MINI-SYMPOSIUM: MALIGNANT BONE TUMOURS: SPECIFIC TUMOURS
(iii) Ewing’s sarcoma of bone
Fabrice Fiorenza
Lee Jeys
Abstract
Ewing’s sarcoma is a primitive malignant bone tumour consisting of small,
blue, round malignant cells that may show varying degrees of neural
differentiation. It accounts for approximately 5% of all malignant bone
tumours and arises most frequently in children or adolescents. Despite
significant progress with the use of intensive multiagent chemotherapy
and local control measures (survival rates have increased from 10e15%
to 65e70% in the last 40 years), a significant proportion of patients
still die of disease progression. Clinical and biological prognostic factors
should be used to guide the therapeutic choices for each patient. The
treatment of Ewing’s sarcoma of bone is currently based on combined
therapy with neoadjuvant chemotherapy, radiation therapy and surgical
resection of the primary tumour. Survival in primary metastatic Ewing’s
sarcoma is poor (less than 30%) and new therapies are needed for
these patients.
Keywords bone tumours; Ewing’s tumour; sarcoma
Introduction
Ewing’s sarcoma is a primitive malignant bone tumour reported
by Ewing in 1921.1 It is composed of small round cells corre-
sponding to the poorly differentiated form of a Primitive Neu-
roectodermal Tumour (PNET). It arises in bone marrow or soft
tissue (when in the chest wall, it is called the Askin tumour).
Ewing’s sarcoma belongs to the group of PNET and therefore
presents several common features: overexpression of the gene
MIC22 and a t(11;22) (q24;q12) chromosomal translocation with
a fusion transcript involving the EWS-FLI-1 or EWS-ERG
genes.3,4 This particular feature has the ability to induce the
growth factor IGF1 and transform normal mesenchymal cells into
cancer cells. Ewing’s sarcoma accounts for approximately 5% of
malignant bone tumours. It is the fourth most common primary
bone tumour following myeloma, osteosarcoma and chon-
drosarcoma. It is rare in patients younger than 5 or older than 30
and the highest frequency of this malignancy occurs in patients
between 10 and 15 years old.5,6 It is the most common malignant
bone tumour in children. Ewing’s sarcoma is more frequent in
males than females (3:2) and is rare in Blacks and Asians.
Fabrice Fiorenza MD Consultant Orthopaedic Surgeon at the Dupuytren
Teaching Hospital, Department of Orthopaedics and Trauma, Limoges
cedex, France.
Lee Jeys MB ChB MSc(Orth Eng) FRCS(Tr & Orth) Consultant Orthopaedic
Oncologist at the Royal Orthopaedic Hospital, The Royal Orthopaedic
Hospital Oncology service NHS Foundation Trust, Northfield,
Birmingham, UK.
ORTHOPAEDICS AND TRAUMA 24:5
Skeletal distribution
The long bones and the pelvis are most commonly affected.5 The
femur is affected in 20e27% of tumours, the tibia and fibula in
15e23% and the humerus in 8e11%. Lesions are classically
located in the diaphysis of long bones but can be meta-
physealeepiphyseal with almost equal frequency. The pelvic
girdle accounts for 20e26% of the tumours and the ribs 7e11%.
Any portion of any bone can be affected but epiphyseal location of
long bones, hand, foot, skull, sternum or ulna is rarely reported.
Symptoms
Localized pain as well as local warmth, inflammation and
swelling are common clinical findings. Most patients complain of
pain months before the development of an obvious swelling.
Pathological fracture may rarely occur.
Systemic symptoms such as fever, malaise and weight loss are
common. Location-specific symptoms are possible and include
pleural effusion (rib lesion) and neurologic symptoms (cauda
equina, lumbo-sacral plexus compression) with involvement of
the spine or pelvis.
Investigations
Blood tests
- ESR and LDH are often increased.
- Occasionally anaemia and leukocytosis are discovered on
full blood count.
Imaging
Plain films: radiographs typically reveal the aggressive nature of
the tumour with osteolysis, cortical destruction, periosteal reac-
tion and a soft tissue mass (Figure 1):
 The bone destruction is usually diffuse and permeative: moth-
eaten bone destruction with poorly defined margins.
 The periosteal reaction is often florid with multiple layers of
new bone (onion skinning periosteal response). The perios-
teal reaction may also, less frequently, be spiculated
(“sunburst”).
 Pure osteolysis, pathologic fracture and osseous expansion
are uncommon.
 A large soft tissue mass (>5 cm) with ill-defined borders and
no calcification is often associated. Rarely, the bone lesion is
very difficult to see and the soft tissue mass can be the
predominant radiographic finding.
Bone scan and chest CT: these investigations are necessary for
systemic staging in order to detect metastatic disease.
MRI scan: MRI is the best tool for staging the extent of local and
regional disease. It shows the extent of intraosseous and soft
tissue involvement (bone marrow, vascular, nerve involvement)
(Figures 2 and 3).
PET scan: recent reports show interest in staging and chemo-
therapy efficiency assessment.7,8
The role of PET scan with or without MRI scan in the
assessment of tumour response to chemotherapy is still being
evaluated.9,10
342 Ó 2010 Elsevier Ltd. All rights reserved.
 MINI-SYMPOSIUM: MALIGNANT BONE TUMOURS: SPECIFIC TUMOURS
Figure 1 Ewing’s sarcoma of the proximal humerus in a 12-year-old girl
with pathological fracture showing a permeative lytic lesion with perios-
teal elevation and soft tissue extension.
Differential diagnosis
 Osteomyelitis (which has a similar presentation with pain,
fever, elevated WBC count and ESR, and can also involve the
diaphysis and metaphysis)
Figure 2 MRI scans of the same patient showing osteolysis and a soft
tissue mass with haemorrhage related to the fracture.
ORTHOPAEDICS AND TRAUMA 24:5
Figure 3 MRI scans of the same patient showing osteolysis and a soft
tissue mass with haemorrhage related to the fracture.
 Lymphoma
 Osteosarcoma
 Eosinophilic granuloma
 Malignant fibrous histiocytoma and fibrosarcoma
Pathology
Macroscopically a soft whitish-grey tissue is observed. Cortical
breakthrough with a soft tissue component is quite frequent. This
soft tissue component is soft and crumbly, with necrotic, hae-
morrhagic and cystic areas.
Histopathologically, the typical form of Ewing’s sarcoma is
characterized by broad sheets of small round cells separated by
septae of fibrous tissue. Cells may contain glycogen. A well
developed vascular network is often present. There is no osteoid
or chondroid production by tumour cells.
On immunohistochemistry, tumour cells show CD99 immu-
noreactivity and the use of antibodies to detect the MIC2 gene
product is a valuable tool for diagnosing Ewing’s sarcoma and
related tumours.11,12
Cytogenetic analysis of Ewing’s sarcoma demonstrates a consis-
tent primary chromosome abnormality: the reciprocal translocation
t(11;22) (q24;q12).13 Consistent translocations resulting in chimeric
proteins are found in most cases of Ewing’s and molecular analysis
of these tumours is fundamental for diagnosis.
Clinical course
Modern combined modality therapies with multiagent chemo-
therapy have given a significant improvement in the prognosis of
Ewing’s sarcoma of bone. Small, distal extremity lesions have
a good prognosis, whereas patients with metastatic disease at
presentation, large lesions, proximal or axial lesions or recurrent
disease have a less favourable prognosis.
Metastases are predominantly haematogenous. The lung is
the most common site of metastasis, followed by bone and bone
marrow.6,14 The incidence of metastatic disease at the time of
diagnosis ranges from 15% to 35%.6,15 The risk of distant
metastasis with a localized tumour is around 40e50%. Metas-
tasis to regional or distal lymph nodes is unusual.
Treatment
The treatment of Ewing’s sarcoma of bone is currently based on
combined therapy with neoadjuvant chemotherapy, radiation
therapy and surgical resection of the primary tumour.16e18 Due to
343 Ó 2010 Elsevier Ltd. All rights reserved.
 MINI-SYMPOSIUM: MALIGNANT BONE TUMOURS: SPECIFIC TUMOURS
the complexity of treatment, it is mandatory for the members of the
multidisciplinary team (oncologists, surgeons, radiation oncolo-
gists as well as pathologists and radiologists) to cooperate closely to
customize treatments to the histologic response and tumour volume
and site, in order to offer the best treatment for each patient.
Primary or neoadjuvant chemotherapy is effective for
shrinking the primary tumour and management of potential
metastatic disease. Drugs commonly used are combinations of
Vincristine, Actinomycin-D, Cyclophosphamide, Adriamycin,
Ifosfamid, Etoposid and Cisplatin. Standard therapy for localized
Ewing’s sarcoma includes preoperative induction chemotherapy
(4e5 cycles) and local treatment with surgery and/or radio-
therapy. Granulocyte colony-stimulating factors (GCSF) are
commonly used in order to permit increased drug dosage without
toxicity.
Surgical resection with adequate margins remains one of the
most important prognostic factors for Ewing’s sarcoma. The role
of surgery and radiation for local disease is still controversial but
surgery gives better disease free survival (DFS) than radiotherapy
alone. Early results from the EICESS92 study show that signifi-
cantly better DFS and overall survival (OS) occur with multi-
modality treatment, i.e. a combination of chemotherapy, surgery
and radiotherapy.
Lesions arising in expendible bones, such as ribs or fibula,
should be excised. Many centres advocate resection of the lesion
after neoadjuvant chemotherapy and radiation for positive or
close margins. Currently, limb salvage surgery is recommended
whenever possible using the range of techniques of conservative
surgery: endoprosthetic replacement19 (Figure 4) including
Figure 4 Endoprosthetic replacement of the proximal humerus for Ewing’s
sarcoma.
ORTHOPAEDICS AND TRAUMA 24:5
growing prostheses for children, osteoarticular allografts,20
allograft prosthetic composite reconstruction techniques,21 bio-
logic reconstructions using autografts or a combination of allo-
grafts autografts and/or vascularized autografts,22 bone transport
techniques23 and induced membrane24 with allo- or autografting
techniques.
Lesions arising in the pelvis or centrally located (sacrum,
spine) remain surgically challenging and should be carefully
evaluated by the multidisciplinary team: radiotherapy may be the
best choice for large volume axial bone tumours (spine, pelvis)
or unresectable lesions, in order to avoid unacceptable mutilating
surgery. Radiation therapy is highly effective in Ewing’s sarcoma,
but careful administration is required to obtain the best effect and
to decrease complications.25,26 Radiotherapy may be used post-
operatively if surgical margins are inadequate. Subsequently,
10e22 weeks of chemotherapy are given for consolidation. The
aim is local control and the eradication of micro-metastases.
New treatments and new strategies are currently being eval-
uated in different trials:27
 GemcitabineDocetaxel: this association induces synergic
effects with encouraging results in sarcomas including PNET/
Ewing.
 Trabectidin (ET 743) is a new molecule which has recently
shown promising results against Ewing’s sarcoma.
 New antiangiogenic strategies are currently under investiga-
tion (trials of phases 1 and 2)28 using anti-IGF1R antibodies:
by inhibiting IGF receptors, anti-IGFR1 antibodies induce
apoptosis of the PNET/Ewing cells leading to an increase
therapeutic synergy with other cytotoxic agents.
 mTor inhibitors (Rapamycin, Deferolimus): the mammalian
target of Rapamycin (mTor) is a protein kinase which plays
a major role in cancer development. The therapeutic effect
relies on the inhibition of the fusion transcript involving the
EWS-FLI-1 with concomitant inhibition of Ewing’s cell growth
by blocking the cell cycle at the G1 phase. The use of Rapa-
mycin as a cytostatic agent may be an efficient tool for the
treatment of Ewing’s sarcoma patient and is currently under
investigation in a phase III study (SUCCEED study).29,30
 Fenretinide is derived from vitamin A and can decrease
proliferation of Ewing’s sarcoma cells by increasing their
differentiation.31
Prognostic factors
Several clinical and pathologic factors have been shown to be
risk factors for decreased survival in Ewing’s sarcoma:32
 metastasis at presentation
 elevated serum LDH level at presentation
 poor histologic response to induction chemotherapy
 tumour in the axial skeleton: patients with a pelvic tumour
have the worst prognosis, with an overall survival rate of
15e35% as compared to 30e77% in patients with a non-
pelvic tumour.15,18,33
Conclusions
Marked improvements in survival have been reported during the
past 40 years for patients with localized disease: OS at 5 years has
improved from 10e15% to 60e70% with chemotherapy
combined with local treatment (surgery and/or
344 Ó 2010 Elsevier Ltd. All rights reserved.
 MINI-SYMPOSIUM: MALIGNANT BONE TUMOURS: SPECIFIC TUMOURS
radiotherapy).17,26,33,34 However, lesser improvements have
been seen for patients with metastatic or recurrent disease with
a 5-year survival rate of less than 10e35%.35,14,15
A better understanding of the complex biology of Ewing’s
sarcoma may lead to the successful development of biologically
targeted therapies. A 18 Wilkins RM, Pritchard DJ, Burgert Jr EO, Unni KK. Ewing’s sarcoma of
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