Ewing sarcoma (ES) is an aggressive tumor of adolescents and young adults, which constitutes 10% to 15% of all bone sarcomas. James Ewing first described it in 1921, and it represents 'classic' Ewing sarcoma of bone, extra-skeletal Ewing sarcoma, malignant small cell tumor of the chest wall (Askin tumor), and soft tissue-based primitive neuroectodermal tumors (PNET). These sarcomas originate from unique mesenchymal progenitor cells due to their similar histologic and immunohistochemical characteristics.
Ewing sarcoma family tumors (ESFT) are characterized by the presence of non-random chromosomal translocations producing fusion genes that encode aberrant transcription factors. The t(11;22)(q24;q12) translocation is associated with 85% of tumors and leads to EWS-FLI-1 formation, whereas t(21;12)(22;12) and other less common translocations induced EWS-ERG fusion comprises the remaining 10% to 15% of cases.
The most common anatomical sites include the pelvis, axial skeleton, and femur; however, it may occur in almost any bone or soft tissue. Typically, patients present with pain and swelling over the site of involvement. Over the last 40 years, both local therapy and multiagent adjuvant chemotherapy have achieved considerable progress in the treatment of localized disease that improved 5–year survival rate from less than 20% to greater than 70% but the recurrence rate remains high. Although most present locally, subclinical metastatic disease is present in almost all. Approximately 25% of patients with initially localized disease ultimately relapse. No standard therapy exists for relapsed and refractory ES, with survival rates being less than 30% in those with isolated lung metastases and less than 20% in those with bone and bone marrow involvement. Given these considerations of toxicity and suboptimal survival from metastatic disease, there is an urgent unmet need to develop novel therapies for ES.
There is no well- established association between ES and environmental risk factors, drug exposure, radiation history, cancer history in the family. Studies have been limited to the small retrospective, case-control studies.
Ewing sarcoma is the second most common primary bone malignancy in adolescents and young adults with a median age of 15 years, and it accounts for less than 5% of all soft tissue sarcomas. There are more than 200 cases per year in the United States. The incidence of Ewing sarcoma in the United States was 2.93 per million during the period between 1973 and 2004. The peak incidence is between 10 to 15 years of age, with around 30% of the cases arising in children under the age of 10, and another 30% are in adults over the age of 20. There is a male predominance with a male to female ratio of 1 to 3. Whites are much more frequently affected than Asians, Hispanics, African-Americans, or Africans. This significant racial discordance has yet to be explored. The actual incidence of Ewing sarcoma in the elderly is not well known.
The cell of origin of Ewing sarcoma has yet to be fully elucidated. ES is characterized by non-random gene rearrangements between the EWS gene and ETS (E26 transformation-specific or E-twenty-six) gene family. Most frequent gene rearrangement is t(11;22)(q24;q12). A hybrid gene EWS–FLI1 is generated by the fusion of the EWS gene on 22q12 with the FLI1 gene on 11q24 occurs in greater than 80% of the cases. The resulting EWS-FLI1 fusion protein acts as an aberrant transcription factor, and thus it can be reasonably assumed that it may play a role in the pathogenesis of ES. However, the underlying etiology of the translocation has not yet been well established. Second most common EWS–ETS gene family rearrangement is t(21;22)(q22;q12)translocation resulting in the fusion of EWS with the ERG gene on 21q22 that founds in about 15% of the cases. In the literature, other detected gene rearrangements are t(7;22)(p22;q12), t(17;22)(q21;q12) and (t(2;22)(q33;q12) where EWS is fused with ETS gene family ETV1, E1AF and FEV, respectively. More chromosomal translocations and complex gene rearrangements have also been reported in the literature; however, it is not yet clear whether it is associated with more aggressive tumor features.
Ewing sarcoma is composed of small round cells with an increased nuclear-cytoplasmic ratio that represents a family of small round blue cell tumors of childhood (e.g., retinoblastoma, neuroblastoma, rhabdomyosarcoma, and nephroblastoma). Ewing cells have scant eosinophilic cytoplasm containing abundant glycogen that is often detected by staining with periodic-acid-Schiff.
High CD99 expression has been shown in more than 80% of the cases. This highly sensitive immunohistochemical biomarker likely plays a key role in facilitating continued migration of leukocytes to endothelium; however, it lacks specificity as it may be detected in other sarcomas and lymphomas.
In addition to MIC2 gene product CD99, Ewing cells often express CD45, synaptophysin, chromogranin, vimentin, vimentin, keratin, desmin, neuron-specific enolase (NSE), and S-100. However, this immunohistochemistry panel has been limited by a lack of specificity. Molecular genetic studies, using fluorescence in situ hybridization (FISH) and/or reverse transcription-polymerase chain reaction (RT-PCR), are required to make the definitive distinction.
Patients with Ewing sarcoma often present with local symptoms such as pain, stiffness, or swelling for a few weeks or months. More than 50% of the patients with ES have intermittent pain that worsens at night. Ewing sarcoma can occur in a wide variety of locations with varying presentations. It is commonly found in the diaphysis of long bones. Bone lesions or metastatic lesions within the long bone can present as pathological fractures. The pelvic location of ES can present as back pain. The presence of systemic symptoms, including fever, weight loss, often indicates metastatic disease. Around 20% of patients present with metastatic disease at the time of diagnosis, and among these cases, more than 20% have lung or pleura involvement.
A comprehensive physical examination is critical. In the setting of lung and pleura metastasis, the patient can present with asymmetric breath sounds, pleural signs, or rales. Petechia or purpura from thrombocytopenia can be observed in patients with bone marrow metastases. Neurologic examination is also critical in patients with CNS involvement.
Initial workups include X-ray of the affected area, which may show the "onion skin" appearance of periosteal reaction. Bone scan, MRI, and CT scan are required for initial staging to look for metastasis.
The primary site and potential metastatic sites should be evaluated by imaging tests. Plain radiographs of the affected area may show destructive confluent '' moth-eaten" lesions, "Codman's triangle" of the elevated periosteum or multilayered "onion-skin" periosteal reaction. According to the updated National Comprehensive Cancer Network (NCCN) guideline from 2017, imaging of primary sites includes MRI with or without CT, with contrast is of prime importance. Other imaging methods, including CT thorax, PET/CT, bone scan, and MRI of the spine/pelvis, can also be used to detect possible metastatic sites. The symptomatic patient should be referred to the orthopedic surgeon if any biopsy is needed. Although the diagnosis can be made with CT-guided core-needle biopsy, adequate sampling is obtained by open biopsy. Molecular cytogenetic analysis of biopsy specimens should be included in the diagnostic workup to evaluate the t(11;22) translocation. Bone marrow aspiration with smear and bone marrow biopsy should be considered. As a prognostic factor, LDH should be included in initial studies. According to NCCN guidelines, the first assessment should consist of serum LDH as it carries prognostic significance. The patients should also be offered fertility counseling before starting the treatment.
The standard of care for patients with or without metastasis includes interprofessional treatment with chemotherapy and local therapy, including surgery and radiotherapy (RT).
Historically, Intergroup Ewing Sarcoma Study trials (IESS-I and IESS-II) showed better results with RT plus adjuvant chemotherapy with VACA (vincristine, dactinomycin, cyclophosphamide, and doxorubicin) as compared to VAC (vincristine, dactinomycin, and cyclophosphamide). Due to the dose limitation of doxorubicin in dactinomycin regimens, trials thereafter demonstrated no significant impact on clinical outcomes with the omission of dactinomycin. Several studies evaluated the addition of ifosfamide and etoposide to standard chemotherapy. The Pediatric Oncology Group-Children’s Cancer Group study INT0091 demonstrated that the VACD-IE group had significantly better survival rates than the VACD group. Also, the VACD-IE group was associated with a lower incidence of local failure.
In the EICESS-92 study (European Intergroup Cooperative Ewing Sarcoma Study), VACA (vincristine, dactinomycin, cyclophosphamide, and doxorubicin) and VAIA (vincristine, dactinomycin, ifosfamide, and doxorubicin) were compared in the standard risk patients (SR), and the effect of cyclophosphamide was found similar to ifosfamide in SR; however, cyclophosphamide was associated with increased toxicity. The 3-year Event-free survival (EFS) rates were 73% and 74% for VACA and VAIA, respectively.
Euro-EWING99-R1 trial (noninferiority trial based on EICESS-92 protocol) evaluated whether cyclophosphamide could replace ifosfamide in consolidation therapy including vincristine and dactinomycin in patients with standard-risk and it suggested that VAC (vincristine, dactinomycin, and cyclophosphamide) was statistically not inferior to VAI (vincristine, dactinomycin, and ifosfamide); however, VAI was associated with slightly higher 3-year EFS.
In a phase III trial (AEWS0031) from the Children’s Oncology Group (COG), patients on the standard arm received VDC alternating with IE every three weeks compared with patients received the same chemotherapy every two weeks. The study demonstrated that 2-week intervals were more effective than 3-week intervals without increasing toxicity.
This has led to VDC/IE being the standard of care in the United States. The chemotherapy is started before the local therapy and continued postoperatively if no evidence of progression.
Surgical resection and RT are local control treatment approaches. There are no trials to date comparing the efficacy of these two approaches. The INT-0091 study did not find significant differences in local failure or event-free survival between surgery alone and RT alone. However, surgery plus RT was found to be associated with a lower incidence of local failure.
The data of 1058 patients from CESS 81, CESS 86, and EICESS-92 trials showed that surgery with or without postoperative RT had a significantly lower rate of local failure than definitive RT. The incidence of local failure was comparable in the preoperative RT group and surgery with or without postoperative RT group.
Data from patients enrolled in INT-0091, INT-0154, or AEWS0031 studies were analyzed by COG that also showed surgery plus RT was associated with a lower risk of local failure than definitive RT.
Similar systemic chemotherapy discussed previously are also used for metastatic disease. The addition of ifosfamide and/or etoposide to standard chemotherapy was found ineffective with no survival benefit for patients with metastatic disease.
A prospective study for the treatment of metastatic ES evaluated dose-intensification approach (doxorubicin, vincristine with or without high-dose cyclophosphamide, followed by ifosfamide and etoposide); however, this approach did not change the survival rates.
The role of high-dose chemotherapy with hematopoietic cell rescue (HDC/HSCT) was also studied for patients with metastatic disease. EURO-EWING 99-R2pulm randomized trial of patients with lung metastases demonstrated no significant survival benefits in patients who underwent busulfan/melphalan high-dose chemotherapy with autologous stem cell rescue (BuMel) compared with those who underwent conventional chemotherapy with whole-lung irradiation.
Local control of the primary site should be considered for metastatic disease. In a retrospective study, patients treated with radiation therapy for local treatment of metastases had significantly better 3-year EFS (35%) than did the patients without local treatment (16%).
Recurrent Ewing sarcoma is associated with poor prognosis, and treatment options are limited. Several studies evaluated gemcitabine, docetaxel, bortezomib, and ecteinascidin-743; however, no clinical benefit was reported. These patients should be considered for participation in clinical trials with new therapeutic agents if available.
Combining immunohistochemical and morphological findings with relevant clinical history can help narrow down the differential diagnosis of ES that includes other small round cell tumors such as neuroblastoma, rhabdomyosarcoma, lymphoma, neuroectodermal tumors, desmoplastic small round cell tumor and synovial sarcoma. Osteomyelitis, osteogenic sarcoma, and eosinophilic granuloma should also be considered in the differential diagnosis of ES.
A phase III study of Vigil immunotherapy in combination with irinotecan and temozolomide for metastatic Ewing sarcoma Family of Tumors (ESFT) is currently recruiting patients. A phase II study of palbociclib (CDK4 and CDK6 inhibitor) and ganitumab (IGF-1R inhibitor) combination is testing safety and efficacy for refractory Ewing sarcoma patients. Several new agents, including LSD1 inhibitors Seclidemstat (SP-2577), INCB059872, PARP inhibitor niraparib, are currently being under investigation.
Ewing sarcoma is associated with an increased risk of adverse health outcomes. Patients treated with current therapy are likely to develop severe neutropenia, and it may be complicated by recurrent fever, opportunistic infections, and mucositis, despite the administration of G-CSF. Potential adverse events of radiotherapy and chemotherapy include an increased risk of a second malignant neoplasm. The cumulative incidence of the second neoplasm in cancer-survivors of large series was less than 2% that usually occurs within three years of initial diagnosis. The commonest malignancies are acute myeloid leukemia, myelodysplastic syndrome, and sarcomas within the radiation field. Drugs that can cause secondary leukemias include alkylating agents (i.e., cyclophosphamide), topoisomerase II inhibitors (i.e., etoposide, teniposide), and anthracycline agents (i.e., doxorubicin). However, in the IESS trial comparing VAC with VAC-IE showed that the addition of etoposide was not associated with the increased risk of a second malignancy. C-arm of the INT 0091 study demonstrated that very high cumulative doses of ifosfamide and cyclophosphamide were associated with a 10% incidence of therapy-related leukemia. Cyclophosphamide and ifosfamide are associated with infertility. Also, ifosfamide can cause renal failure, slowly progressive chronic renal failure or renal tubule cell dysfunction.
Anthracyclines, including doxorubicin, are well known to cause cumulative-dose related cardiotoxicity. Prolonged infusion or dexrazoxane can be administered before doxorubicin to decrease the risk of cardiotoxicity.
Radiation-induced secondary malignant neoplasms, particularly osteosarcomas, have also been observed, especially at high doses. These second malignancies can occur more than 15 years after the diagnosis. Patients treated with radiation therapy should be carefully evaluated for the presence of sarcoma within the radiation field if symptoms occur. Second malignancies after Ewing tumor treatment in 690 patients from a cooperative German, Austrian, and Dutch study.
The commonly used staging system for Ewing sarcoma developed by Musculoskeletal Tumor Society (MSTS) classifies tumor by grade (low grade being stage I, high-grade stage II, distant metastasis stage III) and compartmental status (located in the bone cortex vs. extended beyond the bone cortex). Another classification method is TNM by the American Joint Committee on Cancer (AJCC), which is based on tumor size, lymph node metastasis, distant metastasis, and tumor grade (cellular differentiation, mitotic rate, and extent of necrosis).
Several prognostic factors have been identified in Ewing sarcoma. Patients with ES within distal extremities tend to have a better prognosis compared to patients having a lesion in proximal extremities. The presence of metastatic disease is essential for the assessment of prognosis.
Patients with solitary pulmonary metastases more likely have a better prognosis than the patients with extrapulmonary metastatic sites, and unilateral lung involvement does seem to correlate with a better prognosis than bilateral lung involvement. The development of both bone and lung metastases, extensive tumors are associated with poor prognosis. Tumor size was also found to be an important prognostic factor in studies. Overall, data shows that less than 15 years is another significant clinical prognostic factor. Clinical studies have shown that patients with minimal or no viable residual tumor at surgery following neoadjuvant chemotherapy did seem to have a better outcome than the patients with more significant amounts of viable tumor. Additionally, inadequate response to neoadjuvant chemotherapy is associated with an increased risk of recurrence. It should be noted that EWSR1-ETS translocation is no longer considered as an adverse prognostic factor.
Ewing sarcoma may be complicated by metastases, local recurrence, secondary malignancies, pathological fractures, surgery, and radiation-associated and chemotherapy-associated morbidities.
Ewing sarcoma (ES) is an aggressive tumor of adolescents and young adults, which constitutes 10-15% of all bone sarcomas. Ewing sarcoma can occur in a wide variety of locations with varying presentations. The most common anatomical sites include the pelvis, axial skeleton, and femur; however, it may occur in almost any bone or soft tissue. Patients with ES often present with local symptoms such as pain, stiffness, or swelling for a few weeks or months. More than 50% of the patients with ES have intermittent pain that worsens at night. Bone lesions or metastatic lesions within the long bone can present as pathological fractures. The pelvic location of ES can present as back pain. The presence of systemic symptoms, including fever, weight loss, often indicates metastatic disease. Around 20% of patients present with metastatic disease at the time of diagnosis, and among these cases, more than 20% have lung or pleura involvement.
Over the last 40 years, both local therapy and multi-agent adjuvant chemotherapy have achieved considerable progress in the treatment of localized disease that improved 5–year survival rate from less than 20% to greater than 70% but the recurrence rate remains high. Approximately 25% of patients with initially localized disease ultimately relapse. No standard therapy exists for relapsed and refractory ES, with survival rates being less than 30% in those with isolated lung metastases and less than 20% in those with bone and bone marrow involvement.
Symptoms of bone pain, joint pain, or palpable mass warrant assessment. A comprehensive physical examination is critical. Patients and their families should be educated on these presenting symptoms as they may potentially be related to an osseous neoplasm. Optimal treatment of childhood cancer requires a high level of suspicion by the primary care practitioner and early referral to the pediatric oncologist. Early detection and treatment may reduce disease-related morbidity and complications.
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