Ewing Sarcoma

Ewing sarcoma is a malignant tumor of bone that occurs primarily in children and young adults. It is characterized by a specific genetic mutation identified as the t(11;22) translocation, which leads to the formation of a fusion protein, the most common of which is EWS-FLI1. The cell of origin is unknown but the tumor is believed to arise from mesenchymal stem cells or neural crest-derived stem cells.

Epidemiology

Ewing sarcoma most commonly develops in patients 5 to 25 years old. It is the second most common malignant bone tumor in children and the third most common bone sarcoma, behind osteosarcoma and chondrosarcoma. Ewing sarcoma accounts for approximately 10% of primary malignant bone tumor cases and has a male predominance of 1.4:1. Ewing sarcoma is more common in Caucasians. The most common locations are the metadiaphyseal portion of long bones (femur, tibia, and humerus) and the pelvis (25% of cases). Ewing sarcoma can also be found less commonly in the ribs, skull, vertebrae, scapula, and short tubular bones of the hands and feet.

Clinical Features

Pain, especially at rest or at night, fever, and a palpable mass are the most common clinical features at presentation. A large soft-tissue mass is frequently present.

Fewer than 15% of patients with Ewing sarcoma have a pathologic fracture at the time of diagnosis. Erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and white blood cells (WBC) may be elevated. Anemia is common.

Approximately 25% of patients have diagnosable metastatic disease at presentation, with the lungs and other bones being the most commonly affected sites. Delayed diagnosis of pelvic tumors is particularly common.

Radiologic Features

Radiographs of Ewing sarcoma may appear only slightly abnormal initially, as the bone changes can be subtle due to the permeative behavior of this tumor in bone. More commonly, x-rays will show a destructive lesion within the diaphysis of the bone with a permeative appearance and occasional reactive sclerosis.

Classically, a laminated periosteal reaction, termed “onion skinning,” can develop from the elevation of the periosteum from the bone by the underlying mass (Figure 1A and 1B). A “sunburst” periosteal reaction can also form but is more typical of osteosarcoma. This pattern is believed to indicate a perpendicular interaction between the periosteum and bone at the point of detachment.

Figure 1A and B: AP and lateral xray of child with left femur Ewing sarcoma. Note the “onion-skinning” periosteal reaction most evident on the lateral xray.

Magnetic resonance imaging (MRI) as well as positron emission tomography-computed tomography (PET-CT) is recommended for staging. MRI will most commonly show a soft-tissue mass arising from the bone, which can often be quite large (Figure 2A and 2B).

Figure 2A and B: sagittal STIR and post-contrast axial T1 FS MRI sequences of left femur Ewing sarcoma, demonstrating large soft tissue mass.

Pathology

Grossly, the tumor is usually solid but can be sufficiently liquefied that it can be mistaken for purulence. Histologically, sheets of monotonous small round blue cells are seen with prominent nuclei and minimal cytoplasm (Figure 3). Immunostaining shows positivity for CD99, MIC2, vimentin, PAS, NSE, S100, and Leu7. Cytokeratin, reticulin (lymphoma marker), and neurofilament (neuroblastoma marker) are negative.

Figure 3: H&E stained slide demonstrating solid sheet of monomorphic round tumor cells with high nuclear-to-cytoplasmic ratio and fine chromatin, representative of Ewing sarcoma. (image courtesy of Dr. Gord Zhu)

Nearly all cases (85%) of Ewing sarcoma are associated with a balanced translocation involving the EWSR1 gene on chromosome 22 and a member of the ETS family of transcription factors on chromosome 11 (e.g., FLI1). The translocation, t(11;22)(q24;q12), leads to the formation of a fusion protein, most commonly EWS-FLI1. Confirmed with fluorescence in situ hybridization, this differentiates Ewing sarcoma from other round-cell tumors. CD99 is the diagnostic immunohistochemical stain (Figure 4). Alternative translocations fuse EWSR1 to other ETS family members, which are sometimes characterized as Ewing-like sarcomas, and are treated with similar protocols. The second most common: t(21;22)(q22;q12), fusing EWS with ERG, which accounts for roughly 10% of cases.

Figure 4: CD99 immunostain, Ewing sarcoma: The tumor cells show characteristically strong, diffuse, membranous CD99 immunoreactivity. (image courtesy of Dr. Gord Zhu)

Differential Diagnosis

Ewing sarcoma may be mistaken for other conditions, as shown in Table 1.

Disease Course: Treatment and Prognosis

Once the diagnosis of Ewing sarcoma is confirmed through biopsy, various staging studies such as a CT scan of the chest, PET/CT, bone scans, and an MRI of the spine and pelvis are employed to detect potential metastatic lesions.

Patients should be assumed to have subclinical micro-metastases at diagnosis. Accordingly, neoadjuvant chemotherapy is routinely given for 8-12 weeks, followed by local control with wide surgical excision. This is then followed by adjuvant chemotherapy for an additional six months. Wide resection of the soft-tissue mass and involved bone with reconstruction using endoprostheses or cadaveric allografts is commonly performed.

If the morbidity of surgical resection is too great, or if the tumor is unresectable with negative margins, definitive radiation treatment of the primary tumor is recommended.

For patients with localized disease, the 5 -year and 10-year survival rates are approximately 75% and 60% respectively. For patients with known metastatic disease at presentation, the 5-year survival rate is approximately 35% and about 30% at ten years.

Poor prognostic factors include tumors larger than 8 cm, spine and pelvic locations, LDH greater than 200 IU/L, anemia, and elevated WBC. The presence of metastases within the bone or elsewhere in the bone marrow connotes a worse prognosis than lung metastases. Achieving less than 90% necrosis after the administration of neoadjuvant chemotherapy is also considered a poor prognostic indicator.

Complications can arise with definitive radiation treatment alone when used in young patients. Secondary malignancies, usually post-radiation osteosarcoma, can occur in 5% of patients who receive up to 60 Gy radiation, and in 20% of patients who receive greater than 60 Gy radiation. Extremity radiation therapy can cause unequal limb lengths, joint contractures, muscle atrophy, pathologic fracture, and secondary anemia. Secondary leukemia related to chemotherapy can also develop more than 5 years after treatment. The 5-year survival rate for patients with local recurrence is less than 10%.

Key Test Topics

Recognizing Ewing sarcoma as a diaphyseal tumor in a child with small round blue cells.
Radiographic appearance of periosteal elevation/onion skinning.
t(11;22) translocation forming EWS-FLI1 fusion protein