Ewing's sarcoma

Ewing's sarcoma is the second most common bone tumor in childhood.

The first reports of this tumor belong to Lucke (1866) and Hildebrandt (1890), however, it was identified as an independent nosological form by Ewing in 1921. Although the author proposed calling it “diffuse endothelioma” and later “endothelial myeloma”, the nosology was named after the author - Ewing's sarcoma.

What is Ewing's sarcoma?

It is currently accepted that Ewing's sarcoma is a malignant tumor developing in bone and originating from bone marrow stromal cells. Histologically, its tissue is characterized by small cells with round nuclei, but without noticeable cytoplasmic borders and nuclear convexity. The WHO classification of bone tumors (1993) provides the following definition of this neoplasm: "A malignant tumor with a fairly monomorphic histological picture, represented by densely located small cells with a round nucleus, with poorly distinguishable outlines of the cytoplasm and unclear nucleoli. In typical cases, the tumor tissue is divided by fibrous layers into stripes and lobes of irregular shape. The dense reticulin framework, so characteristic of malignant lymphoma, is absent in the tumor. Mitoses are rare. Foci of hemorrhage and necrosis are usually observed."

ICD-10 code

• C40. Malignant neoplasm of bone and articular cartilage of extremities.
• C41. Malignant neoplasm of bone and articular cartilage of other and unspecified sites.

Epidemiology

The peak incidence occurs in the second decade of life. The incidence in children under 15 is 3.4 per 1,000,000 children. Boys get sick slightly more often. The average annual incidence fluctuates around 0.6 cases per 1 million population. This tumor is rarely found in people under 5 and over 30 years old, the peak incidence occurs at the age of 10-15 years. The incidence of boys and girls is related as 1.5:1, while the difference between the incidence of boys and girls is minimal in the younger age group and increases with age.

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Causes of Ewing's Sarcoma

The pathogenetic source was not determined for a long time, until this tumor was classified as a neoplasm of unknown origin. For a long time, it was believed that Ewing's sarcoma was a bone metastasis of neuroblastoma with an undetected primary focus of this neoplasm.

Ewing's sarcoma is closely associated with primitive neuroectodermal tumors. In these diseases, the same chromosomal translocations t(ll;22) or t(21;22) are detected, as well as the surface protein p30/32 mic2 (CD99). The differential criterion is the expression of neuronal markers (NSE, Leu7, PGP9.5, S100). In Ewing's sarcoma, no more than one marker is expressed, while in primitive neuroectodermal tumors, two or more are expressed.

With the above-mentioned chromosomal translocations, the EWS/FL11 and EWS/ERG genes are formed - markers of residual disease.

Histologically, Ewing's sarcoma is represented by small round anaplastic cells with intraplasmic glycogen deposits. Immunohistochemically, a mesenchymal marker (vimentin) is detected, and in some cases, neuronal markers (NSE. S100, etc.).

The lesion in Ewing's sarcoma is most often localized in the area of the diaphysis of long tubular bones. The femur is affected in 20-25% of cases, the bones of the lower limb as a whole - in half of the cases of the disease. The bones of the pelvis account for 20% of all cases of the tumor, the bones of the upper limb - 15%. Less common localizations are the spine, ribs, and skull bones.

Ewing sarcoma is characterized by early metastasis to the lungs, bones and bone marrow.

Metastatic lesions are observed in 20-30% of cases of primary tumors, and micrometastasis - in 90%. Metastatic lesions of the lymph nodes occur rarely, which gives grounds to consider Ewing's sarcoma as a primarily systemic disease.

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How does Ewing's sarcoma manifest itself?

Most often, the primary lesion is located in the pelvic bones (20%) and femur (20%), less often in the tibia (10%), fibula (10%), ribs (10%), scapula (5%), vertebrae (8%) and humerus (7%). Flat bones of the skeleton and diaphyses of long tubular bones are more often affected. At the same time, the frequency of damage to the diaphyses of long tubular bones does not exceed 20-30%, which does not allow us to consider this localization of the neoplasm characteristic of this neoplasm. When the diaphysis is affected, two types of radiographic picture can be identified: with the formation of layered periostitis (from a pathomorphological point of view, it is more correct to call it periostea) and with the formation of spicules.

• In the first case, repeated “breakthroughs” of the periosteum by tumor tissue occur, which leads to the appearance of an X-ray picture of layered (“onion”) periostitis.
• In the second case, reactive bone formation takes a direction perpendicular to the bone axis.

The presence of one or another type of X-ray picture does not affect the prognosis of the disease.

In 70-80% of cases of long tubular bone lesions, Ewing's sarcoma develops in the metadiaphyseal zones. In this case, a clinical and radiological picture similar to that of osteogenic chondrosarcoma and MFG of the bone is noted.

Symptoms of Ewing's sarcoma are non-specific. Local symptoms in the form of swelling and tissue compaction predominate. Pain at the site of tumor development often becomes the first symptom that prompts a visit to the doctor. Over time, the nature of the pain changes from intermittent to constant, its intensity increases. These symptoms necessitate differential diagnostics with osteomyelitis. If the lower extremities are affected, lameness may develop, and if the spine is affected, neurological symptoms in the form of paresis and paralysis of the extremities may develop. Systemic manifestations (deterioration of the general condition, fever) are observed in advanced stages of the disease.

Classification

A number of leading researchers (Soloviev Yu.N., 2002) currently classify Ewing's sarcoma as a group of malignant small round-blue cell tumors. It also includes neuroblastoma, peripheral neuroepithelioma, extraosseous Ewing's sarcoma, malignant small-cell neuroectodermal tumor of the thoracopulmonary region in children (Askin's tumor), primitive neuroectodermal neoplasms of soft tissues and bones.

The existence of two gradations can be considered legitimate:

• Ewing's sarcoma (affects only bones);
• Peripheral primitive neuroectodermal tumor (pPNET) does not involve bone.

Histologically, these tumors form a single group and differ in the localization of the primary lesion in one or another type of tissue. Therefore, the frequently used term "PNET of bone" should be replaced by the term "Ewing's sarcoma of bone". In turn, the term "Ewing's sarcoma of soft tissue" is also untenable. The term "Askin's tumor" means a tumor with a PNET histostructure that developed in the thoracopulmonary region, without indicating a source of growth in bone or soft tissue.

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Diagnostics

In addition to careful history and physical examination, imaging studies play an important role in the diagnosis of Ewing sarcoma.

Radiological assessment is performed according to the same criteria as for osteosarcoma. A characteristic radiological sign of Ewing's sarcoma is a periosteal reaction in the form of lamellar layers ("onion peel"). Bone spicules may be detected. CT or MRI is recommended to clarify the extent of the lesion and the involvement of surrounding tissues.

Bone scintigraphy is important in the diagnosis of bone metastases.

Approximately 20% of patients have metastases during the initial examination. About half of these are metastatic lesions of the lungs. Approximately 40% are multiple metastatic lesions of the bones and diffuse metastatic lesions of the bone marrow. Lymphogenous metastases are noted in approximately 10% of cases. CNS lesions are not typical for primary treatment, but are possible in advanced cases.

Ewing's sarcoma is diagnosed in the same way as bone tumors. Particular attention should be paid to the myelogram: with its help, metastatic bone marrow lesions can be diagnosed with this tumor. Increased LDH activity is possible in the blood serum, although this is not necessary. Increased activity of serum neuron-specific enolase (NSE) is detected in some patients.

Morphological examination of the neoplasm biopsy, along with routine light microscopy, includes additional diagnostic procedures, in particular immunohistochemistry. It is invaluable for differentiating the disease from other small round-blue cell tumors. Cytogenetic examination reveals a persistent chromosomal translocation t(ll;22)(q24:ql2) in most cell lines. This distinguishes the neoplasm from most other neoplasms, in which such constancy of cytogenetic changes is not detected.

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Treatment

Treatment of Ewing's sarcoma is complex: it includes chemotherapy, radiation therapy and surgery. In modern protocols for treatment, vnicristin, alkylating agents (cyclophosphamide, ifosfamide), topoisomerase inhibitors (ztoposide), anthracycline antibiotics (doxorubicin), actinomycin-D are used. The effective dose of radiation therapy is 60 Gy. When planning organ-preserving surgery - 451 rubles.

Patients in the high-risk group - with tumors in unresectable locations (spine, pelvic bones, skull bones), initially generalized neoplasms, in cases of Ewing's sarcoma resistance to standard chemotherapy regimens - are prescribed high-dose chemotherapy with bone marrow transplantation.

In case of pulmonary metastases, their surgical removal is indicated.

What is the prognosis for Ewing's sarcoma?

The overall 5-year survival rate for Ewing's sarcoma, with programmatic treatment, is 50-60%. This figure in the high-risk group, with high-dose chemotherapy and bone marrow transplantation, is 15-30%. The prognosis worsens if Ewing's sarcoma is large, proximally localized in the limb (compared to distal), has a high LDH level (more than 200 IU), is male, and is under 17 years of age. The prognosis is fatal with unresectable pulmonary metastases, metastases to bones and lymph nodes.