eMedicine Specialties > Radiology > Musculoskeletal

Ewing Sarcoma

Author: Ludwig G Strauss, MD, Associate Director, Professor, Department of Innovative Cancer Diagnostics and Therapy, CCU Nuclear Medicine, German Cancer Research Center
Contributor Information and Disclosures

Updated: Feb 19, 2009

Introduction

Background

Ewing sarcoma, a highly malignant primary bone tumor that is derived from red bone marrow, was first described by James Ewing in 1921.¹ This tumor is most frequently observed in children and adolescents aged 4-15 years and rarely develops in adults older than 30 years.^2,3

Pathophysiology

Although the tumor is derived from bone marrow, Ewing sarcoma is histologically related to reticulum cell sarcoma. Most frequently, the tumor is diagnosed as a monostotic lesion in the metaphysis or diaphysis of the long bones of the extremities. The tumor may also occur, although less frequently, in the pelvic area, ribs, and scapulae. In fact, any bone may be involved.

Typically, the periosteal reaction and new bone formation with an onion-skin appearance may suggest the diagnosis of Ewing sarcoma. The radiographic appearance of Ewing sarcoma may vary highly from a lytic one to a dominantly sclerotic one.

Frequency

United States

The frequency of Ewing sarcoma depends on the patient's age. Tumor occurrence ranges from 0.3 cases per 1 million children younger than 3 years to as high as 4.6 cases per 1 million adolescents aged 15-19 years.

International

The annual incidence of Ewing sarcoma is less than 2 cases per 1 million children.

Mortality/Morbidity

• The European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) studied 369 patients who were randomized to receive treatments with local therapy and chemotherapy based on 14 courses of vincristine, actinomycin D, cyclophosphamide or ifosfamide, and Adriamycin (doxorubicin) with or without etoposide.⁹ The 3-year, event-free survival rate was 66% in patients with localized tumors, 43% in those with lung metastases at the initial diagnosis, and 29% in those with other metastases. A large tumor volume and/or a tumor primarily localized to the pelvic area were negative prognostic factors.
• In the United States, bone tumors are the third leading cause of mortality in children aged 10-14 years.
• The National Cancer Data Base Report collected data from 1985-2003 for various sarcomas, including Ewing sarcoma.¹⁰ The relative 5-year survival rate (minimum 5-year follow-up from 1985-1998) was 50.6% for Ewing sarcoma.
• In a small, single-center, retrospective study from the Netherlands, the 5-year overall survival was 58% in adult patients (age >16 y) with either Ewing sarcoma (27 patients) or peripheral primitive neuroectodermal tumors (PNET) (20 patients).¹¹

Race

Ewing sarcoma occurs predominantly in whites and, to a lesser extent, in blacks and Asians. This condition is rare in black and Chinese children.

Sex

Males are affected more frequently than females, with a ratio of approximately 1.5:1.

Age

Ewing sarcoma most commonly occurs in children and adolescents aged 4-15 years and rarely develops in adults older than 30 years. Although Ewing sarcoma is uncommon in older individuals, it has been reported in those as old as 60-70 years. Ewing sarcoma is the most lethal and second most common malignant bone tumor in young patients.⁴

Anatomy

Ewing sarcoma and peripheral neuroepithelioma belong to the Ewing family of tumors (EFTs) and are considered neural tumors.^4,12 Ewing sarcoma represents a less differentiated form of the tumors, whereas neuroepithelioma represents a more differentiated form. Unlike neuroblastomas, these neural tumors are not derived from the sympathetic system, and catecholamine metabolites are not excreted in the urine. In vitro, these tumors show neural differentiation and have neural features. Results with neuron-specific enolase and S-100 protein testing are positive. In addition, electron microscopy reveals neural structures such as neurites and dense-core granules. Glycogen granules are present, and alkaline phosphatase is absent.

Presentation

Ewing sarcoma is rare; therefore, a screening program is not recommended. The most important and earliest symptom is pain, which is initially intermittent but becomes intense. The pain may radiate to the limbs, particularly with tumors in the vertebral or pelvic region. Neurologic signs such as nerve root signs and cord compression are present in 50% of patients with involvement of the axial skeleton. Rarely, a patient may have a pathologic fracture.^13,14,15

Occasionally, the clinical picture may be similar to that of acute or chronic osteomyelitis and include remittent fever, mild anemia, leukocytosis, and an elevated erythrocyte sedimentation rate (ESR). Increased serum lactic dehydrogenase (LDH) levels and weight loss may also be observed. Symptoms usually last a few weeks to a few months. Eventually, most patients have a large palpable mass, which grows rapidly, with a tense and tender local swelling. Patients with Ewing sarcoma usually are assigned to 1 of 2 groups, and the tumor is classified as either localized or metastatic disease. The prognosis is highly affected by the group to which the patient is assigned. Some prognostic factors may be used to subdivide the local disease classification into a high-risk group and a low-risk group.¹⁶

A European study of 359 patients with nonmetastatic Ewing sarcoma revealed that the following factors are associated with a poor prognosis¹⁷ :

• Male sex
• Age older than 12 years
• Anemia
• Elevated LDH levels
• Radiation therapy only for local control
• Poor chemotherapeutic course

Preferred Examination

No single morphologic or functional imaging method provides findings for a specific diagnosis of Ewing sarcoma, but the results do contribute to tumor staging. Therefore, obtaining a histologic specimen of the lesion in all patients is essential in planning therapy. Because the clinical symptoms of Ewing sarcoma are nonspecific and because they frequently suggest osteomyelitis, an initial conventional radiographic and/or magnetic resonance imaging (MRI) examination is performed.^18,19 These studies may reveal the classic signs of Ewing sarcoma. Although plain radiographs may show typical signs of Ewing sarcoma, MRI provides more accurate information about tumor size. MRI is also superior to computed tomography (CT) scanning in delineating the extent of the neoplasms and their relation to the surrounding structures.^20,21

Limitations of Techniques

The radiographic appearance of Ewing sarcoma may mimic that of osteomyelitis, as well as those of other malignant tumors, such as leukemia. The appearance of Ewing sarcoma may vary from that of pure lysis to sclerosis. MRI findings alone may not be conclusive for a malignant lesion, but MRIs help to show the full extent of tumor spread.

Differential Diagnoses

Chondrosarcoma
Eosinophilic Granuloma, Skeletal
Lymphoma, Bone
Osteomyelitis, Acute Pyogenic
Osteomyelitis, Chronic
Osteosarcoma, Variants

Other Problems to Be Considered

Osteomyelitis – Especially in the long bones, particularly when the lesion is in the metaphysis
 
Round-cell tumors – Metastatic neuroblastoma, leukemia 
 
Osteosarcomas – Bone-forming tumors, usually located in metaphysis of long bones; more homogeneous, cloudlike, osteoid formation  
 
Osteolytic osteosarcoma and fibrosarcoma – Difficult to differentiate between these 2 entities, because of lytic lesions, periosteal reaction 
 
Myeloma – Frequently has multiple lytic areas, patients much older than those with Ewing sarcoma 
 
Lymphoma – May cause bone destruction or bone sclerosis; extent and type of bone involvement not predictable; usually, no major periosteal reaction in the primary lymphoma in the bone marrow; lytic, poorly defined, or predominantly osteoblastic secondary malignant lesions 
 
Eosinophilic granules and osteomyelitis – Consider these within benign lesions. Both have a less aggressive appearance than that of Ewing sarcoma; thus, the margins of these 2 may be better defined, and the periosteal reaction may have sharper borders.
 
Extraosseous Ewing sarcoma – Rare occurrence but has been reported (eg, adrenal masses); early metastases is possible; metastatic spread to lung or bone is common and present in as many as 26% of patients; occurrence of metastases not related to tumor size or location
 
PNETs (peripheral neuroectodermal tumors)– These tumors are similar to Ewing sarcoma, and the 2 entities may be difficult to histologically differentiate from one another. Many Ewing sarcomas and PNET tumors can be differentiated from other similar tumors, such as rhabdomyosarcoma, by the presence of the cell-surface glycoprotein p30/32 MIC2. This protein is produced from the MIC2 gene on the short arms of the X and Y chromosomes. 

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