Ewing's sarcoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [2] Assistant Editor(s)-In-Chief: Michael Maddaleni, B.S.

Ewing’s sarcoma is the common name for primitive neuroectodermal tumor. Ewing’s sarcoma is the second most common malignant bone tumor in patients younger than 20 years. Ewing’s sarcoma is a small round-cell tumor in which cancer cells are found in the bone or in soft tissue. Ewing’s sarcoma may occur anywhere in the body, but most commonly occurs in the pelvis and proximal long tubular bones. The pathogenesis of Ewing’s sarcoma includes a t(11;22) chromosomal translocation. On microscopic histopathological analysis, presence of small round cells that have a high nuclear to cytoplasmic ratio, vacuolated cytoplasm, and faded boundaries are characteristic findings of Ewing’s sarcoma. There are no established causes for Ewing’s sarcoma. The most common symptoms of Ewing’s sarcoma include localized bone pain, swelling, fever, loss of appetite, and weight loss. On x-ray, Ewing’s sarcoma is characterized by permeative lytic lesion, periosteal reaction, and soft tissue calcification. On MRI, Ewing’s sarcoma is characterized by low to intermediate signal on T1, heterogenously high signal intensity on T2, and heterogenous but prominent enhancement on T1 contrast.

There is no classification system established for Ewing’s sarcoma.

Ewing’s sarcoma may occur anywhere in the body, but most commonly in the pelvis and proximal long tubular bones. The pathogenesis of Ewing’s sarcoma include t(11;22) chromosomal translocation. On microscopic histopathological analysis, presence of small round cells that have a high nuclear to cytoplasmic ratio, vacuolated cytoplasm, and faded boundaries are characteristic findings of Ewing’s sarcoma.

There are no established causes for Ewing’s sarcoma.

Ewing’s sarcoma must be differentiated from osteosarcoma, hematological malignancy, eosinophilic granuloma, and malignant fibrous histiocytoma.

Ewing’s sarcoma is the second most common malignant bone tumor in patients younger than 20 years. Ewing’s sarcoma typically occurs in children and adolescents between 10 and 20 years of age. The overall incidence of Ewing’s sarcoma is 0.1 cases per 100,000 individuals. The incidence of Ewing’s sarcoma in children aged 10 to 19 years is 1 case for 100,000 individuals. Males are more commonly affected with Ewing’s sarcoma than females.

Common risk factors in the development of Ewing’s sarcoma are age, gender, and race.

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for Ewing’s sarcoma.^[1]

Common complications of Ewing’s sarcoma include pathologic fracture and metastasis. Pretreatment factors that influence outcome of the Ewing’s sarcoma are site of the tumor, size of the tumor, serum LDH levels, and site of metastasis. After administration of preoperative chemotherapy, patients with minimal or no residual viable tumor have a significantly better prognosis than do patients with larger amounts of viable tumor.

There is no established system for the staging of Ewing’s sarcoma.

The most common symptoms of Ewing’s sarcoma include localized bone pain, swelling, fever, loss of appetite, and weight loss. The affected bone is not as strong as normal bones and may fracture with minor trauma (a pathological fracture).

Common physical examination findings of Ewing’s sarcoma are fever, localized swelling, and tenderness at the site of the tumor.

Laboratory tests for Ewing’s sarcoma include complete blood count, erythrocyte sedimentation rate, serum alkaline phosphatase, and lactate dehydrogenase

Biopsy of Ewing’s sarcoma is important for confirming the diagnosis and determining histologic subtype.^[2] Biopsy may be performed percutaneously with either a fine-needle, or wide-bore needle, or through a formal incision.

On x-ray, Ewing’s sarcoma is characterized by permeative lytic lesion, periosteal reaction, and soft tissue calcification.

CT scan in Ewing’s sarcoma may be helpful in biopsy and staging. CT scan adds little to plain radiography and MRI in direct assessment of the tumor.

On MRI, Ewing’s sarcoma is characterized by low to intermediate signal on T1, heterogenously high signal intensity on T2, and heterogenous but prominent enhancement on T1 contrast.

Bone scan in Ewing’s sarcoma is used to observe abnormal areas of bone and metastasis.^[3]

No additional tests are recommended for the diagnosis of Ewing’s sarcoma.

The treatment of Ewing’s sarcoma depends on the stage of the tumor. The options are surgery, radiation therapy, chemotherapy, or a combination of these methods. Rather than using the standard staging system, a simpler system is often used when deciding treatment for Ewing’s sarcoma. This system divides Ewing’s sarcoma of the bone into 2 groups: localized and metastatic.

Surgery in Ewing’s sarcoma may be used to remove the tumor following chemotherapy. If necessary, radiation therapy may be used before surgery to help make surgery possible. Surgery may also be used to remove metastases.

There is no established method for the prevention of Ewing’s sarcoma.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [2]

James Ewing (1866-1943) first described the tumor, establishing that the disease was separate from lymphoma and other types of cancer known at that time. A more famous case of Ewing’s sarcoma occurred at Boston College in Chestnut Hill, Massachusetts. A football player for BC, named Mark Herzlich, was diagnosed with Ewing’s sarcoma in 2009. With help from new treatments and surgery, he was able to beat the cancer.

• James Ewing (1866-1943) first described the tumor, establishing that the disease was separate from lymphoma and other types of cancer known at that time.

• A more famous case of Ewing’s sarcoma occurred at Boston College in Chestnut Hill, Massachusetts.
• A football player for BC, named Mark Herzlich, was diagnosed with Ewing’s sarcoma in 2009.
• With help from new treatments and surgery, he was able to beat the cancer.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [2]

There is no classification system established for Ewing’s sarcoma.

There is no classification system established for Ewing’s sarcoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [2];Assistant Editor(s)-In-Chief:Michael Maddaleni, B.S.

Ewing’s sarcoma may occur anywhere in the body, but most commonly occurs in the pelvis and proximal long tubular bones. The pathogenesis of Ewing’s sarcoma include t(11;22) chromosomal translocation. On microscopic histopathological analysis, the presence of small round cells that have a high nuclear to cytoplasmic ratio, vacuolated cytoplasm, and faded boundaries are characteristic findings of Ewing’s sarcoma.

Ewing’s sarcoma may occur anywhere in the body, but most commonly in the pelvis and proximal long tubular bones. The diaphyses of the femur are the most common sites, followed by the tibia and the humerus.

Ewing’s sarcoma is the result of a translocation between chromosomes 11 and 22, which fuses the EWS gene of chromosome 22 to the FLI1 gene of chromosome 11.^[1]

• The EWSR1 gene is a member of the TET family [TLS/EWS/TAF15] of RNA-binding proteins. The FLI1 gene is a member of the ETS family of DNA-binding genes.
• Characteristically, the amino terminus of the EWSR1 gene is juxtaposed with the carboxy terminus of the ETS family gene.
• In most cases (90%), the carboxy terminus is provided by FLI1, a member of the family of transcription factor genes located on chromosome 11 band q24.
• Other family members that may combine with the EWSR1 gene are ERG, ETV1, ETV4 (also termed E1AF), and FEV.
• Rarely, TLS, another TET family member, can substitute for EWSR1.

The MIC2 gene product, CD99, is a surface membrane protein that is expressed in most cases of Ewing’s sarcoma and is useful in diagnosing these tumors when the results are interpreted in the context of clinical and pathologic parameters. MIC2 positivity is not unique to Ewing’s sarcoma, and positivity by immunochemistry is found in several other tumors, including synovial sarcoma, non-Hodgkin lymphoma, and gastrointestinal stromal tumors.

Ewing’s sarcoma belongs to the group of neoplasms commonly referred to as small, round, and blue-cell tumors of childhood:^[1][2]

• On microscopic histopathological analysis, Ewing’s sarcoma consists of a homogeneous population of small round blue cells that have a high nuclear to cytoplasmic ratio.
• The tumor cells are tightly packed and grow in a diffuse pattern without evidence of structural organization.
• The individual cells of Ewing’s sarcoma contain round-to-oval nuclei, with fine dispersed chromatin without nucleoli.
• Occasionally, cells with smaller, more hyperchromatic, and probably degenerative nuclei are present, giving a light cell/dark cell pattern.
• The cytoplasm varies in amount, but in the classic case, it is clear and contains glycogen, which can be highlighted with a periodic acid-Schiff stain.
• The nuclei have intense color which make them easily visible.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [2]

There are no established causes for Ewing’s sarcoma.

There are no established causes for Ewing’s sarcoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [2]; Assistant Editor(s)-In-Chief: Michael Maddaleni, B.S.

Ewing’s sarcoma must be differentiated from osteosarcoma, hematological malignancy, eosinophilic granuloma, and malignant fibrous histiocytoma.^[1]

Ewing’s sarcoma must be differentiated from:^[1]

• Osteosarcoma

• ALP is not elevated in Ewing sarcoma.
• Ewing sarcoma tends to arise from the diaphysis whereas in osteosarcoma it tends to arise from the metaphysis.

• Osteomyelitis
• Hematological malignancy

• Large cell lymphoma

• Eosinophilic granuloma
• Malignant fibrous histiocytoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [2];Assistant Editor(s)-In-Chief: Michael Maddaleni, B.S.

Ewing’s sarcoma is the second most common malignant bone tumor in patients younger than 20 years. Ewing’s sarcoma typically occurs in children and adolescents between 10 and 20 years of age. The overall incidence of Ewing’s sarcoma is 0.1 cases for 100,000 individuals. The incidence of Ewing’s sarcoma in children aged 10 to 19 years is 1 case per 100,000 individuals. Males are more commonly affected with Ewing’s sarcoma than females.

Ewing’s sarcoma is the second most common malignant bone tumor in patients younger than 20 years. The most frequent is osteosarcoma.^[1]

• The incidence of Ewing’s sarcoma has remained unchanged for 30 years.^[2]
• The overall incidence of Ewing’s sarcoma is 0.1 cases per 100,000 individuals.
• The incidence of Ewing’s sarcoma in children aged 10 to 19 years is 1 case for 100,000 individuals.

• Incidence of Ewing’s sarcoma in the United States is nine times greater in whites than in African Americans, with an intermediate incidence in Asians.^[2]
• The relative paucity of Ewing’s sarcoma in people of African or Asian descent may be explained, in part, by a specific polymorphism.
• The polymorphism associated with the increased risk is found at a much higher frequency in whites than in blacks or Asians, possibly explaining the epidemiology of the relative infrequency of Ewing’s sarcoma in the latter populations.
• Ewing’s sarcoma usually affects individuals of the Caucasian race. African American individuals are less likely to develop chordoma.^[1]

• Ewing’s sarcoma typically occurs in children and adolescents between 10 and 20 years of age (95% between 4 and 25 years of age).
• The median age at diagnosis of Ewing’s sarcoma is 15 years.
• Well-characterized cases of Ewing’s sarcoma in neonates and infants have been described.
• Review of the SEER database from 1973 to 2011 identified 1,957 patients with Ewing sarcoma. Thirty-nine of these patients (2.0%) were younger than 12 months at diagnosis.

• Males are more commonly affected with Ewing’s sarcoma than females.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [2]

Common risk factors in the development of Ewing’s sarcoma are age, gender, and race.

The common risk factors in development of Ewing’s sarcoma are:

• Age: Ewing’s sarcoma typically occurs in children and adolescents between 10 and 20 years of age (95% between 4 and 25 years of age).
• Gender: males are more commonly affected with Ewing’s sarcoma than females.
• Race: incidence of Ewing’s sarcoma in the United States is nine times greater in whites than in African Americans, with an intermediate incidence in Asians.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [2]

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for Ewing’s sarcoma.^[1]

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for Ewing’s sarcoma.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [2];Assistant Editor(s)-In-Chief: Michael Maddaleni, B.S.

Common complications of Ewing’s sarcoma include pathologic fracture and metastasis. Pretreatment factors that influence outcome of the Ewing’s sarcoma are site of the tumor, size of the tumor, serum LDH levels, and site of metastasis. After administration of preoperative chemotherapy, patients with minimal or no residual viable tumor have a significantly better prognosis than do patients with larger amounts of viable tumor.

• The most frequent complications of Ewing’s sarcoma are pathologic fracture and the development of metastatic disease.
• Approximately 25% of patients with Ewing’s sarcoma have metastatic disease at the time of diagnosis.

• Out of all primary musculoskeletal tumors, Ewing’s sarcoma has maintained the form with the most unfavorable long term prognosis.^[1] In fact, prior to multi-drug chemotherapy, the survival rate was less than 10%. Now that there have been many options developed, such as chemotherapy, surgery, and irradiation, long-term survival has increased to greater than 50% due to increased treatment options.^[1]
• Staging attempts to distinguish patients with localized from those with metastatic disease. Most commonly, metastases occur in the chest, bone and/or bone marrow. Less common sites include the central nervous system and lymph nodes.
• Survival for localized disease is 65-70% when treated with chemotherapy. Long term survival for metastatic disease can be less than 10% but some sources state it is 25-30%.

The two major types of prognostic factors for patients with Ewing’s sarcoma are grouped as follows:^[2]

• Pretreatment factors.
• Response to initial therapy factors.

Site of tumor

• Patients with Ewing’s sarcoma in the distal extremities have the best prognosis.
• Patients with Ewing’s sarcoma in the proximal extremities have an intermediate prognosis, followed by patients with central or pelvic sites.

Tumor size or volume

• Tumor size or volume has been shown to be an important prognostic factor in most studies.
• Cutoffs of a volume of 100 mL or 200 mL and/or single dimension greater than 8 cm are used to define larger tumors.
• Larger tumors tend to occur in unfavorable sites.

Age

• Infants and younger patients have a better prognosis than patients aged 15 years and older.
• Early death was more common in infants, but the overall survival (OS) did not differ significantly from that of older patients.

Gender

• Girls with Ewing’s sarcoma have a better prognosis than boys with Ewing’s sarcoma.

Serum LDH

• Increased serum LDH levels before treatment are associated with poor prognosis.
• Increased LDH levels are also correlated with large primary tumors and metastatic disease.

Metastases

• Any metastatic disease defined by standard imaging techniques or bone marrow aspirate/biopsy by morphology is an adverse prognostic factor.
• The presence or absence of metastatic disease is the single most powerful predictor of outcome.
• Patients with metastatic disease confined to the lung have a better prognosis than do patients with extra pulmonary metastatic sites.
• The number of pulmonary lesions does not seem to correlate with outcome, but patients with unilateral lung involvement do better than patients with bilateral lung involvement.
• Patients with metastasis to only bone seem to have a better outcome than do patients with metastases to both bone and lung.
• Based on an analysis from the SEER database, regional lymph node involvement in patients is associated with an inferior overall outcome when compared with patients without regional lymph node involvement.

Previous treatment for cancer

• Patients with Ewing’s sarcoma as a second malignant neoplasm were older (secondary Ewing’s sarcoma, mean age of 47.8 years; primary Ewing’s sarcoma, mean age of 22.5 years), more likely to have a primary tumor in an axial or extraskeletal site, and had a worse prognosis (5-year OS for patients with secondary Ewing’s sarcoma, 43.5%; patients with primary Ewing’s sarcoma, 64.2%).

Detectable fusion transcripts in morphologically normal marrow

• Reverse transcriptase polymerase chain reaction can be used to detect fusion transcripts in bone marrow. Fusion transcript detection in marrow or peripheral blood was associated with an increased risk of relapse.

Other biological factors

• Over expression of the p53 protein, Ki67 protein, and loss of 16q may be adverse prognostic factors.
• High expression of microsomal glutathione S-transferase, an enzyme associated with resistance to doxorubicin, is associated with inferior outcome for Ewing’s sarcoma.

• Multiple studies have shown that patients with minimal or no residual viable tumor after presurgical chemotherapy have a significantly better prognosis than do patients with larger amounts of viable tumor.

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