differentiated); their immunohistochemical, cytogenetic, and molecular
uniformity; and their identical
response to Ewing-based chemotherapy regimens, it was determined that
these sarcomas are related and that
they originate from unique mesenchymal stem cells capable of multilineage differentiation.6 A common
chromosomal translocation that results in EWS-ETS fusion (between
the EWS gene on chromosome 22
and an ETS-type gene, most commonly the FLI1 gene on chromosome 11) has been implicated in
80% to 95% of cases of ES, PNET,
and Askin tumor.6,7 Thus, these le-

Journal of the American Academy of Orthopaedic Surgeons

Aditya V. Maheshwari, MD, and Edward Y. Cheng, MD

sions have been grouped as the same

entity, called ESFT. Treatment principles are the same regardless of anatomic location. Herein we have chosen to focus on ES of the bone.

Epidemiology
Currently, it is believed that ES most
likely can be ascribed to spontaneous
genetic translocations rather than to
exposure to environmental factors or
drugs, mendelian inheritance, disease, or traumatic events.6,8 The incidence of secondary ES after radiotherapy (RT) has been reported to be
<3%.9 The histogenesis of these tumors remains unknown, and debate
continues regarding the neuroectodermal or mesenchymal lineage.
Although rare, ES is the third most
frequent primary sarcoma of bone,
after osteosarcoma and chondrosarcoma.10 It is the second most common bone tumor (after osteosarcoma) occurring in children and
adolescents, accounting for approximately 3% of all pediatric malignancies and approximately 10% of all
primary malignant bone tumors.10,11
ES is reported in all age groups,
from infancy to advanced age, but
the condition is most commonly diagnosed in persons in the second decade of life.12-17 The annual incidence
is low (0.6 per million) in patients
aged <5 years but rises in concordance with the arrival of puberty to
approach a peak rate of 5 per million.11 The median age of patients
with ES is 15 years, and >50% of patients are adolescents. In the European Intergroup Cooperative Ewings
Sarcoma Study 86 trial, only 10% of
cases were diagnosed in patients
aged >20 years.18-20 Patient age has
diagnostic importance. In patients
aged >30 years who present with
primary lung disease, small-cell
carcinoma should be excluded. In
younger patients, alternative diagFebruary 2010, Vol 18, No 2

noses must be considered, such as

lymphoma/leukemia, rhabdomyosarcoma, medulloblastoma, and neuroblastoma. ES is more common in
males than in females, with a reported ratio of 1.3 to 1.5:1.12-17 Caucasians are much more frequently affected than Asian persons; African
and African-American persons rarely
suffer from ES.16,17
Esiashvili et al17 searched the Surveillance, Epidemiology, and End Results (SEER) database for information on ES in patients aged 1 through
19 years. Based on data reported
from 1973 through 2004, the mean
annual incidence of ES is 2.9 cases
per 1,000,000 population. Of the
906 patients with ES, 830 were Caucasian and 18 were African American (91.6% versus 2%, respectively).
There was a male preponderance
(553 patients [61%]), and 212 cases
were reported in children aged <10
years (23%).

Clinical Features
Site
ES occurs most often in bone. Softtissue involvement is rare. Almost
any bone can be affected, and the
sites of origin are roughly split anatomically between the central and
peripheral skeleton.8,15,21-24 Osteosarcoma typically involves long bones;
however, in ES, flat and long bones
are nearly equally represented, with
pelvic involvement in 23% to 27%
of cases.8,15,21-24 Older patients have a
higher proportion of pelvic tumors
as well as of large tumors. Pathologic
fracture may be present in up to
15% of patients.25

Signs and Symptoms

The most common presenting symptoms of ES are pain, swelling, and a
mass, especially in an extremity.26
The patient with a large pelvic tumor
may present with signs of bowel or

bladder disturbances in addition to

pain. Paraspinal tumors are generally
associated with back pain, with or
without neurologic impairment.
Children with Askin tumor may
present with respiratory symptoms,
including cough, shortness of breath,
and, in some cases, chest pain and
pleural effusion.
Patients may also present with systemic signs and symptoms, and approximately 20% to 28% present
with a fever.10,26 Laboratory studies
are nonspecific but may reveal anemia, leukocytosis, or an increased
erythrocyte sedimentation rate. Although the differential diagnosis includes osteomyelitis, distinguishing
features usually help avoid delay in
the management of either condition.
Patients with osteomyelitis often
present with systemic illness and
usually do not have the large extraosseous solid mass that is common with ES. However, because necrotic tumor can look like purulence,
it is vital to culture all suspected tumors and biopsy all sites with suspected osteomyelitis.
Delay between symptom onset and
diagnosis is common. In one study,
50% of patients had symptoms for
>6 months before the tumor was diagnosed.27 Delayed diagnosis of pelvic tumors is particularly common
because a mass in that area is not
palpable until it becomes quite large.
In another study, 26% of patients
with ES related the onset of symptoms to minor injury.28 Thirty-four
percent of patients with ES had a
palpable mass at initial presentation.
The most frequent initial misdiagnoses in older patients with ES were
tendinitis (21%) and sciatica (11%)
and, in younger patients, coxitis simplex (9%) and osteomyelitis (6%).
The mean delay in diagnosis from
the first medical visit was 19 weeks
(range, 1 to 72 weeks). A high index
of suspicion, along with persistent
follow-up and early diagnostic imag-

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Ewing Sarcoma Family of Tumors

ing, is helpful in obtaining an earlier

diagnosis.
Several factors have been associated with metastatic disease: the
presence of constitutional symptoms,
a shorter interval between the onset
of symptoms and diagnosis, pelvic
location, older age, larger tumors,
and a high level of serum lactic dehydrogenase.29

Imaging Features
Plain Radiography
Unlike osteosarcoma, which usually
originates in the metaphysis, ES of
the long bones tends to arise from
the diaphysis or metadiaphysis. Of
the 206 patients in the Intergroup
Ewings Sarcoma Study 7299 group,
121 (58.7%) presented with lesions
located in the metadiaphysis, 73
(35.4%) with lesions in the diaphysis, 11 (5.3%) with lesions in the metaphysis, and only 1 with a lesion in
the epiphysis (0.5%).25
Typically, ES appears as an ill-defined,
permeative, mottled, or focally motheaten, destructive intramedullary lesion.
Periosteal reaction, with a laminated or
onion skin appearance (a prominent
multilayered reaction), is common in
ES, but it is not pathognomonic. Periosteal reactions may be seen, such as a
sunburst or spiculated pattern (the latter displaying as a perpendicular reaction), as well as the Codman triangle (ie,
triangular lifting of the periosteum from
the bone at the site of detachment).
However, these presentations are less
common in ES than in osteosarcoma.
An ill-defined soft-tissue mass adjacent
to the primary bone lesion is very common in ES. Of the 373 patients in the
Intergroup Ewings Sarcoma Study
7299, common radiographic findings
(present in >30% of evaluated cases) included poor margination (ie, indistinct
lesion borders; 96%), soft-tissue component (80.4%), permeative component (76.1%), laminated periosteal

96

reaction (56.6%), and sclerotic component (39.7%).25 The major radiographic differential diagnoses included osteosarcoma, osteomyelitis,
and eosinophilic granuloma.

Advanced Imaging Studies

Initial plain radiographs, particularly
of the pelvis, may appear to be normal, and advanced imaging studies
are needed for tumor localization.
MRI provides the most precise definition of the local extent of bone tumor, including the degree of expansion into the intramedullary region,
extent of soft-tissue involvement,
and the relationship of the lesion to
adjacent neurovascular structures.
MRI may also be used to assess responses to neoadjuvant chemotherapy and irradiation. CT is useful for
staging the disease and detecting
macrometastasis. As an adjunct to
MRI, CT may also be helpful in target planning for radiation. A technetium Tc-99m whole-body bone scan
is important in detecting skip or distant metastases; these occur in 10%
of patients.10 False-negative bone
scans occasionally occur. In conjunction with the aforementioned studies,
fluorodeoxyglucose positron emission tomography, thallium-201 scintigraphy, and dynamic MRI also may
be used to assess responses after neoadjuvant therapy.30

Staging
Currently, most commonly used
staging systems for malignant bone
tumors are also applied to ESFT, but
these systems are problematic. Nodal
status and grade, as defined by the
American Joint Committee on Cancer staging system for sarcoma,31 are
irrelevant for ESFT because such tumors rarely spread to the lymph
nodes. In addition, by definition,
these are high-grade tumors.6 According to the Enneking staging sys-

tem adopted by the Musculoskeletal

Tumor Society, almost all ESFT neoplasms are classified as stage IIB
or III.32 Clinically apparent metastasis (macrometastasis) has prognostic significance, and the staging
work-up is based on proper imaging
of the primary tumor and sites of
likely metastasis, including plain radiography and MRI of the primary
site, chest radiography and CT of the
lung, bone scanning, and bone marrow biopsy. Laboratory studies include a complete blood count, an
erythrocyte sedimentation rate assay
(increased in up to 50% of patients),
serum lactate dehydrogenase measurement, and baseline chemistries.
Additional scans, such as the multiple gated acquisition scan, may be
required before initiation of chemotherapy because of the cardiotoxicity
associated with doxorubicin.

Pathology
Grossly, ESFT presents as a graywhite tumor with a variable amount
of necrosis, hemorrhage, or cyst
formation. Morphologically, ESFT
are composed of sheets of small
round cells with a high nuclear-tocytoplasmic ratio. They are often
classified into a group of small, blue,
round-cell tumors that include neuroblastoma, alveolar rhabdomyosarcoma, and lymphoblastic lymphoma.
The cells typically have scant, weakly
eosinophilic cytoplasm that usually
contains glycogen (making them positive on periodic acid-Schiff [PAS]
stain), diastase degradable granules,
and round nuclei with evenly distributed chromatin and little mitotic activity (Figure 1). Tumor histology
may range from undifferentiated (ES)
to more differentiated (PNET). The
PNET type may exhibit neural differentiation under light microscopy (ie,
Homer Wright rosettes in >20% of
tumor tissue). In addition, neuroen-

Journal of the American Academy of Orthopaedic Surgeons

Aditya V. Maheshwari, MD, and Edward Y. Cheng, MD

docrine differentiation can be observed on ultrastructural studies,

which visualize the presence of neurosecretory granules.
Immunohistochemical findings are
helpful in distinguishing ESFT from
other neoplasms. However, they
should be interpreted alongside cytogenetic and molecular studies to be
most definitive. CD99 is nearly universally expressed at high levels by
ESFT cells (95%) (Figure 2), even in
the absence of the characteristic
11;22 translocation, but is not specific for this tumor type.10,33 Depending on their neural differentiation,
ESFT can also express neuronspecific enolase (NSE), S-100 protein, Leu-7 (ie, CD57), and protein
gene product 9.5, as well as neurofilaments and synaptophysin. ESFT
cells are reactive with antivimentin
antibodies and, in fewer than one
quarter of cases with anticytokeratin antibodies. In addition, ESFT
neoplasms are often PAS-positive,
because of the presence of intracellular glycogen, and reticulin-negative.
In contrast, lymphomas are PASnegative and reticulin-positive. Lymphocyte-derived tumors also stain
positive for leukocyte common antigen and other T and B cell markers
(eg, CD45, TdT, or both). Neuroblastoma cells are NSE- and S-100
positive; however, unlike their ESFT
counterparts, they are vimentinnegative and neurofilament-positive.
Embryonal rhabdomyosarcoma may
express CD99, but it also expresses
desmin, myoglobin, and musclespecific actins (eg, MyoD1, myogenin, or both).
Genetic studies, along with histopathology and immunochemistry, are
essential for diagnosis. At the genetic
level, ESFT is defined by the presence
of these EWS-ETS fusion gene arrangements (Table 1).6,34,35 The rearrangements of EWS with FLI1 or
FLI1-related genes make up >95%
of all ESFT; t(11;22)(q24;q12) transFebruary 2010, Vol 18, No 2

location, a chromosomal abnormality specific to ESFT, is detected in

approximately 80% to 95% of cases6,34,35 (Figure 3). Recently, the EWS
gene has been found to be rearranged with still other ETS-like
genes in other cancers, such as clear
cell sarcoma (ie, melanoma of soft
parts [EWS-ATF1]) and desmoplastic
small round-cell tumor of the abdomen (EWS-WT1).38,39 Fluorescence in
situ hybridization has been reported
to be a more sensitive and reliable
ancillary technique than reversetranscription polymerase chain reaction for the diagnosis of ESFT in
formalin-fixed paraffin-embedded
tissue; however, the latter provides
additional information regarding fusion transcript subtype and prognosis.36 These methods are particularly
helpful in differentiating synovial
sarcoma from ESFT because synovial
sarcoma usually harbors a wellcharacterized t(X;18) translocation.1
However, one must be careful, because although the occurrence is
rare, other tumors (eg, polyphenotypic tumors, rhabdomyosarcomas)
have been found to have the EWSFLI1 transcript.37

Prognosis and Prognostic

Risk Factors
It is important to identify the patient
at high risk for ESFT and calculate
the prognostic stratification because
different subgroups may require dif-

Figure 1

Ewing sarcoma family of tumors

present as small round uniform
cells with high nucleus-tocytoplasmic ratio and grow in
dense, solid sheets (hematoxylineosin, original magnification 600).
(Courtesy of J. Carlos Manivel,
MD, and Michelle Dolan, MD,
Minneapolis, MN.)

Figure 2

Strong immunoreactivity for CD99

is seen in all tumor cells
(immunoperoxidase stain, original
magnification 600). (Courtesy
of J. Carlos Manivel, MD, and
Michelle Dolan, MD, Minneapolis, MN.)

Table 1
Chromosomal Translocations in Ewing Sarcoma Family of
Tumors6,7,21,34-37
Translocation

Gene Fusion

Incidence (%)

t(11;22)(q24;q12)
t(21;22)(q22;q12)
t(7;22)(p22;q12)
t(17;22)(q12;q12)
t(2;22)(q33;q12)

EWS-FLI1
EWS-ERG
EWS-ETV1
EWS-EIAF
EWS-FEV

80-95
5-10
Rare
Rare
Rare

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Ewing Sarcoma Family of Tumors

onystimulating factor. In the United

States, current standard chemotherapeutic agents used include vincristine, doxorubicin, and cyclophosphamide, alternating with ifosfamide
and etoposide.22 The mode of administration and dose intensity within
courses differs markedly between
protocols. The duration of primary
chemotherapy ranges from 6 months
to approximately 1 year.

Figure 3

Local Control

G-banded karyotype demonstrating a balanced 11;22 translocation (arrows):

46,XX,t(11;22)(q24;q12). (Courtesy of J. Carlos Manivel, MD, and Michelle
Dolan, MD, Minneapolis, MN.)

ferent treatment intensities. Although the literature differs on the

exact impact of individual prognostic factors,6,12-15,29 clinically evident
metastatic disease remains the most
important independent prognostic
indicator in ESFT. The relative importance of tumor site and size as a
prognostic factor is diminishing with
the use of modern treatment protocols. Recently, analysis of risk factors
has come to include the amount of
tumor load (ie, volume, macrometastasis pattern, amount of bone
marrow disease by polymerase chain
reaction) and the biologic factors (ie,
histologic response, gene expression,
type of fusion transcript)6,12-15,29 (Table 2).

Treatment
Most patients with apparently localized disease at diagnosis have subclinical micrometastatic (ie, systemic)
disease; thus, systemic therapy using
multidrug chemotherapy as well as
local disease control via surgery
and/or RT is indicated in the treatment of all patients (Figure 4). Regardless of tumor extent, most pa-

98

tients receive four to eight cycles of

neoadjuvant chemotherapy.6 Thereafter, treatment varies based on the
eventual resectability of the tumor.
With these protocols, event-free survival and overall survival have increased to 65% to 82% at 5 years in
patients with localized disease and
to 25% to 39% in those with detectable metastatic disease at
diagnosis.6,12,17-22,40-45 The corresponding 10-year survival rate has been reported to be 63% for localized disease and 32% for metastatic
disease.17

Chemotherapy
Despite various local control measures, chemotherapy is usually provided both before (ie, neoadjuvant)
and after (ie, adjuvant) definitive local control therapy. The clinical trials
performed in the past 15 years have
been undertaken in an attempt to improve survival by maximizing the
chemotherapy dose per cycle, increasing the total number of cycles
provided, or decreasing the interval between cycles (dose-dense or
dose intensification therapies)
with the addition of granulocyte col-

Currently, treatment is centered on

the use of neoadjuvant chemotherapy with the goal of eradicating micrometastases and reducing the size
of the primary tumor so as to
achieve better tumor demarcation
and improve the success of subsequent local control measures.10 The
precise indications for local control
in the form of surgical resection
and/or RT are controversial. The
treatment plan should be individualized based on the stage and resectability of the tumor.

Surgery
The role of surgery continues to
evolve in the treatment of patients
with ESFT. Careful patient selection
has led to local failure rates of
<10%, although bias exists, in that
smaller, more peripheral tumors tend
to be selected for definitive surgical
management and larger, more central
tumors are managed with surgery
and/or RT.12 The risk of secondary
malignancy and the potential for
growth retardation may be important considerations in the decision to
select surgical treatment rather than
RT. Surgery affords local control and
may prevent late recurrence of
chemoresistant cells.10 Another potential benefit with surgical resection
of the primary tumor is in the opportunity to gather information concerning the amount of necrosis in the
resected tumor. Patients with residual

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Aditya V. Maheshwari, MD, and Edward Y. Cheng, MD

Table 2
Prognostic Factors for Ewing Sarcoma Family of Tumors6,12-17,20,29,34,40-53
Pretreatment
Factor
Location

Tumor size and

volume
Age
Sex
Laboratory
parameters

Metastases

Time to relapse
Histopathology
Molecular
pathology47-53

Detectable fusion
transcripts in morphologically normal
bone marrow
Treatment response
factors

Description
Ewing sarcoma family of tumors (ESFT) located in the distal extremities has the best prognosis, followed by
the proximal extremities and then by central or pelvic sites. Cutaneous and subcutaneous lesions tend to
have an indolent course associated with good outcome.
Tumor size (>8 cm) and volume (>100-200 mL) are adverse prognostic factors. Larger tumors tend to occur
in unfavorable sites (eg, pelvis).
Patients aged 14 years have the best prognosis of any age group.
Females have a better prognosis than males.
Increased serum lactate dehydrogenase levels (LDH >200 IU/L) pretreatment are associated with inferior
prognosis. However, increased LDH levels are correlated with large primary tumors and metastatic disease.
Anemia as well as elevated white blood cell counts and erythrocyte sedimentation rate (with constitutional
symptoms) may indicate extensive disease and poorer prognosis.
Any metastatic disease is an adverse prognostic factor. Patients with metastatic disease confined to the lung
have a better prognosis than do patients with extrapulmonary metastases (eg, bone, bone marrow). A skip
metastasis in the same bone has a better clinical outcome than does metastasis to another site.
The 5-year survival rate is considerably worse in patients who experience recurrence within 2 years of diagnosis.
Degree of neural differentiation has not been found to be a prognostic factor.
The EWS-FLI1 translocation associated with ESFT can occur at several potential breakpoints in each of the
genes that join to form the novel segment of DNA. Some variants of the novel gene created by the translocation (type 1, EWS exon 7 fused to FLI1 exon 6) have been associated with a more favorable prognosis
than other EWS-FLI1 fusion types independent of tumor size and location. Overexpression of tumorsuppressor gene p53, cell proliferation nuclear antigen Ki-67, and proto-oncogene HER-2/neu are associated with poor prognosis in some tumors. The prognosis is better when <20% of cells express p53. Loss of
16q and increased telomerase activity may carry an adverse prognostic significance. In a recent study, the
presence of p16(INK4a) alteration was a statistically significant predictor of prognosis for patients with Ewing sarcoma;51 however, its definite role remains to be determined.
Reverse-transcription-polymerase chain reaction can be used to detect fusion transcripts in bone marrow. In
a single retrospective study of patients with normal marrow morphology and no other metastatic site, fusion
transcript detection in marrow was associated with an increased risk of relapse.52
Patients with minimal or no residual viable tumor after preoperative chemotherapy (radiologic and/or pathologic) have significantly better event-free survival compared with patients with larger amounts of viable tumor. Contrary to the classic prognostic factors, treatment intensification may not have a major impact on
patients with a favorable histologic response, likely because biologic factors influence the response to treatment. Decreased positron emission tomography uptake following chemotherapy was correlated with good
histologic response in patients who received pre- and postinduction chemotherapy.53

viable tumor in the resected specimen have a worse outcome than patients with complete necrosis. In the
third study of the French Society of
Paediatric Oncology (EW88), eventfree survival at 5 years for patients
with <5% viable tumor, 5% to 30%
viable tumor, and >30% viable tumor was 75%, 48%, and 20%, respectively.46
When surgery is selected, complete
resection is required because there is
a strong correlation between a positive surgical margin and local recurFebruary 2010, Vol 18, No 2

rence.20,54 Patients who are treated

with adequate margins (ie, wide, radical) have been shown to have better
5-year event-free survival than those
with inadequate margins (ie, intralesional, marginal) (58.2% versus
46.7%, respectively).54 Overall survival is also better with adequate
margins than with inadequate ones
(60.2% versus 40.1%). When positive margins are found, a repeat resection should be done, when possible. Although the addition of RT has
also been recommended when resec-

tion margins are microscopically

positive after an attempted wide excision, planned intralesional debulking procedures followed by RT do
not improve local control rates and
should be avoided.40,41
Limb salvage is now possible in
most patients and should be performed in cases in which survival
rates are anticipated to be the same
regardless whether amputation is
performed and in cases in which the
salvaged limb is expected to provide
satisfactory function with an accept-

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Ewing Sarcoma Family of Tumors

Figure 4

Treatment algorithm for Ewing sarcoma family of tumors.6

* Consider dose-dense therapy for children (q 2 weeks)
IGFR-1 = insulin-like growth factor-1, LDH = lactate dehydrogenase, PET = positron emission tomography
Adapted with permission from Ludwig JA: Ewing sarcoma: Historical perspectives, current state-of-the-art, and opportunities for targeted therapy in the future. Curr Opin Oncol 2008;20:412-418.

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Aditya V. Maheshwari, MD, and Edward Y. Cheng, MD

Figure 5

A 27-year-old woman presented with pain and an enlarging mass in her right groin region. A, AP radiograph
demonstrating a large soft-tissue shadow in the right lower pelvis with marked destruction of the superior and inferior
pubic rami. B, Coronal MRI (TR 5220, TE 44) confirming the presence of a 14.6 12.1 11.0-cm heterogeneous
mass with osseous destruction of the entire right superior and inferior pubic rami with involvement of the ischium and
extension into the true pelvis and the adductor compartment. C, Coronal F-18 fluorodeoxyglucose positron emission
tomography (FDG-PET) CT scan showing the hypermetabolic mass with a standard uptake value of 8.8. Biopsy
confirmed the diagnosis of Ewing sarcoma, and the patient underwent four cycles of neoadjuvant chemotherapy.
D, Coronal MRI (TR 5910, TE 38) study demonstrating a substantial reduction in tumor volume. E, Coronal F-18 FDGPET CT scan demonstrating minimal hypermetabolic activity. F, AP radiograph following wide local excision of the
tumor and reconstruction using an allograft-prosthetic composite. The patient was disease-free at 30-month follow-up,
after completing adjuvant chemotherapy.

able risk of complications.55,56 Pathologic fracture may not preclude surgical resection and is not necessarily
associated with an adverse outcome.10 Conditions for which amputation is likely include extremely
large tumors involving vital structures, an unmanageable or displaced
pathologic fracture, and a lesion in
the ankle or foot. Overall survival
rates are similar whether amputation
or limb salvage is performed; in general, functional outcomes and patient acceptance are better with limb
salvage than with amputation, alFebruary 2010, Vol 18, No 2

though complications are more common with limb salvage.55

Many reconstruction options are
available, including vascularized and
nonvascularized autograft reconstruction (eg, fibula, scapula, iliac crest, rib,
clavicle), allograft reconstruction,
allograft-prosthetic composites, and endoprosthetic reconstruction, including
expandable prosthesis, rotationplasty,
and amputation.56 The technique selected should be tailored to each individual patient (Figures 5 and 6).
Because it is usually more durable
than prostheses, biologic precon-

struction is preferable in younger patients. The use of allograft-prosthetic

composites and endoprostheses is expected to increase with continued
improvement in bioengineering and
metallurgy.

Radiotherapy
RT traditionally has been used for
local disease control in patients with
ESFT.18,19,57,58 Radiation for local control is recommended for unresectable
tumors and when there is a low likelihood that adequate surgical margins can be achieved. RT may also

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Ewing Sarcoma Family of Tumors

Figure 6

Attempted frog leg view radiograph (A) and axial MRI (TR 2500, TE 70) scan
(B) demonstrating cortical involvement with a sunburst type periosteal
reaction and an associated large soft-tissue mass in the proximal
metadiaphyseal region of the femur in a 15-year-old boy who presented with
left hip pain. Ewing sarcoma was confirmed on biopsy and treatment with
neoadjuvant chemotherapy, and the patient underwent wide local resection
and reconstruction using an allograft-prosthetic composite. C and D, AP
radiographs obtained at 15-year follow-up demonstrating a stable, wellaligned hemiarthroplasty component with a well-healed grafthost bone
junction (arrow in panel D). (Panels A and C reproduced from Ewings
sarcoma. Your Orthopaedic Connection. Rosemont, IL, American Academy of
Orthopaedic Surgeons. Available at: http://orthoinfo.aaos.org/
topic.cfm?topic=A00082. Accessed September 22, 2009.)

have a role in improving local disease control in patients with poor

chemotherapeutic response.
The recommended doses in various

102

clinical situations have been recently

summarized in a retrospective review
of large-group experiences.57 The irradiation treatment field should in-

clude the pretreatment tumor volume

plus an adequate margin. A coneddown boost is then administered to
the postinduction chemotherapy volume, also with an adequate margin.
Most local treatment failures following RT alone are within the radiated
field; thus, a 2- to 3-cm margin beyond the affected area is usually considered adequate. The dose for local
control using radiation alone is 55.8
to 60.0 Gy. Typically, 45 Gy is administered, followed by a boost of
10.8 Gy. No adjuvant radiation is
necessary in the setting of adequate
margins and a good histologic response to prior chemotherapy. No
difference has been found in overall
survival regardless whether standard
whole-bone radiation or RT of the
involved field only is performed.19
Similarly, standard fractionation
(180 to 200 cGy/d, 5 days a week) is
as effective as hyperfractionation
(120 to 160 cGy twice daily); however, hyperfractionation has been reported to cause less late toxicity.58
With the increase in long-term survival rates as a result of modern chemotherapy, the problems of late local
recurrence, functional impairment secondary to radiation complications, and
radiation-induced sarcomas have become more apparent.59 Radiationrelated complications have been reported in up to 63% of patients and
are most pronounced in skeletally
immature patients.59 These complications include limb-length discrepancy, joint contracture, muscle atrophy, pathologic fracture, and
secondary malignancies.

Surgery Versus
Radiotherapy
Traditionally, ES has been treated with
chemotherapy and radiation, with resection reserved for expendable
bones.8 Advancements in imaging
technology and technique have led to
better planning for both resection

Journal of the American Academy of Orthopaedic Surgeons

Aditya V. Maheshwari, MD, and Edward Y. Cheng, MD

and RT. Many protocols have demonstrated superior local control and
survival with surgery with or without RT compared with RT alone
(5% to 10% versus 35% local recurrence).10,12,14,40,49,60,61 One possible
explanation for the increased survival rate is that tumor resection
eliminates residual clones of chemotherapy-resistant cells before they
have a chance to recur locally or to
metastasize.10 Selection bias for performing surgery on smaller and more
surgically resectable tumors may explain these more favorable results.
Conversely, other studies of modern
chemotherapy protocols have noted
no difference in survival or local failure based on treatment protocol, radiation dose, or surgery.62,63
Thus, the question whether to perform surgery or RT for local control
cannot be answered with confidence.
Only level III and IV evidence is
available, and there is known selection bias in that resectable lesions
tend to be operated on. A level I randomized trial comparing the two
treatments is not feasible practically;
thus, a level II individual comparative study will likely be the only and
best evidence possible to answer this
question. The trends, however, favor
surgical resection in all cases in
which the surgeon believes that the
primary tumor can be removed
completely, particularly in expendable or surgically reconstructible
sites.10,12,14,40,49,60,61 RT is still used for
tumors in anatomic sites in which
wide resection cannot be done, when
the functional deficit is unacceptable
to the patient, when an attempted resection has unacceptable margins,
and when the chemotherapeutic response has been poor.10

High-dose Chemotherapy
With Stem Cell Rescue
High-dose chemotherapy with hematopoietic stem cell transplant (HSCT) has
February 2010, Vol 18, No 2

been developed to treat patients at high

risk of relapse following conventional
treatment. However, the results with
this therapy are difficult to evaluate
in the absence of large randomized
trials with heterogeneous patient
groups.64,65 In one recent study, 33
patients with recurrent or progressive ES were treated with high-dose
chemotherapy and HSCT with and
without total-body irradiation.64 The
2- and 5-year event-free survival
rates were 42.5% and 38.2%, respectively. In another study, Meyers
et al65 reported 2-year event-free survival to be 20% and concluded that
consolidation with total-body irradiation and high-dose chemotherapy
with HSCT did not significantly improve survival in patients with ES
metastasized to bone and bone marrow. Results are often superior for
patients with isolated lung metastases than in those with bone and bone
marrow disease and those with lung,
bone, and bone marrow disease. Relapse and regimen-related toxicity remain the main obstacles to success.

Metastatic Ewing Sarcoma

ES has a strong potential to metastasize. In the SEER study, 26% to 28%
of patients presented with distant
macrometastasis.17 More than 10%
of patients present with multiple
bone metastases at initial diagnosis.10
Although metastases in the lungs,
bone, bone marrow, or a combination thereof are detectable in approximately 25% of patients, metastases
to lymph nodes, the liver, and the
brain are rare.17,66
Despite advances in the treatment
of localized ES, the prognosis for patients with detectable metastatic disease remains poorer than apparently
localized disease.17,67 Standard chemotherapy combined with adequate
local control measures applied to primary and metastatic sites may result
in complete or partial responses;

however, the 8-year event-free survival is approximately 20%, and the

overall cure rate is 14% to 28%.67 A
cure rate of 32% was reported for
patients with lung/pleural metastases
only. A worse outcome was reported
without lung radiation than with it.
Patients with only bone/bone marrow metastases were reported to
have an approximate 20% to 25%
cure rate. Patients with combined
lung and bone/bone marrow metastases had a cure rate of <15%.
RT to the primary tumor as well as
to the sites of metastatic disease
should be considered; however, this
modality may interfere with delivery
of chemotherapy if too much bone
marrow is included in the field. All
patients with pulmonary metastases
should undergo whole-lung radiation, even when complete resolution
of overt pulmonary metastatic disease has been achieved with chemotherapy. Radiation doses are modulated based on the amount of lung to
be radiated and on pulmonary function. Doses between 12 and 15 Gy
are generally used when the whole
lung is treated.
More intensive therapies, many of
which incorporate high-dose chemotherapy with or without total-body
irradiation in conjunction with stem
cell support, have not been found to
demonstrate consistent improvement
in event-free survival for patients
with recurrent or metastatic disease.65,67,68

Recurrent Ewing Sarcoma

The prognosis for patients with recurrent or progressive ES is poor;
5-year event-free survival and overall
survival following recurrence often
are <10%.13,42,43 Patients with both
local and distant recurrence have a
worse outcome than do those with
either local or distant recurrence.
Most relapses occur within 5 years
of diagnosis, with 10% to 15% oc-

103

Ewing Sarcoma Family of Tumors

curring after 5 years.42,43 Moreover,

very few patients who relapse later
than 5 years after initial diagnosis
are salvageable. The prognosis for
patients who relapse >2 years following completion of primary therapy is
better than for patients who relapse
while on their initial chemotherapy
regimen or within 2 years of completing primary therapy.13,42,43
The selection of further treatment
depends on many factors, including
the site of recurrence and prior treatment, as well as individual patient
considerations. RT to bone lesions
may provide a palliative effect,
whereas radical resection may improve outcome.13 Patients with pulmonary metastases should undergo
whole-lung irradiation.13 Residual
disease in the lung may be surgically
removed. Ifosfamide and etoposide
should be considered for patients
who have not previously received
these agents. Second-line drugs such
as topotecan, irinotecan, busulfan,
melphalan, thiotepa, and temozolomide have also been shown to
achieve responses.6,10,64,69 Aggressive
attempts to control the disease, including myeloablative regimens, may
be warranted.68

Second Malignant
Neoplasms
Patients treated for ES show a trend toward a higher risk of developing second
malignancies than do persons in the
general population. Treatment-related
acute myeloid leukemia and myelodysplastic syndrome have been reported to
occur in 1% to 2% of survivors of ES,
and some dose-intensive regimens appear to be associated with a higher risk
of hematologic malignancy.69-73 Treatment-related acute myeloid leukemia
and myelodysplastic syndrome arise
most commonly at 2 to 5 years following diagnosis. The risk of developing solid tumors appears to be
greatest in patients treated with RT,

104

and sarcomas usually occur within

the prior radiation field.70,72
The cumulative risk of developing
a bone sarcoma following treatment
for ES is estimated to be 20% at 20
years.9 Of the 397 patients with ES
treated at the Mayo Clinic during a
25-year period, 26 (6.5%) developed
29 secondary malignancies: 12 sarcomas, 8 hematologic malignancies,
and 9 carcinomas.72 The authors attributed sarcoma to RT and hematologic malignancy to chemotherapy.
The mean latent period for the development of sarcoma was 10.9 years
(range, 1.5 to 32.5 years) and for hematologic malignancy, 4.8 years
(range, 1.7 to 12.9 years). The prognosis with carcinoma was better than
with either sarcoma or hematologic
malignancy. A similar prevalence has
been reported by Kuttesch et al,70
who found a 6.5% incidence of secondary sarcoma within the irradiated field in ES patients at 20-year
follow-up. The incidence was dosedependent; patients who received
60 Gy had a 20% incidence of second malignancy. Those who received
a dose of 48 to 60 Gy had an incidence of 5%, and those who received
a dose of <48 Gy did not develop a
second malignancy.

Future and Novel

Therapies
Several insights have been made
regarding the biology of ESFT.
The most important may be the identification of the EWS/ETS gene rearrangement as the key event in
malignant transformation and the
development of the understanding of
the influence of this rearrangement
on the regulation of various pathways involved in cell proliferation,
differentiation, and apoptosis. These
insights have led to the identification
of potential targets for the development of new molecular therapeutics.

Some of the promising targets include insulin-like growth factor-1

and its receptors (ie, IGF-1/IGFR-1),
p53 pathway, CD99 expression, tyrosine kinase, mammalian target
of rapamycin (mTOR), mitogenactivated protein kinase (MAPK),
PI3K/Akt, epidermal growth factor
receptor (EGFR), platelet-derived
growth factor C (PDGFC), vascular
endothelial growth factor (VEGF),
and tumor necrosis factorrelated
apoptosis-inducing ligand.74 Inhibiting EWS/FLI1 expression with antisense oligodeoxynucleotides directed
to the fusion RNA or with shortinterfering RNA would significantly
reduce tumor growth in vitro and in
vivo.74 Whereas it is unlikely that
any of these specific therapeutics on
its own will be able to completely
eliminate ESFT, it is expected that
any of these agents in combination
with standard chemotherapy will
synergistically increase tumor kill
and decrease the development of resistance by interfering with different
pathways essential for tumor cell survival.

Summary
ESFT is a rare malignancy of unknown origin that most often affects
young children and adolescents. Because most patients with apparently
localized disease at diagnosis have
occult metastatic (systemic) disease,
multidrug chemotherapy as well as
local disease control with surgery
and/or RT is currently indicated for
all patients. Despite marked improvement in survival during the
past 40 years for patients with localized disease, improvements have
been relatively lesser in patients with
metastatic or recurrent disease. The
treatment plan must be individualized on the basis of tumor location,
stage, and size. An improved understanding of the complex biology of

Journal of the American Academy of Orthopaedic Surgeons

Aditya V. Maheshwari, MD, and Edward Y. Cheng, MD

ESFT may lead to the successful development of biologically targeted

therapies. As our understanding of
the regulatory pathway responsible
for ESFT transformation, growth,
and metastasis becomes more refined, the number of potential therapeutic targets will expand in parallel.

histogenesis. Cancer 1979;43:24382451.

5.

Jaffe R, Santamaria M, Yunis EJ, et al:

The neuroectodermal tumor of bone. Am
J Surg Pathol 1984;8:885-898.

6.

Ludwig JA: Ewing sarcoma: Historical

perspectives, current state-of-the-art, and
opportunities for targeted therapy in the
future. Curr Opin Oncol 2008;20:412418.

7.

Delattre O, Zucman J, Melot T, et al:

The Ewing family of tumors: A subgroup
of small-round-cell tumors defined by
specific chimeric transcripts. N Engl J
Med 1994;331:294-299.

8.

Grier HE: The Ewing family of tumors:

Ewings sarcoma and primitive
neuroectodermal tumors. Pediatr Clin
North Am 1997;44:991-1004.

9.

Tucker MA, DAngio GJ, Boice JD Jr,

et al: Bone sarcomas linked to
radiotherapy and chemotherapy in
children. N Engl J Med 1987;317:588593.

Acknowledgment
The authors would like to thank J.
Carlos Manivel, MD, and Michelle
Dolan, MD, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis,
Minnesota, for providing the histopathologic slides as well as the karyotype and fluorescence in situ hybridization images used in this
article.

References
Evidence-based Medicine: Levels of
evidence are described in the table of
contents. In this article, references 22
and 60 are level I studies. Level II
studies include references 7, 12, 1419, 23-25, 27, 29, 31-33, 38, 43, 44,
46, 48, 61, 66, and 68-74. Level III
studies include references 9, 13, 3437, 39-42, 47, 51, and 54-57.
References 28, 52, and 62-65 are level
IV studies. Level V studies include
references 5, 8, 10, 11, 21, 30, 45, 49,
50, 53, 59, and 67.
Citation numbers printed in bold type
indicate references published within
the past 5 years.
1.

Stout AP: A tumor of the ulnar nerve.

Proc NY Pathol Soc 1918;18:2-13.

2.

Ewing J: Diffuse endothelioma of bone.

Proc NY Pathol Soc 1921;21:17-24.

3.

Angervall L, Enzinger FM: Extraskeletal

neoplasm resembling Ewings sarcoma.
Cancer 1975;36:240-251.

4.

Askin FB, Rosai J, Sibley RK, Dehner

LP, McAlister WH: Malignant small cell
tumor of the thoracopulmonary region
in childhood: A distinctive clinicopathologic entity of uncertain

February 2010, Vol 18, No 2

10.

Gibbs CP Jr, Weber K, Scarborough MT:

Malignant bone tumors. Instr Course
Lect 2002;51:413-428.

end results data. J Pediatr Hematol

Oncol 2008;30:425-430.
18.

Dunst J, Jrgens H, Sauer R, et al:

Radiation therapy in Ewings sarcoma:
An update of the CESS 86 trial. Int J
Radiat Oncol Biol Phys 1995;32:919930.

19.

Dunst J, Schuck A: Role of radiotherapy

in Ewing tumors. Pediatr Blood Cancer
2004;42:465-470.

20.

Ozaki T, Hillmann A, Hoffmann C,

et al: Significance of surgical margin on
the prognosis of patients with Ewings
sarcoma: A report from the Cooperative
Ewings Sarcoma Study. Cancer 1996;78:
892-900.

21.

Ginsberg JP, Woo SY, Johnson ME,

Hicks MJ, Horowitz ME: Ewings
sarcoma family of tumors: Ewings
sarcoma of bone and soft tissue and the
peripheral primitive neuroectodermal
tumors, in Pizzo PA, Poplack DG, eds:
Principles and Practice of Pediatric
Oncology, ed 4. Philadelphia, PA,
Lippincott Williams and Wilkins, 2002,
pp 973-1016.

22.

Grier HE, Krailo MD, Tarbell NJ, et al:

Addition of ifosfamide and etoposide to
standard chemotherapy for Ewings
sarcoma and primitive neuroectodermal
tumor of bone. N Engl J Med 2003;348:
694-701.

23.

Kissane JM, Askin FB, Foulkes M,

Stratton LB, Shirley SF: Ewings sarcoma
of bone: Clinicopathologic aspects of
303 cases from the Intergroup Ewings
Sarcoma Study. Hum Pathol 1983;14:
773-779.

11.

Herzog CE: Overview of sarcomas in the

adolescent and young adult population.
J Pediatr Hematol Oncol 2005;27:215218. Medline

12.

Rodrguez-Galindo C, Navid F, Liu T,

Billups CA, Rao BN, Krasin MJ:
Prognostic factors for local and distant
control in Ewing sarcoma family of
tumors. Ann Oncol 2008;19:814-820.

13.

Rodriguez-Galindo C, Billups CA, Kun

LE, et al: Survival after recurrence of
Ewing tumors: The St. Jude Childrens
Research Hospital experience, 19791999. Cancer 2002;94:561-569.

24.

Paulussen M, Ahrens S, Dunst J, et al:

Localized Ewing tumor of bone: Final
results of the cooperative Ewings
Sarcoma Study CESS 86. J Clin Oncol
2001;19:1818-1829.

14.

Rodrguez-Galindo C, Liu T, Krasin MJ,

et al: Analysis of prognostic factors in
ewing sarcoma family of tumors: Review
of St. Jude Childrens Research Hospital
studies. Cancer 2007;110:375-384.

25.

Reinus WR, Gilula LA, IESS Committee:

Radiology of Ewings sarcoma:
Intergroup Ewings Sarcoma Study.
Radiographics 1984;4:929-944.

15.

Cotterill SJ, Ahrens S, Paulussen M,

et al: Prognostic factors in Ewings tumor
of bone: Analysis of 975 patients from
the European Intergroup Cooperative
Ewings Sarcoma Study Group. J Clin
Oncol 2000;18:3108-3114.

26.

Green DM: Diagnosis and Management

of Malignant Solid Tumors in Infants
and Children. Boston, MA, Martinus
Nijhoff Publishing, 1985.

27.

Pritchard DJ, Dahlin DC, Dauphine RT,

Taylor WF, Beabout JW: Ewings
sarcoma: A clinicopathological and
statistical analysis of patients surviving
five years or longer. J Bone Joint Surg
Am 1975;57:10-16.

28.

Widhe B, Widhe T: Initial symptoms and

clinical features in osteosarcoma and
Ewing sarcoma. J Bone Joint Surg Am
2000;82:667-674.

29.

Bacci G, Balladelli A, Forni C, et al:

Ewings sarcoma family tumours:
Differences in clinicopathological
characteristics at presentation between

16.

17.

Gurney JG, Swensen AR, Bulterys M:

Malignant bone tumors, in Ries LA,
Smith MA, Gurney JG, et al, eds: Cancer
Incidence and Survival Among Children
and Adolescents: United States SEER
Program 1975-1995. Bethesda, MD,
National Institutes of Health, 1999, pp
99-110.
Esiashvili N, Goodman M, Marcus RB
Jr: Changes in incidence and survival of
Ewing sarcoma patients over the past 3
decades: Surveillance epidemiology and

105

Ewing Sarcoma Family of Tumors

localised and metastatic tumours. J Bone
Joint Surg Br 2007;89:1229-1233.
30.

van der Woude HJ, Bloem JL,

Hogendoorn PC: Preoperative evaluation
and monitoring chemotherapy in
patients with high-grade osteogenic and
Ewings sarcoma: Review of current
imaging modalities. Skeletal Radiol
1998;27:57-71.

41.

31.

Greene FL: Musculoskeletal sites, in Page

DL, Fleming ID, Fritz AG, Balch CM,
Haller DG, Morrow M, eds: AJCC
Cancer Staging Manual, ed 6. New York,
NY, Springer, 2002, pp 185-200.

42.

32.

Enneking WF, Spanier SS, Goodman

MA: A system for the surgical staging of
musculoskeletal sarcoma. Clin Orthop
Relat Res 1980;153:106-120.

33.

34.

35.

36.

37.

38.

39.

Sebire NJ, Gibson S, Rampling D,

Williams S, Malone M, Ramsay AD:
Immunohistochemical findings in
embryonal small round cell tumors with
molecular diagnostic confirmation. Appl
Immunohistochem Mol Morphol 2005;
13:1-5.

Bridge RS, Rajaram V, Dehner LP,

Pfeifer JD, Perry A: Molecular diagnosis
of Ewing sarcoma/primitive
neuroectodermal tumor in routinely
processed tissue: A comparison of two
FISH strategies and RT-PCR in
malignant round cell tumors. Mod
Pathol 2006;19:1-8.
Thorner P, Squire J, Chilton-MacNeil S,
et al: Is the EWS/FLI-1 fusion transcript
specific for Ewing sarcoma and
peripheral primitive neuroectodermal
tumor? A report of four cases showing
this transcript in a wider range of tumor
types. Am J Pathol 1996;148:11251138.
Ladanyi M, Gerald W: Fusion of the
EWS and WT1 genes in the desmoplastic
small round cell tumor. Cancer Res
1994;54:2837-2840.
Zucman J, Delattre O, Desmaze C, et al:
EWS and ATF-1 gene fusion induced by
t(12;22) translocation in malignant
melanoma of soft parts. Nat Genet
1993;4:341-345.

40. Bacci G, Ferrari S, Longhi A, et al: Role

of surgery in local treatment of Ewings
sarcoma of the extremities in patients
undergoing adjuvant and neoadjuvant

106

43.

44.

Lin PP, Brody RI, Hamelin AC, Bradner

JE, Healey JH, Ladanyi M: Differential
transactivation by alternative EWS-FLI1
fusion proteins correlates with clinical
heterogeneity in Ewings sarcoma.
Cancer Res 1999;59:1428-1432.
Urano F, Umezawa A, Yabe H, et al:
Molecular analysis of Ewings sarcoma:
Another fusion gene, EWS-E1AF,
available for diagnosis. Jpn J Cancer Res
1998;89:703-711.

INK4a alteration for Ewing sarcoma: A

meta-analysis. Cancer 2007;110:13511360.

chemotherapy. Oncol Rep 2004;11:111120.

45.

46.

Bacci G, Forni C, Longhi A, et al: Longterm outcome for patients with nonmetastatic Ewings sarcoma treated with
adjuvant and neoadjuvant
chemotherapies: 402 patients treated at
Rizzoli between 1972 and 1992. Eur J
Cancer 2004;40:73-83.

52.

Schleiermacher G, Peter M, Oberlin O,

et al: Increased risk of systemic relapses
associated with bone marrow
micrometastasis and circulating tumor
cells in localized ewing tumor. J Clin
Oncol 2003;21:85-91.

53.

Hawkins DS, Schuetze SM, Butrynski JE,

et al: [18F]Fluorodeoxyglucose positron
emission tomography predicts outcome
for Ewing sarcoma family of tumors.
J Clin Oncol 2005;23:8828-8834.

54.

Sluga M, Windhager R, Lang S, et al:

The role of surgery and resection
margins in the treatment of Ewings
sarcoma. Clin Orthop Relat Res 2001;
392:394-399.

55.

Renard AJ, Veth RP, Schreuder HW, van

Loon CJ, Koops HS, van Horn JR:
Function and complications after
ablative and limb-salvage therapy in
lower extremity sarcoma of bone. J Surg
Oncol 2000;73:198-205.

56.

Thacker MM, Temple HT, Scully SP:

Current treatment for Ewings sarcoma.
Expert Rev Anticancer Ther 2005;5:319331.

57.

Rodriguez-Galindo C, Spunt SL, Pappo

AS: Treatment of Ewing sarcoma family
of tumors: current status and outlook for
the future. Med Pediatr Oncol 2003;40:
276-287.

Donaldson SS: Ewing sarcoma:

Radiation dose and target volume.
Pediatr Blood Cancer 2004;42:471-476.

58.

Oberlin O, Deley MC, Bui BN, et al:

Prognostic factors in localized Ewings
tumours and peripheral neuroectodermal
tumours: The third study of the French
Society of Paediatric Oncology (EW88
study). Br J Cancer 2001;85:1646-1654.

Bolek TW, Marcus RB Jr, Mendenhall

NP, Scarborough MT, Graham-Pole J:
Local control and functional results after
twice-daily radiotherapy for Ewings
sarcoma of the extremities. Int J Radiat
Oncol Biol Phys 1996;35:687-692.

59.

Paulino AC: Late effects of radiotherapy

for pediatric extremity sarcomas. Int J
Radiat Oncol Biol Phys 2004;60:265274.

60.

Pritchard DJ: Indications for surgical

treatment of localized Ewings sarcoma
of bone. Clin Orthop Relat Res 1980;
153:39-43.

61.

DuBois SG, Krailo MD, Cook EF, et al:

Abstract: Evaluation of local control in
patients with non-metastatic Ewing
sarcoma of bone: A report from the
Childrens Oncology Group. J Clin
Oncol 2007;25(Jun 20 suppl):10013.
Available at: http://www.asco.org/
ASCOv2/Meetings/
Abstracts?&vmview=abst_detail_view&
confID=47&abstractID=31798.
Accessed September 16, 2009.

62.

Dunst J, Hoffmann C, Ahrens S, Jrgens

H: Surgery versus radiotherapy in
Ewings sarcoma with good prognosis:
Analysis of the CESS-86 data [German].
Strahlenther Onkol 1996;172:244-249.

63.

Ullmann C, Beck JD, Holter W, et al:

Long-term results following
multidisciplinary treatment of localized

Bacci G, Longhi A, Ferrari S, et al:

Pattern of relapse in 290 patients with
nonmetastatic Ewings sarcoma family
tumors treated at a single institution
with adjuvant and neoadjuvant
chemotherapy between 1972 and 1999.
Eur J Surg Oncol 2006;32:974-979.
Bacci G, Longhi A, Ferrari S, Mercuri M,
Versari M, Bertoni F: Prognostic factors
in non-metastatic Ewings sarcoma
tumor of bone: An analysis of 579
patients treated at a single institution
with adjuvant or neoadjuvant
chemotherapy between 1972 and 1998.
Acta Oncol 2006;45:469-475.
Ahrens S, Hoffmann C, Jabar S, et al:
Evaluation of prognostic factors in a
tumor volume-adapted treatment
strategy for localized Ewing sarcoma of
bone: The CESS 86 experience.
Cooperative Ewing Sarcoma Study. Med
Pediatr Oncol 1999;32:186-195.

47.

Abudu A, Mangham DC, Reynolds GM,

et al: Overexpression of p53 protein in
primary Ewings sarcoma of bone:
relationship to tumour stage, response
and prognosis. Br J Cancer 1999;79:
1185-1189.

48.

Amir G, Issakov J, Meller I, et al:

Expression of p53 gene product and cell
proliferation marker Ki-67 in Ewings
sarcoma: Correlation with clinical
outcome. Hum Pathol 2002;33:170-174.

49.

Ohali A, Avigad S, Cohen IJ, et al:

Association between telomerase activity
and outcome in patients with
nonmetastatic Ewing family of tumors.
J Clin Oncol 2003;21:3836-3843.

50.

Ozaki T, Paulussen M, Poremba C, et al:

Genetic imbalances revealed by
comparative genomic hybridization in
Ewing tumors. Genes Chromosomes
Cancer 2001;32:164-171.

51.

Honoki K, Stojanovski E, McEvoy M,

et al: Prognostic significance of p16

Journal of the American Academy of Orthopaedic Surgeons

Aditya V. Maheshwari, MD, and Edward Y. Cheng, MD

Ewings sarcoma in children and
adolescents [German]. Strahlenther
Onkol 2008;184:137-144.
64. McTiernan A, Driver D, Michelagnoli
MP, Kilby AM, Whelan JS: High dose
chemotherapy with bone marrow or
peripheral stem cell rescue is an effective
treatment option for patients with
relapsed or progressive Ewings sarcoma
family of tumours. Ann Oncol 2006;17:
1301-1305.
65.

Meyers PA, Krailo MD, Ladanyi M,

et al: High-dose melphalan, etoposide,
total-body irradiation, and autologous
stem-cell reconstitution as consolidation
therapy for high-risk Ewings sarcoma
does not improve prognosis. J Clin
Oncol 2001;19:2812-2820.

66.

Riggi N, Stamenkovic I: The biology of

Ewing sarcoma. Cancer Lett 2007;254:
1-10.

67.

Miser JS, Krailo MD, Tarbell NJ, et al:

Treatment of metastatic Ewings sarcoma
or primitive neuroectodermal tumor of

February 2010, Vol 18, No 2

68.

69.

70.

bone: Evaluation of combination

ifosfamide and etoposide. A Childrens
Cancer Group and Pediatric Oncology
Group study. J Clin Oncol 2004;22:
2873-2876.

71.

Dunst J, Ahrens S, Paulussen M, et al:

Second malignancies after treatment for
Ewings sarcoma: A report of the CESSstudies. Int J Radiat Oncol Biol Phys
1998;42:379-384.

Burdach S, van Kaick B, Laws HJ, et al:

Allogeneic and autologous stem-cell
transplantation in advanced Ewing
tumors: An update after long-term
follow-up from two centers of the
European Intergroup study EICESS.
Stem-Cell Transplant Programs at
Dsseldorf University Medical Center,
Germany and St. Anna Kinderspital,
Vienna, Austria. Ann Oncol 2000;11:
1451-1462.

72.

Fuchs B, Valenzuela RG, Petersen IA,

Arndt CA, Sim FH: Ewings sarcoma and
the development of secondary
malignancies. Clin Orthop Relat Res
2003;415:82-89.

73.

Bhatia S, Krailo MD, Chen Z, et al:

Therapy-related myelodysplasia and
acute myeloid leukemia after Ewing
sarcoma and primitive neuroectodermal
tumor of bone: A report from the
Childrens Oncology Group. Blood
2007;109:46-51.

74.

Kontny U: Regulation of apoptosis and

proliferation in Ewings sarcoma:
Opportunities for targeted therapy.
Hematol Oncol 2006;24:14-21.

Wagner LM, McAllister N, Goldsby RE,

et al: Temozolomide and intravenous
irinotecan for treatment of advanced
Ewing sarcoma. Pediatr Blood Cancer
2007;48:132-139.
Kuttesch JF Jr , Wexler LH, Marcus RB,
et al: Second malignancies after Ewings
sarcoma: Radiation dose-dependency of
secondary sarcomas. J Clin Oncol 1996;
14:2818-2825.

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