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Ewing sarcoma cells

Image: „Ewing sarcoma cells“ by Lance Liotta Laboratory. License: CC BY 2.5

Definition of Ewing’s Sarcoma

Ewing’s sarcoma is the second most commonly diagnosed malignant bone cancer among children and adolescents, after osteosarcoma. It represents 6% of all childhood cancers (Uptodate, 2018). The tumor is characterized by small, round, blue cells as well as by the translocation between tumor-specific chromosomes, which fuse the EWS (Ewing’s sarcoma) gene and another gene.

Epidemiology of Ewing’s Sarcoma

The spread of Ewing’s sarcoma

Over 80% of the patients are diagnosed with Ewing’s sarcoma before they are 20 years of age. The average age of diagnosis is 10–15 years. The incidence rate is 0.3 per 100,000 habitants and boys are 1.5 times more frequently affected than girls. Race-specific incidences indicate that the incidence among dark-skinned and Asian children is significantly lower.

Studies show that Ewing’s sarcoma is more common in children who have umbilical hernias, but the mechanism underlying this possible association between hernias and Ewing’s sarcoma is unclear. It may be attributed to a disruption in normal embryologic development.

Etiology of Ewing’s Sarcoma

Translocation in Ewing’s sarcoma

The malignant bone tumor originates from the connecting tissues of the bone marrow structure and stems from the pluripotent cells of the neural tubes. Ewing’s sarcoma was the first solid tumor in which a balanced translocation was detected. The translocation involves the fusion of the EWS gene and the chromosome 22q12, mostly resulting in a translocation t (11;22) in 85–90% of cases. In 44% of the cases, trisomy of chromosomes 1q, 2, 8, and 12 can be detected.

Ewing’s sarcoma usually arises in the diaphysis of long bones and flat bones such as scapula and the vertebra. In two-thirds of all cases, the tumor is localized in the section of the legs (especially the femur) and the pelvic region. The os ilium is most commonly affected.

Note: In comparison to osteosarcoma, the flat bone of the axial skeleton is significantly more frequently affected in Ewing’s sarcoma cases. In cases of tubular bones, the Ewing’s sarcoma is almost always diaphyseal and in cases of osteosarcoma, it is characteristically metaphyseal.

Distribution of Ewing sarcoma

Image: Distribution of Ewing’s sarcoma. By Frank Gaillard. License: CC BY-SA 3.0.

The metastases occur at an early stage in the lungs and the bones. In 20% of the patients, metastasis can be detected at the time of the diagnosis.

Macroscopic view and histology

The tumor is greyish-white and is either a slimy or thick inconsistency.

Macroscopic picture of a Ewing's sarcoma

Image: Macroscopic picture of Ewing’s sarcoma. By Openi. License: CC BY 4.0.

The tumor cells are unripe and roundish without distinguished cell boundaries. The PAS coloring in the glycogen deposits of the cells is visible. The examination must go beyond the immunohistochemical analysis to differentiate between the tumor cells from the lymphoma cells or the neuroblastoma. The expression of the product of the MIC2 gene CD99 is characteristic. The expression of the mesenchymal marker, vimentin, and the S100 protein of the neuron-specific enolase are frequently observed.

Ewing sarcoma cells

Image: Ewing’s sarcoma cells. By Lance Liotta Laboratory. License: CC BY 2.5.

Based on fine-tissue properties and the point of origin of the tumor, the tumor types within the Ewing’s sarcoma group are as follows:

Histopathological Image of Ewing Sarcoma

Image: Histopathologic image. By Ed Uthman. License: CC BY-SA 2.0.

  • Classical Ewing’s sarcoma
  • Peripheral malignant primitive neuroectodermal tumor
  • Askin tumor (primitive neuroectodermal tumor of the thoracic wall)
  • Ewing’s tumor of the pelvic region

Clinical Findings of Ewing’s Sarcoma

Symptoms of Ewing’s sarcoma

The symptoms mainly include pain or swelling lasting a week or a month. The pain may appear to be a trivial trauma and is commonly misinterpreted as a pain arising out of an injury or a growth-related pain. Often, the pain is augmented by stress and persists through the night. Depending on the localization, the movements can be restricted. For example, if the spinal column or the peripheral nerves are affected, the neurologic failures such as paralysis are more prominent.

massive scapular swelling

Image: Massive scapular swelling. By Openi. License: CC BY 2.0.

In some cases, a tissue mass is associated with other symptoms such as pain to palpation and erythema, fever, night sweats, fatigue, and weight loss. These symptoms are present in 15% of all patients.

Note: With every case of suspected osteomyelitis, Ewing’s sarcoma should be ruled out because similar symptoms such as pain, swelling, redness, and fever and can be secondarily infected.

Diagnosis of Ewing’s Sarcoma

Radiologic examination

X-ray (anteroposterior) of an Ewing's sarcoma in the tibia of a child

Image: X-ray (anteroposterior) of an Ewing’s sarcoma in the tibia of a child. By Michael Richardson. License: CC BY-SA 3.0.

Based on the diagnostic evidence, the radiologic examination includes X-ray, computed tomography (CT), or magnetic resonance imaging (MRI). The X-ray displays images of a moth-eaten pattern of bone deconstruction and typical onion-shaped periosteal called the Codman triangle.

Next steps in diagnosis

The gold standard in diagnosis is a biopsy with histopathologic examination and immunohistochemistry.

For staging, CT scan, bone scintigraphy, or 18 fluorodeoxyglucose positron emission tomography (PET) and bone marrow must be conducted to rule out skeletal (bone marrow) and pulmonary metastasis. (Pulmonary metastasis is the most frequent site of metastasis.)

Note: In 25% of patients, metastases are present at the point of diagnosis.

MRI showing Ewing's sarcoma of the left hip

Image: MRI showing Ewing’s sarcoma of the left hip. By Stevenfruitsmaak. License: Public domain.

Laboratory studies include hemoglobin and serum chemistry with lactate dehydrogenase levels (LDH) because it is a prognostic factor correlated with the tumor weight and dissemination. However, there is no specific tumoral marker for Ewing’s sarcoma.

Therapy of Ewing’s Sarcoma

Combination therapy in Ewing’s sarcoma

The therapy for Ewing’s sarcoma is a combination of polychemotherapy, surgery, and radiation. After chemotherapy (with vincristine, actinomycin D, cyclophosphamide, and doxorubicin), a total resection of the tumor is carried out. If the tumor grows along the medullary canal, the entire affected bone must be operated and radiated.

A prosthetic treatment or a rotationplasty is not necessary. Recovery of bone metastasis is only possible through stem cell transplantation. Pulmonary metastases can be treated with bilateral pulmonary radiation.

Note: Ewing’s sarcoma must be treated as a systemic disease without metastatic evidence and, as such, normally requires chemotherapy.
Surgical Treatment of Ewing Sarcoma

Image: Surgical treatment. By Openi. License: CC BY 2.0.

Prognosis of Ewing’s Sarcoma

The survival rate of Ewing’s sarcoma

The prognosis of this bone tumor is dependent on the tumor volume and the initial metastatic status. The overall 5-year survival rate for Ewing’s sarcoma is 64%.

The prognosis of the initial extent of the spread of the tumor depends on the existence of the metastasis and its reaction to the cytostatic therapies.

Follow-up Control and Care of Ewing’s Sarcoma

The chances of a relapse after the diagnosis are highest in the first 3 years; therefore, it is during this critical period that the regular findings of the lung metastasis based on X-ray and skeleton metastases from the scintigraphy are highly important.

Risks of developing a secondary malignant tumor

The development of secondary malignancy is a major risk after the chemotherapy and radiotherapy. After 20 years, the risk of a secondary malignant tumor is approximately 5%. The therapy associated with secondary malignancy comprises secondary myelodysplastic syndrome, acute myelogenous leukemia, and osteogenic sarcoma.

Furthermore, the long-term consequence of chemotherapy with alkylated substances is linked to infertility, especially among young men. In adolescent patients, an offer for pretherapeutic sperm cryopreservation is important, because it helps them plan for their life and the quality of life.

Special Form of Ewing’s Sarcoma

Extraosseous Ewing’s tumor

Purely extraskeletal or extraosseous Ewing’s tumors are rare. Unlike the classic Ewing’s sarcoma of the bone, the incidences among young boys are not higher compared to adolescent girls. Mainly, the stem is affected. The guidelines for diagnosis and therapy are the same.

Note: The molecular proof of the Ewing’s tumor–specific EWS can be looked at as pathognomonic.
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