Ewing's sarcoma

Ewing's sarcoma is the second most frequent tumor of bones in childhood.

The first reports of this tumor belong to Lucke (1866) and Hildebrandt (1890), but it was isolated into an independent nosological form by Ewing in 1921. Although the author suggested calling it "diffuse endothelioma" and later "endothelial myeloma", the nosology was named after the author's surname is Ewing's sarcoma.

What is Ewing's sarcoma?

Currently, it is commonly believed that Ewing's sarcoma is a malignant tumor that develops in the bone and originates from the bone marrow stromal cells. Its tissue is histologically characterized by small cells with round nuclei, but without noticeable cytoplasmic boundaries and convexity of the nuclei. Classification of bone tumors WHO (1993) gives the following definition of this tumor: "Malignant tumor with a sufficiently monomorphic histological picture, represented by densely located small cells with a rounded nucleus, with poorly discernible outlines of the cytoplasm and fuzzy nucleoli. In typical cases, the tumor tissue is divided by fibrous layers into bands and lobes of irregular shape. A dense reticulin frame, so characteristic of malignant lymphoma, is absent in the tumor. Mitoses are rare. Usually there are foci of hemorrhage and necrosis. "

ICD-10 code

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

Epidemiology

The peak of incidence falls on the second decade of life. The incidence of children under 15 years of age is 3.4 per 1,000,000 children. Boys get sick more often. The average annual incidence varies about 0.6 cases per 1 million of the population. This tumor is rarely found in people younger than 5 and older than 30 years, the peak incidence falls on the age of 10-15 years. The incidence of boys and girls is 1.5: 1, with the difference between the incidence of boys and girls being minimal in the younger age group and increasing with age.

[1], [2], [3], [4], [5], [6], [7], [8]

Causes of Ewing's sarcoma

The pathogenetic source has not been determined for a long time, up to including this tumor in a group of neoplasias of unknown origin. For a long time, there was an opinion that Ewing's sarcoma is a bone metastasis of a neuroblastoma with an undiagnosed primary focus of this neoplasm.

Ewing's sarcoma is closely related to primitive neuroectodermal tumors. In these diseases, the same chromosomal translocations t (ll; 22) or t (21; 22), as well as the surface protein p3O / 32 mic2 (CD99) are detected. Differential criterion is the expression of neuronal markers (NSE, Leu7, PGP9.5, S100). With Ewing sarcoma, no more than one marker is expressed, with primitive neuroectodermal tumors - two or more.

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

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

The defeat in Ewing's sarcoma is most often localized in the area of 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 the cases of the disease. The pelvic bone accounts for 20% of all cases of tumors, on the bones of the upper limb - 15%. More rare localizations - the spine, ribs, skull bones.

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

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

[9], [10], [11]

How is Ewing's sarcoma manifested?

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

• In the first case, repeated "breakthroughs" of the periosteum with tumor tissue occur, which leads to the appearance of an X-ray picture of the lamellar ("bulbous") periostitis.
• In the second case, reactive bone formation receives a direction perpendicular to the axis of the bone.

The presence of this or that type of radiographic picture does not affect the prognosis of the disease.

In 70-80% of cases of damage to the long tubular bones of Ewing's sarcoma develops in the metadialphisal zones. At the same time, a clinical and radiological picture similar to that of osteogenic chondrosarcoma and bone ZFG is noted.

Symptoms of Ewing sarcoma are nonspecific. Local symptoms predominate in the form of swelling, tissue tightening. Pain at the site of the development of the tumor often becomes the first symptom that makes one consult a doctor. Over time, the nature of pain changes from intermittent to constant, its intensity increases. This symptomatology necessitates differential diagnosis with osteomyelitis. With lesions of the lower extremities, lameness may develop, with spinal cord injury - neurological symptoms in the form of paresis and paralysis of the limbs. Systemic manifestations (worsening of the general condition, fever) are observed in advanced stages of the disease.

Classification

A number of leading researchers (Solovyov, Yu.N., 2002) now classify Ewing's sarcoma as a group of malignant, small-rounded-sinecellular tumors. It also includes neuroblastoma, peripheral neuroepithelioma, extraangular 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.

We can consider the existence of two gradations:

• Ewing's sarcoma (affects only bones);
• peripheral primitive neuroectodermal tumor (pPNET) does not affect the bones.

Histologically, these tumors form a single group and differ in the localization of the primary focus in one form or another of the tissue. Therefore, the frequently used term "PNET bones" should be replaced by the term "Ewing bones sarcoma". In turn, the term "Ewing soft tissue sarcoma" is also untenable. The term "Askin tumor" refers to a tumor with a PNET histone that developed in the thoracopulmonary area, without indicating the source of growth in the bone or in soft tissues.

[12], [13], [14], [15], [16], [17]

Diagnostics

In the diagnosis of Ewing sarcoma, along with careful study of the history and physical examination, imaging methods play an important role.

X-ray evaluation is performed according to the same criteria as in osteosarcoma. A characteristic x-ray sign of Ewing's sarcoma is a periosteal reaction in the form of lamellar layers ("onion husks"). Possible detection of bone spicules. To determine the extent of the lesion and involve surrounding tissues, CT or MRI is recommended.

Scintigraphy of the bones of the skeleton is important in the diagnosis of bone metastases.

Approximately 20% of patients with a primary examination reveal metastases. About half is metastatic damage to the lungs. Approximately 40% occur in multiple metastatic bone lesions and diffuse metastatic bone marrow lesions. Lymphogenous metastases are noted in about 10% of cases. CNS lesion is not typical for primary treatment, but it is possible in far-reaching cases.

Ewing's sarcoma is diagnosed according to a general plan for bone neoplasms. It should pay special attention to the myelogram: with its help with this tumor can be diagnosed metastatic damage to the bone marrow. In the serum, an increase in LDH activity is possible, although this is not necessary. In some patients, an increase in serum neuron-specific enolase (NSE) activity is detected.

Morphological examination of the neoplasm biopsy along with routine light microscopy includes additional diagnostic procedures, in particular immunohistochemical examination. It is invaluable for differentiation of the disease among other small-circular-sinecellular tumors. In a cytogenetic study, a stable chromosomal translocation t (ll; 22) (q24: ql2) is detected in most cell lines. This distinguishes the neoplasm from most other neoplasias, in which there is no such persistence of cytogenetic changes.

[18], [19], [20], [21]

Treatment

Treatment of Ewing's sarcoma is complex: it includes chemotherapy, radiotherapy and surgical treatment. In modern protocols for treatment use vykristin. Alkylating agents (cyclophosphamide, ifosfamide), topoisomerase inhibitors (ztoposide), anthracycline antibiotics (doxorubicin), actinomycin-D. The effective dose of radiation therapy is 60 Gy. When planning an organ-saving operation - 451r.

Patients at high risk - for tumors of unresectable localizations (spine, pelvic bone, skull bones), initially generalized neoplasms, in cases of Ewing sarcoma resistance to standard chemotherapy regimens, high-dose chemotherapy with bone marrow transplantation is prescribed.

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

What is the prognosis of Ewing's sarcoma?

The overall 5-year survival rate for Ewing sarcoma, subject to programmed treatment, is 50-60%. This indicator in the high-risk group, subject to high-dose chemotherapy and bone marrow transplantation, is 15-30%. The prognosis worsens if Ewing's large sarcoma, proximal localization in the limb (in comparison with the distal one), high LDH level (more than 200 ME), in males, in persons under 17 years old. The prognosis is fatal for unresectable pulmonary metastases, bone metastases and lymph nodes.