Ewing sarcoma: current concepts in diagnosis

and treatment
John G. Kennedy, MD, FRCSI, Peter Frelinghuysen, MD, and Bang H. Hoang, MD

Orthopaedic Surgery Service, Department of Surgery, Memorial Sloan-Kettering

Cancer Center, New York, New York, USA. Affiliated with Weill Medical College of
Cornell University.
Address all correspondence to Bang H. Hoang, MD Orthopaedic Surgery Service,
Suite A342, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New
York, NY 10021, USA; e-mail: bhoang@pol.net
Current Opinion in Pediatrics 2003, 15:5357
Abbreviations
PNET

primitive neuroectodermal tumor

ISSN 10408703 2003 Lippincott Williams & Wilkins, Inc.

Ewing sarcoma (ES) accounts for about 1% of all childhood tumors, yet it is the second most common primary
malignant bone tumor, second only to osteosarcoma. The
annual incidence of this disease is approximately 3 new
cases per 1,000,000 Caucasians under the age of 21 years
in the United States. The incidence amongst those of
other race is significantly less [1].
Historically, the prognosis for patients with a diagnosis of
Ewing sarcoma was poor. However, with newer chemotherapeutic strategies, combined with selective surgery,
outcome has improved with overall survival approaching
80%. As the disease is systemic in nature, many patients
have micrometastases at presentation. These micrometastases have been targeted by chemotherapy drugs, thus
improving survival. Those patients, however, who have
recognized multiple metastases at presentation or who
have a recurrence continue to have a poor prognosis. It is
this group of patients that newer generation treatment
strategies will focus on.

Molecular characterization
Ewing sarcoma is characterized by the translocation t (11;
22) (q24; q12) in up to 85% of cases. Chromosomal translocations, identified by polymerase chain reaction, are
becoming increasingly important not only in identifying
fusion proteins, but also by aiding in differentiating Ewing sarcoma from other tumors, including childhood neuroblastoma. In addition, with modern molecular cytogenetics, translocations are proving to be of prognostic
significance. The primary genetic alteration in Ewing
sarcoma is a specific fusion of EWS with the ETS transcription factor FLI1 (90%95%) or ERG (5%10%).
Differences in the location of the translocation breakpoints result in the insertion of different combinations of
exons from EWS and FLI1 or ERG in the final fusion
product. The most common type of EWS-FLI1 fusion

transcript, type 1, has been shown to be associated with

a favorable prognosis independent of tumor size, site, or
stage [2].
Secondary genetic alterations in Ewing sarcoma have
also been studied as to their prognostic significance. Although the tumor suppressor gene P53 is found rarely in
patients with ES, this particular alteration is associated
with a poor prognosis. In addition, recent work has established that there may be a correlation between P53
and the cell proliferation nuclear antigen Ki-67 [3]. Both
markers have been found to be associated with a poorer
outcome in ES when present. The most frequent secondary molecular genetic alteration found to date in ES
is the INK4A deletion [4]. Although there is no clear role
defined yet by the presence of this genetic alteration,
clinical trials are ongoing to establish the usefulness of
this exciting genetic marker.
HER2/Neu gene expression has been seen in breast and
other cancers; however, it has not been found conclusively to be involved in Ewing sarcoma, although some
investigators believe it be present in some osteogenic
sarcomas. As such, recent enthusiasm for monoclonal antibody therapy in patients with refractory ES must be
tempered with caution [5].

Location
Ewing sarcoma is found most frequently in the diaphysis
of long bones. The femur is the most common location
followed by the tibia, humerus, and fibula bones. The
pelvis is the next most common site, which can give rise
to an insidious delayed presentation with a poor prognosis [6]. The ribs, vertebrae, scapula, and clavicle can also
be involved. Extraskeletal Ewing sarcoma is rare;
however, it can be found in most soft-tissue parts of the
body [7].

Pathology and laboratory studies

At present, Ewing sarcoma is regarded as a member of
the primitive neuroectodermal tumor (PNET) family.
The gross pathologic description of Ewing sarcoma is
one of a soft grey/ white mass with areas of hemorrhage
and necrosis. The degree of necrosis is an important
prognostic indicator following resection after neoadjuvant chemotherapy [8].
Ewing sarcoma is a small round cell tumor and as such
requires differentiation from other similar round cell tu53

54 Orthopedics

mors (Fig. 1). In children, these include neuroblastoma,

rhabdomyosarcoma, histiocytosis, small cell osteosarcoma, and osteomyelitis. In adults, it must be differentiated from lymphoma, multiple myeloma, and small cell
cancer of the lung. The histopathologic picture is one of
monotonous round cells with small hyperchromatic nuclei and a complete absence of intracellular material. Cytoplasm is sparse and the nuclei are large in comparison.
Intracellular accumulation of glycogen in Ewing sarcoma
confers a positive acid-Schiff test on these cells. The
diagnosis of Ewing sarcoma has to date largely been one
of clinical and radiologic suspicion confirmed by biopsy.
Recent work has been encouraging using fine-needle aspiration (FNA) and immunohistochemistry in the primary and recurrent diagnosis of ES [9]. Typical immunohistochemical markers used in the diagnosis of Ewing
include MIC2, NFP, Vimentin, and HBA-71. The advantages of FNA are that the procedure is rapid, accurate, and relatively atraumatic. It may also prevent gross
biopsy error that can occur with conventional intralesional biopsy, compromising both the oncological and
functional end result [10]. More work will need to be
done confirming this method of diagnosis as accurate
with low sampling error before it can be uniformly
adopted.
Laboratory studies used in the diagnosis of Ewing sarcoma and in the evaluation of treatment include an elevated lactate dehydrogenase (LDH) and alkaline phosphatase. A fall in the level of LDH is a useful indicator
of the efficacy of the chemotherapeutic regimen. The
LDH level is especially useful as a marker of recurrent
disease [11].

Clinical and radiographic presentation

The clinical presentation of a child with Ewing sarcoma
is one usually of pain and swelling about the affected
limb, with mild or moderate erythema. This may mimic
a playground trauma, and often it is an incidental trauma
that may lead to the ultimate diagnosis. Occasionally
(1015%) a pathologic fracture, typically of the femur,
will lead to the diagnosis [12]. Children may also display
systemic symptoms, including pyrexia and loss of energy.
In those cases where the tumor is in the pelvis, symptoms and signs will be delayed. These patients typically
present with gait abnormalities from root compression,
bowel or bladder dysfunction, or back pain [13].
The radiographic features of ES are of a metadiaphyseal
or diaphyseal lesion in long bones. Typically the lesion
will show the periosteal reaction of a rapidly expanding
tumor (Fig. 2). The Codmans triangle, not exclusive to
ES, is also a valuable diagnostic radiographic sign. The
lesion is typically poorly marginated with permeative
pattern of osteolysis. The host bone will often show cortical erosion, and often a soft-tissue extension can be
visualized on plain radiograph. This is best appreciated
on magnetic resonance imaging (MRI) where the true
nature of the large soft-tissue component of this tumor is
seen (Fig. 3). Magnetic resonance imaging is also a useful
tool in establishing the true extent of marrow infiltration
of the lesion that may not be appreciated on plain radiograph (Fig. 4).
Other imaging modalities used in the initial staging and
in follow-up posttreatment in Ewing sarcoma include
bone scan and chest computed tomography. Recent

Figure 1. Histologic features of Ewing sarcoma

Ewing sarcoma is composed of small round cells with little
or no identifiable matrix. Under high magnification,
homogenous cells with uniform nuclei are typical cytologic
features of this tumor.

Ewing sarcoma: diagnosis and treatment Kennedy et al. 55

Figure 2. Plain radiograph of Ewing sarcoma

Ewing sarcoma of the distal fibula showing abundant periosteal reaction (arrow).

work has suggested that a triple-phase bone scan may be

more advantageous and sensitive than the standard
single-phase scan used in most institutions [14,15]. This
is particularly so when evaluating the soft-tissue component of Ewing sarcomas, which would have been missed
if only the delayed bone scan had been performed.

Treatment
Treatment of Ewing sarcoma has evolved so that patients can now expect 60%80% survival when presenting as a nonmetastatic, nonrecurrent disease. The introFigure 3. The utility of MRI in Ewing sarcoma
Axial T1- (A) and T2-weighted (B) MRI of the distal fibula
demonstrating a large soft-tissue mass associated with
Ewing sarcoma in this location.

duction of chemotherapeutic agents supplanted previous

radiotherapy and amputation that were ineffective in
prolonging survival. Currently, treatment strategies for
Ewing sarcoma combine neoadjuvant chemotherapy
with surgical resection followed by adjuvant chemotherapy. The role of radiotherapy is controversial, and
many centers reserve its use for patients with positive or
close margins following local resection.
At present in the United States, the Childrens Oncology
Group coordinates the chemotherapy protocols administered around the country. Most drug regimens include
combinations of the following drugs: doxorubicin, actinomycin, dactinomycin, cyclophosphamide, and vincristine. The introduction of ifosfamide into this chemotherapy protocol was prompted by a comparative study
conducted using two treatment groups. Those patients
in the first group received vincristine, actinomycin, cyclophosphamide, and doxorubicin. Those patients in the
alternate arm of the study received the same drugs in
addition to ifosfamide. The overall 3-year survival for
patients who received ifosfamide was 80% as compared
with 56% 3-year survival for those patients who received
the VAC/Dox combination alone. Additional studies by
the Intergroup Ewing Sarcoma Study Group have shown
that the 5-year event-free survival of patients with Ewing
or Ewing family of tumors could be increased with the
addition of ifosfamide and etoposide. In a study of 54
newly diagnosed patients treated with vincristine, doxorubicin, and cyclophosphamide, the 5-year event-free
survival was 45%. In the group treated with the addition
of ifosfamide and etoposide, this figure increased to 64%
[16]. In those patients regarded as poor risk due to large
tumor volume, high-dose cyclophosphamide, doxorubicin, and vincristine given in a seven-course regimen has
proved to give excellent anti-tumor toxicity in these previously poor responders [17]. In those patients who did
not respond well to first-line chemotherapeutic modalities or who experienced a recurrence, the 5-year survival
rates have been poor. A recent study on patients with

56 Orthopedics
Figure 4. Marrow involvement in Ewing sarcoma

Sagittal T1- (A) and T2-weighted (B) MRI reveal the extent of marrow infiltration
with Ewing sarcoma of the tibial diaphysis.

recurrent disease from St. Jude Childrens Research

Hospital demonstrated 17% 5-year postrecurrence survival [18]. However, patients with relapse more than
2 years after diagnosis had significantly better outcome.
Also, patients with local recurrence alone fared better than patients with both local and distant recurrences.
In this study, lung irradiation appeared to improve
outcomes of patients with isolated pulmonary metastasis [18].
Recent work using Irinotecan, an antineoplastic agent
that works by inhibiting topoisomerase, has been encouraging. In a study of pretreated solid tumors that had
relapsed, Irinotecan appeared to have promising singleagent activity. This drug is currently being used in cases
of recurrence in combination with other active chemotherapeutic agents and has promise for the future [19].
Recent work on insulin-like growth factor (IGF) receptors has shown that they play an essential role in the
pathogenesis of ES. In a multicenter trial using IGF1
receptor antisense agents in nude mice, investigators
have demonstrated that survival was increased and that
tumor formation was delayed compared with those mice
not treated with the IGF1 antisense agent. In addition, it
was shown that inhibiting IGF1 receptors enhanced the
sensitivity of tumor cells to doxorubicin [20]. IGF1 receptor antisense agents may have a future role in treatment strategies in patients with ES, both by reducing the
malignant potential of the sarcoma and by augmenting
conventional chemotherapeutic agents.
Radiation to the primary tumor in patients with ES has
had reported rates of up to 90% local control, particularly

for distal extremity lesions. The rate decreases for more

axial and larger lesions. Radiation alone has theoretical
advantages, the most important being the reduction of
surgical mortality. Problems associated with radiation,
however, include growth arrest, pathologic fractures, and
radiation-induced sarcomas. Wagner et al. [12] report that
64% of fractures occurring in patients with ES occurred
following radiation. The authors caution that when fractures do occur following high-dose radiotherapy, a recurrence or a second malignancy must be suspected.
In an effort to control for adverse effects of high-dose
radiation, surgical resection and low dose radiation have
been investigated as a means of achieving local control.
Merchant et al. [21] investigated 25 patients using a median irradiation dose to the primary site of 30 Gy. In this
study cohort, no patients had a local recurrence. Twentyfive percent of patients progressed from established metastases, and 25% of patients had a distal recurrence.
Despite that, however, the investigators found that lowdose radiation is effective in controlling local recurrence
when combined with wide surgical resection and that
few complications were experienced.
The ideal interval between surgical resection and commencement of radiotherapy has not been fully established. Early postsurgical radiotherapy must be evaluated against cell turnover and wound healing. In a study
of 153 patients who had radiotherapy prior to and following the 60th postoperative day, Schuck et al. found that
there was no difference in event-free survival between
the two groups at 5 years [22]. In this study, a trend was
seen, however, for improved local control in those patients treated with early onset radiotherapy.
The impact of wide surgical margins on survival in patients with ES has been considerable. Advanced diagnostic investigative methods including 3D computed tomography and MRI now allow the establishment of
precise resection margins preoperatively. In a study of
86 patients with ES, the 5-year overall survival for those
patients treated with wide or radical resection was 60% as
compared with 40% for those patients treated with marginal or intralesional resection [23]. Better diagnostic
imaging is also helping establish resection margins
following induction chemotherapy, where the soft-tissue
component of ES may have diminished greatly in
size. This may facilitate limb-sparing resection and improve long-term function without compromising local
recurrence.
At present, the value of stem cell transplant in the treatment of ES has not been fully established. High-dose
chemotherapy supported by autologous stem cell transplants has shown encouraging results; however, there is
some concern about long-term treatment outcomes, particularly secondary malignancies [24,25]. This may tem-

Ewing sarcoma: diagnosis and treatment Kennedy et al. 57

per the use of stem cell transplantation in the current

format.
Limb salvage surgery is now the primary goal, once the
tumor has been removed, of the orthopaedic oncologist.
Newer designs, coupled with modularity of components,
are increasing the durability and function of contemporary endoprosthesis [26]. The decision for limb-sparing
surgery is still dependent, however, on the stage of the
tumor, the feasibility of obtaining a wide margin, and the
tumors response to neoadjuvant treatment.

Prognostic indicators
Prognostic indicators in ES are both laboratory based and
clinical. The EWS-FLI1 fusion transcript has been
shown by multivariate analysis to be a true predictor of
overall survival. In a study of 99 patients in whom identification of the fusion transcript could be performed,
those patients with a type 1 fusion had fewer metastases
and longer survival times than those patients with less
common fusion types. This prognostic indicator appears
to be independent of clinical factors including tumor site
and size [27]. Recent work has also established that there
may be a correlation between P53 and the cell proliferation nuclear antigen Ki-67 [3]. Both markers have been
found to be associated with a poorer outcome in ES
when present, and continued investigation is needed to
establish their role as prognostic markers. Clinical prognostic indicators include the histologic response to chemotherapy and the size of the primary tumor. Wunder
et al. [8] studied a series of 74 patients with ES treated
with pre- and postoperative chemotherapy with and
without radiation following operative resection. The
event-free survival at 5 years for patients with grade I
response was zero and for patients with grade III or IV
response was 84%, clearly implicating the histologic response to chemotherapy as a significant prognostic indicator.

Conclusion
The overall survival for patients with Ewing sarcoma has
improved significantly over the past 20 years. Continued
advances in molecular and genetic analysis, diagnostic
imaging as well as chemo- and radiotherapy will undoubtedly make current survival figures redundant in
the coming years.

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Wagner LM, Neel MD, Pappo AS, et al.: Fractures in pediatric Ewing sarcoma. J Pediatr Hematol Oncol 2001, 23:568571.

13

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14

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15

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16

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17

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18

Cosetti M, Wexler LH, Calleja E, et al.: Irinotecan for pediatric solid tumors:
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Irinotecan promising single-agent activity against solid tumors, particularly rhabdomyosarcoma and its tolerability, warranted further investigation of this agent.
19

Toretsky JA, Steinberg SM, Thakar M, et al.: Insulin-like growth factor type 1
(IGF-1) and IGF binding protein-3 in patients with Ewing sarcoma family of
tumors. Cancer 2001, 92:29412947.
IGF-1 level was significantly lower in patients with bone or bone marrow metastasis
when compared with patients without metastasis. There was a trend toward better
survival in patients with a high IGFBP-3 to IGF-1 ratio.
20

21

Merchant TE, Kushner BH, Sheldon JM, et al.: Effect of low-dose radiation
therapy when combined with surgical resection for Ewing sarcoma. Med Pediatr Oncol 1999, 33:6570.

22

Schuck A, Rube C, Konemann S, et al.: Postoperative radiotherapy in the

treatment of Ewing tumors: influence of the interval between surgery and
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References and recommended reading

23

Papers of particular interest, published within the annual period of review,

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Of special interest

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margins in the treatment of Ewing sarcoma. Clin Orthop 2001, 392:394
399.

24

Krishnan A, Bhatia S, Slovak ML, et al.: Predictors of therapy-related leukemia

and myelodysplasia following autologous transplantation for lymphoma: an
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Gou W, Xu W, Huvos AG, et al.: Comparative frequency of bone sarcomas

among different racial groups. Chin Med J (Engl) 1999, 112:11011104.

25

De Avala E, Panizo A, Antonescu CR, et al.: Association of EWS-FLI1 type 1

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Park S, Brice P, Noguerra ME, et al.: Myelodysplasias and leukemias after

autologous stem cell transplantation for lymphoid malignancies. Bone Marrow Transplant 2000, 26:321326.

26

Kawai A, Healey JH, Boland PJ, et al.: A rotating-hinge knee replacement for
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27

De Alava E, Kawai A, Healey JH, et al.: EWS-FLI1 transcript structure is an

independent determinant of prognosis in Ewings sarcoma. J Clin Oncol
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Amir G, Issakov J, Meller I, et al.: Expression of p53 gene product and cell
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