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 Ewing sarcoma accounts for approximately 5% of biopsy-analyzed bone tumors and approximately 33% of primary bone tumors.2 This disease is the second most common malignant bone tumor in young patients, and it is the most lethal bone tumor.3 An association exists between Ewing sarcoma and primitive peripheral neuroectodermal tumor (PNET).4, 5 (See also the eMedicine article Ewing Sarcoma and Primitive Neuroectodermal Tumors, as well as the articles.
New Standard of Care for Ewing’s Sarcoma and Treatment Effects in Pediatric Soft Tissue and Bone Tumors, on Medscape.)
For excellent patient education resources, visit eMedicine’s Cancer and Tumors Center and Blood and Lymphatic System Center. Also, see eMedicine’s patient education articles Cancer: What You Need to Know and Leukemia.)
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.6 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.7 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).8
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.3
Anatomy
Ewing sarcoma and peripheral neuroepithelioma belong to the Ewing family of tumors (EFTs) and are considered neural tumors.3, 9 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.
Clinical Details
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.
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. (See also the eMedicine article Osteomyelitis, Chronic [in the Radiology section] and Osteomyelitis [in the Emergency Medicine section], as well as Chronic Osteomyelitis From Staphylococcus Aureus, on Medscape.)
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.10
A European study of 359 patients with nonmetastatic Ewing sarcoma revealed that the following factors are associated with a poor prognosis11:
— 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.12, 13 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.14, 15
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. (See also the eMedicine articles Acute Myelogenous Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, and Chronic Lymphocytic Leukemia, as well as Risk Factors for Acute Leukemia in Children: A Review and ASCO 2007: Hematologic Malignancies, on Medscape.)
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