Ewing sarcoma

Ewing sarcoma is a type of

Ewing sarcoma is more common in males (1.6 male:1 female) and usually presents in childhood or early adulthood, with a peak between 10 and 20 years of age. It can occur anywhere in the body but most commonly in the

Signs and symptoms include intermittent fevers, anemia, leukocytosis, increased sedimentation rate, and other symptoms of inflammatory systemic illness.^[14]

According to the Bone Cancer Research Trust (BCRT), the most common symptoms are localized pain, swelling, and sporadic bone pain with variable intensity. The swelling is most likely to be visible if the sarcoma is located on a bone near the surface of the body, but when it occurs in other places deeper in the body, like on the pelvis, it may not be visible.^[15]

Genetics

Genetic exchange between chromosomes can cause cells to become cancerous. Most cases of Ewing sarcoma (about 85%) are the result of a defining genetic event; a reciprocal

A 2012 genome-wide association study (GWAS) identified three susceptibility loci located on chromosomes 1, 10 and 15.[16] A 2015 continuative study discovered that the Ewing sarcoma susceptibility gene EGR2, which is located within the chromosome 10 susceptibility locus, is regulated by the EWSR1-FLI1 fusion oncogene via a GGAA-microsatellite.^[17][18] A 2018 GWAS (Machiela, et al, 2018)^[5] reaffirmed the susceptibility loci on chromosomes 1, 10 and 15 and added 3 additional loci on chromosomes 6 and 20; totaling 1p36.22, 6p25.1, 10q21.3, 15q15.1, 20p11.22 and 20p11.23. The latter locus is near NKX2-2, a highly overexpressed gene in Ewing sarcoma.^[5]

The definitive diagnosis is based on

]

Medical imaging

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On conventional radiographs, typical findings of Ewing sarcoma consist of multiple confluent lytic bone lesions that have a "moth eaten" pattern due to permeative destruction of bone.^[11] There will also be a displaced periosteum as the new sub-periosteal layer of bone begins to grow on top of the tumor. This raised or displaced periosteum is consistent with the classic radiographic finding of the Codman triangle.^[11] The proliferative reaction of bone can also create delicate laminations constituting the periosteal layers and giving the radiographic appearance of an onion peel.^[11] Plain films add valuable information in the initial evaluation or screening. The wide zone of transition (e.g. permeative) is the most useful plain film characteristic in differentiation of benign versus aggressive or malignant lytic lesions.

Magnetic resonance imaging (MRI) should be routinely used in the work-up of malignant tumors. It will show the full bony and soft tissue extent and relate the tumor to other nearby anatomic structures (e.g. vessels). Gadolinium contrast is not necessary as it does not give additional information over noncontrast studies, though some current researchers argue that dynamic, contrast-enhanced MRI may help determine the amount of necrosis within the tumor, thus help in determining response to treatment prior to surgery.^[27]

Radiographically, Ewing sarcoma presents as "moth-eaten" destructive radiolucencies of the medulla and erosion of the cortex with expansion.[29]

Differential diagnosis

Other entities with similar clinical presentations include

Almost all people receive multidrug chemotherapy (most often vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide),^[34] as well as local disease control with surgery and/or radiation.^[35] An aggressive approach is necessary because almost all people with apparently localized disease at the time of diagnosis actually have asymptomatic metastatic disease.^{[citation needed]}

The surgical resection may involve limb salvage or amputation. Complete excision at the time of biopsy may be performed if malignancy is confirmed at the time it is examined.^{[citation needed]} Treatment lengths vary depending on location and stage of the disease at diagnosis. Radical chemotherapy may be as short as six treatments at three-week cycles, but most people undergo chemotherapy for 6–12 months and radiation therapy for 5–8 weeks.^{[citation needed]} Radiotherapy has been used for localized disease. The tumor has a unique property of being highly sensitive to radiation, sometimes acknowledged by the phrase "melting like snow", but the main drawback is that it recurs dramatically after some time.^{[citation needed]}

In most pediatric cancers including sarcoma, proton beam radiation (also known as proton therapy) delivers an equally effective dose to the tumor with less damage to the surrounding normal tissue compared to photon radiation.^[40]

Prognosis

Staging attempts to distinguish people with localized from those with metastatic disease.^[41] The most common areas of metastasis are the lungs, bone and bone marrow with less common areas of metastasis being the lymph nodes, liver and brain.^[11] The presence of metastatic disease is the most important prognostic factor in Ewing Sarcoma with the 5 year survival rate being only 30% when metastasis is present at the time of diagnosis as compared to a 70% 5 year survival rate with no metastasis present.^[11] Another important prognostic factor is the location of the primary tumor; proximal tumors (located in the pelvis and sacrum) are worse prognostic indicators as compared to more distal tumors.^[11] Other factors associated with a poor prognosis include a large primary neoplasm, older age at diagnosis (older than 18 years of age) and increased lactate dehydrogenase (LDH) levels.^[11]

Five-year survival for localized disease is greater than 70% after therapy.^[42] Prior to the use of multi-drug chemotherapy, long-term survival was less than 10%. The development of multi-disciplinary therapy with chemotherapy, irradiation, and surgery has increased current long-term survival rates in most clinical centers to greater than 50%.^[43] However, some sources state it is 25–30%.^[44]

Retrospective research showed that two chemokine receptors, CXCR4 and CXCR7, can be used as molecular prognosis factors. People who express low levels of both chemokine receptors have the highest odds of long-term survival with >90% survival at five years post-diagnosis versus <30% survival at five years for patients with very high expression levels of both receptors.^[45] A recent study also suggested a role for SOX2 as an independent prognostic biomarker that can be used to identify patients at high risk for tumor relapse.^[46]

Epidemiology

Ewing sarcomas represent 16% of primary bone sarcomas.^[14] In the United States, they are most common in the second decade of life,^[14] with a rate of 0.3 cases per million in children under 3 years of age, and as high as 4.6 cases per million in adolescents aged 15–19 years. Nearly 80% of patients are aged less than 20 years of age.^[47] It is uncommon in patients younger than 5 years and older than 30 years.^[47]

Internationally, the annual incidence rate averages less than 2 cases per million children.^[48] In the United Kingdom, an average of six children per year are diagnosed; mainly males in early stages of puberty. With occurrences primarily arising in older children and teenagers, one causal theory is puberty, e.g. its rapid growth spurts making bone tissue more cancer susceptible during development years.^[49]

A grouping of three unrelated teenagers in Wake Forest, North Carolina, have been diagnosed with Ewing sarcoma. All three children were diagnosed in 2011 and all attended the same temporary classroom together while the school underwent renovation. A fourth teenager living nearby was diagnosed in 2009. The odds of this grouping are considered significant.^[50] Ewing sarcoma occurs about 10- to 20-fold more commonly in people of European descent compared to people of African descent.^[51][11]

Ewing sarcoma is the second most common bone cancer in children and adolescents, with poor prognosis and outcome in ~70% of initial diagnoses and 10–15% of relapses.^[52]

References