9/13/2007 Ewing Sarcoma Background: Ewing sarcoma, a highly malignant primary bone tumor, was first described by James Ewing in 1921. The tumor is derived from red bone marrow. Most frequently, it is observed in children and adolescents aged 4-15 years and rarely develops in adults older than 30 years. Ewing sarcoma accounts for approximately 5% of biopsy-analyzed bone tumors and approximately one third of primary bone tumors. Ewing sarcoma is the second most common malignant bone tumor in young patients, and it is the most lethal bone tumor. Males are affected more frequently than females, with a ratio of approximately 1.5:1. Ewing sarcoma occurs in African Americans and Asians. An association exists between Ewing sarcoma and primitive peripheral neuroectodermal tumor. Pathophysiology: Although the tumor is derived from bone marrow, it 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 also may 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 onionskin 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: In the US: The frequency in the United States depends on the patient's age. Tumor occurrence ranges from 0.3 case per 1,000,000 children younger than 3 years to as high as 4.6 cases per 1,000,000 adolescents aged 15-19 years. Internationally: The annual incidence rate averages less than 2 cases per 1,000,000 children. Mortality/Morbidity: The European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) included 369 patients who were treated with local therapy and chemotherapy based on 14 courses of vincristine, actinomycin D, cyclophosphamide or ifosfamide, and Adriamycin with or without etoposide. The 3-year event-free survival rate was 66% in patients with localized tumors, 43% in those with lung metastases at 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. Race: Ewing sarcoma occurs in African Americans and Asians. Ewing sarcoma is rare in black and Chinese children. Sex: The male-to-female ratio is 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. Anatomy: Both Ewing sarcoma and peripheral neuroepithelioma belong to the Ewing family of tumors and are considered neural tumors. Ewing sarcoma represents a less differentiated form, whereas neuroepithelioma represents a more differentiated form. Unlike neuroblastoma, 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 initially is 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 one half 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 sedimentation rate. Increased serum lactic dehydrogenase levels and weight loss also may be observed. Symptoms usually last a few weeks to a few months. Eventually, most patients have a large palpable mass, which rapidly grows, 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 disease 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. A study of 359 patients with nonmetastatic Ewing sarcoma revealed that patients the following are associated with a poor prognosis: Male sex Age older than 12 years Anemia Elevated lactic dehydrogenase 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 are nonspecific and because they frequently suggest osteomyelitis, an initial conventional radiographic and/or MRI examination is performed. These 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 superior to CT in delineating the extent of the neoplasms and their relation to the surrounding structures. 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.