Ewing's Sarcoma
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Ewing's sarcoma / Peripheral Primitive Neuroectodermal Tumours (PNET) of bone is a type of cancer usually found in children and young adults. The peak incidence is between ages 10 and 20, it is less common in children under 5 or in adults over 30. Ewing's s can occur in any bone in the body; the most common sites are the pelvis, thigh, lower leg, upper arm, and rib. The tumour is composed of small round blue cells. Ewing's sarcoma can also arise in soft tissue (extra-skeletal); see Soft Tissue Sarcoma in this guide.

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See also: Genetic features of Ewing's Sarcoma

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Max D, Kühnöl CD, Burdach S, et al.
Indoleamine-2,3-dioxygenase in an immunotherapy model for Ewing sarcoma.
Anticancer Res. 2014; 34(11):6431-41 [PubMed] Related Publications
BACKGROUND/AIM: Interleukin-2 (IL2) transgenic Ewing sarcoma cells reduce tumor growth in vivo and in vitro. In the present study we analyzed the expression of immune suppressive indoleamine-2,3-dioxygenase (IDO) in this model.
MATERIALS AND METHODS: Expression of IDO was analyzed by polymerase chain reaction. The impact of the cluster of differentiation 137 (CD137)/CD137 ligand (CD137L) co-stimulatory system on expression of IDO and different cytokines was analyzed both in vivo and in vitro.
RESULTS: Tumors that developed in vivo in the presence of IL2 transgenic tumor cells expressed IDO. The presence of CD137L transgenic tumor cells led to down-regulation of IDO. Further in-vitro analysis of this phenomenon indicated that IDO was expressed in tumor cells as a consequence of interferon-gamma produced by lymphocytes in response to IL2. Depending on the concentration of IL2, stimulation of CD137 increased or reduced cytokine production in lymphocytes.
CONCLUSION: Our data indicate that the CD137/CD137L pathway can modulate the immune response against Ewing sarcoma cells.

Related: Bone Cancers Cytokines Interleukin 2 (Aldesleukin)


De Meis E, Brandão BC, Capella FC, et al.
Catastrophic antiphospholipid syndrome in cancer patients: an Interaction of clotting, autoimmunity and tumor growth?
Isr Med Assoc J. 2014; 16(9):544-7 [PubMed] Related Publications
Thrombosis is a common phenomenon in patients with malignancies. It is believed that thrombosis is multifactorial and that in addition to mechanisms directly associated with cancer and its treatment, it may also be related to the interaction between the immune system and clotting. The present work describes four cancer patients (three adults and one child) whose clinical course was characteristic of catastrophic antiphospholipid syndrome (CAPS) in intensive care units of the National Cancer Institute of Rio de Janeiro. The presence of findings similar to those in CAPS can be attributed to an unbalanced interaction between the immune system and coagulation.

Related: Extra-Hepatic Bile duct cancer (cholangiocarcinoma) Bone Cancers Lung Cancer


Oksüz DC, Tural D, Dincbas FÖ, et al.
Non-metastatic Ewing's sarcoma family of tumors of bone in adolescents and adults: prognostic factors and clinical outcome-single institution results.
Tumori. 2014 Jul-Aug; 100(4):452-8 [PubMed] Related Publications
AIMS AND BACKGROUND: There is limited data regarding outcomes of Ewing's sarcoma family of tumors in adolescents and adults compared with the same tumors in childhood. The aim of the study was to analyze prognostic factors and treatment results in a cohort of adolescents and adults with non-metastatic skeletal Ewing's sarcoma family of tumors.
METHODS AND STUDY DESIGN: From 1992-2008, 90 adolescents and adults with Ewing's sarcoma family of tumors of the bone were referred to our institution. Sixty-five (72%) non-metastatic patients with analyzable data and treated in our institution were retrospectively evaluated. All patients were treated with alternated chemotherapy regimens administered every 3 weeks. The local treatment modality was selected according to tumor and patient characteristics.
RESULTS: The median age was 21 years (range, 13-50). Most patients (74%) were >17 years of age. Forty-six percent of the tumors were located in the extremities. Local therapy was surgery in 45 patients and radiotherapy alone in 19 patients. Twenty-one patients received preoperative and 13 patients postoperative radiotherapy. Median follow-up was 43 months (range, 7-167). The 5-year event-free and overall survival rates for all patients were 44% and 49%, respectively. On univariate survival analysis, event-free and overall survival were worse for patients >17 years of age, tumor size >8 cm in diameter, an axial location, positive surgical margins, and poor histopathological response (<90% necrosis). Age, tumor site and tumor size on event-free and overall survival remained significant on multivariate analysis.
CONCLUSIONS: We identified age, tumor size, and tumor site as independent prognostic factors, in accord with the Western literature. These patients require novel treatment modalities.

Related: Bone Cancers


Amita R, Sandhyamani S, Nair S, Kapilamoorthy TR
Intracranial ewings sarcoma/peripheral primitive neuroectodermal tumor.
Neurol India. 2014 Jul-Aug; 62(4):432-3 [PubMed] Related Publications
Central nervous system primitive neuroectodermal tumours (CNS PNET) are aggressive embryonal tumours composed of undifferentiated or poorly differentiated neuroepithelial cells seen in the pediatric age group. This is rare and only a handful of cases of ES/pPNET in CNS are reported. We report such a case in a 3 year old child. Reporting of more such cases is needed to better define these rare tumours of the dura.


Mei J, Zhu XZ, Wang ZY, Cai XS
Functional outcomes and quality of life in patients with osteosarcoma treated with amputation versus limb-salvage surgery: a systematic review and meta-analysis.
Arch Orthop Trauma Surg. 2014; 134(11):1507-16 [PubMed] Related Publications
INTRODUCTION: To perform a meta-analysis for comparing the functional outcomes and quality of life (QOL) of osteosarcoma patients receiving amputation or limb-salvage surgeries.
MATERIALS AND METHODS: A search was conducted of the Medline, Cochrane, EMBASE, and Google Scholar on September 30, 2013. Studies were included in the analysis if there were patients who underwent amputation and limb-salvage surgery for osteosarcoma or Ewing's sarcoma, and for whom postoperative functional outcomes and QOL were evaluated. Outcomes were compared between participants who underwent limb-salvage operation and those who underwent amputation. The methodological quality of non-randomized comparative studies was assessed using the Newcastle-Ottawa Scale.
RESULTS: A total of 121 studies were identified and 6 were included in the meta-analysis. Quality assessment indicated that all six studies were of high quality. The mean age of the participants ranged from 17 to 37 years, and among them 118 underwent amputations and 138 underwent limb-salvage procedures. The mean length of follow-up ranged from 28 to 145 months. The meta-analysis indicated that functional outcomes and QOL were similar between patients who underwent amputation and those who underwent a limb-salvage procedure.
CONCLUSIONS: This meta-analysis including six high-quality studies indicates that amputation and limb-salvage surgery provide similar functional outcomes and quality of life for patients with osteosarcomas.

Related: Bone Cancers Osteosarcoma


Moore DD, Haydon RC
Ewing's sarcoma of bone.
Cancer Treat Res. 2014; 162:93-115 [PubMed] Related Publications
Ewing's sarcoma of bone is a primary bone sarcoma found predominantly in patients during their second decade of life. It is a high-grade aggressive small round blue cell tumor that is part of the Ewing's family of tumors. Its exact eitiology is unknown but it commonly demonstrates reproducible staining of CD99 and translocations of the EWS gene. Historically, this diagnosis was associated with near certain metastasis and subsequent mortality. However, current management consists of extensive chemotherapy in addition to local control with surgical resection and/or radiation. As a result, survival has improved to the 55-75% range in those patients who present without known metastases. Current research aims to continue this improvement by looking further into the associated gene abnormalities and possibly targeted therapies.

Related: Bone Cancers


Xia T, Guan Y, Chen Y, Li J
Askin tumor: CT and FDG-PET/CT imaging findings and follow-up.
Medicine (Baltimore). 2014; 93(6):e42 [PubMed] Related Publications
The aim of the study was to describe the imaging findings of Askin tumors on computed tomography (CT) and fluorine 18 fluorodeoxyglucose-positron emission tomography (FDG-PET/CT).Seventeen cases of Askin tumors confirmed by histopathology were retrospectively analyzed in terms of CT (17 cases) and FDG-PET/CT data (6 cases).Fifteen of the tumors were located in the chest wall and the other 2 were in the anterior middle mediastinum. Of the 15 chest wall cases, 13 demonstrated irregular, heterogeneous soft tissue masses with cystic degeneration and necrosis, and 2 demonstrated homogeneous soft tissue masses on unenhanced CT scans. Two mediastinal tumors demonstrated the irregular, heterogeneous soft tissue masses. Calcifications were found in 2 tumors. The tumors demonstrated heterogeneously enhancement in 16 cases and homogeneous enhancement in 1 case on contrast-enhanced scans. FDG-PET/CT images revealed increased metabolic activity in all 6 cases undergone FDG-PET/CT scan, and the lesion SUVmax ranged from 4.0 to 18.6. At initial diagnosis, CT and FDG-PET/CT scans revealed rib destruction in 9 cases, pleural effusion in 9 cases, and lung metastasis in 1 case. At follow-up, 12 cases showed recurrence and/or metastases, 4 cases showed improvement or remained stable, and 1 was lost to follow-up.In summary, CT and FDG-PET/CT images of Askin tumors showed heterogeneous soft tissue masses in the chest wall and the mediastinum, accompanied by rib destruction, pleural effusion, and increased FDG uptake. CT and FDG-PET/CT imaging play important roles in the diagnosis and follow-up of patients with Askin tumors.

Related: Bone Cancers


Casey DL, Alektiar KM, Gerber NK, Wolden SL
Whole lung irradiation for adults with pulmonary metastases from Ewing sarcoma.
Int J Radiat Oncol Biol Phys. 2014; 89(5):1069-75 [PubMed] Related Publications
PURPOSE: To evaluate feasibility and patterns of failure in adult patients with Ewing sarcoma (ES) treated with whole lung irradiation (WLI) for pulmonary metastases.
METHODS AND MATERIALS: Retrospective review of all ES patients treated at age 18 or older with 12-15 Gy WLI for pulmonary metastases at a single institution between 1990 and 2014. Twenty-six patients met the study criteria.
RESULTS: The median age at WLI was 23 years (range, 18-40). The median follow-up time of the surviving patients was 3.8 years (range, 1.0-9.6). The 3-year cumulative incidence of pulmonary relapse (PR) was 55%, with a 3-year cumulative incidence of PR as the site of first relapse of 42%. The 3-year event-free survival (EFS) and overall survival (OS) were 38 and 45%, respectively. Patients with exclusively pulmonary metastases had better outcomes than did those with extrapulmonary metastases: the 3-year PR was 45% in those with exclusively lung metastases versus 76% in those with extrapulmonary metastases (P=.01); the 3-year EFS was 49% versus 14% (P=.003); and the 3-year OS was 61% versus 13% (P=.009). Smoking status was a significant prognostic factor for EFS: the 3-year EFS was 61% in nonsmokers versus 11% in smokers (P=.04). Two patients experienced herpes zoster in the radiation field 6 and 12 weeks after radiation. No patients experienced pneumonitis or cardiac toxicity, and no significant acute or late sequelae were observed among the survivors.
CONCLUSION: WLI in adult patients with ES and lung metastases is well tolerated and is associated with freedom from PR of 45% at 3 years. Given its acceptable toxicity and potential therapeutic effect, WLI for pulmonary metastases in ES should be considered for adults, as it is in pediatric patients. All patients should be advised to quit smoking before receiving WLI.

Related: Bone Cancers Secondary Bone Cancer (bone metastasis)


Shibuya R, Matsuyama A, Nakamoto M, et al.
The combination of CD99 and NKX2.2, a transcriptional target of EWSR1-FLI1, is highly specific for the diagnosis of Ewing sarcoma.
Virchows Arch. 2014; 465(5):599-605 [PubMed] Related Publications
Ewing sarcoma (ES) is a high-grade malignant neoplasm primarily affecting children and young adults. The diagnosis of ES is often difficult because of its broad differential diagnosis comprising a diverse group of small round cell tumors (SRCTs). Although the identification of tumor type-specific fusion genes by molecular testing is the gold standard for the diagnosis of ES, such approaches are not always available in a routine pathology practice. Thus, a reliable immunohistochemical marker is required. A recent study using a limited number of tumor samples has shown that NKX2.2, a putative transcriptional target of EWSR1-FLI1, is a useful marker for the diagnosis of ES. In the present study, the immunohistochemical expression of NKX2.2 was evaluated on 46 genetically confirmed ES and 85 non-ES SRCTs, together with comparative assessment of CD99 and other molecular targets of EWSR1-FLI1, including NR0B1, E2F3, and EZH2. NKX2.2 was expressed in 37 (80 %) of the ES samples with a mostly diffuse and strong staining pattern, and 14 (16 %) of the non-ES SRCTs, including olfactory neuroblastomas, extraskeletal myxoid chondrosarcoma, mesenchymal chondrosarcoma, small cell carcinomas, and Merkel cell carcinoma, also expressed this marker. The sensitivity and specificity of the NKX2.2 expression in this cohort were 80 and 84 %, respectively. The specificity when combined with CD99 was 98 %, with exceptional expression of both markers in only two non-ES SRCTs, including one case each of mesenchymal chondrosarcoma and small cell carcinoma. NR0B1, E2F3, and EZH2 were less sensitive for specific markers for ES when applied singly or in any combination. In conclusion, the study reinforces that NKX2.2 is a useful immunohistochemical marker for ES, and that the combination of CD99 and NKX2.2 is a powerful diagnostic tool that can differentiate ES from other SRCTs.

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Sugita S, Arai Y, Tonooka A, et al.
A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma.
Am J Surg Pathol. 2014; 38(11):1571-6 [PubMed] Related Publications
Differential diagnosis of small round cell sarcomas (SRCSs) grouped under the Ewing sarcoma family of tumors (ESFT) can be a challenging situation for pathologists. Recent studies have revealed that some groups of Ewing-like sarcoma show typical ESFT morphology but lack any EWSR1-ETS gene fusions. Here we identified a novel gene fusion, CIC-FOXO4, in a case of Ewing-like sarcoma with a t(X;19)(q13;q13.3) translocation. The patient was a 63-year-old man who had an asymptomatic, 30-mm, well-demarcated, intramuscular mass in his right posterior neck, and imaging findings suggested a diagnosis of high-grade sarcoma. He was treated with complete resection and subsequent radiotherapy and chemotherapy. He was alive without local recurrence or distant metastasis 6 months after the operation. Histologic examination revealed SRCS with abundant desmoplastic fibrous stroma suggesting a desmoplastic small round cell tumor. Immunohistochemical analysis showed weak to moderate and partial staining for MIC2 (CD99) and WT1, respectively. High-throughput transcriptome sequencing revealed a gene fusion, and the genomic rearrangement between the CIC and FOXO4 genes was identified by fluorescence in situ hybridization. Aside from the desmoplastic stroma, the CIC-FOXO4 fusion sarcoma showed morphologic and immunohistochemical similarity to ESFT and Ewing-like sarcomas, including the recently described CIC-DUX4 fusion sarcoma. Although clinicopathologic analysis with additional cases is necessary, we conclude that CIC-FOXO4 fusion sarcoma is a new type of Ewing-like sarcoma that has a specific genetic signature. These findings have important implications for the differential diagnosis of SRCS.

Related: Bone Cancers FISH CIC gene


Sadri N, Barroeta J, Pack SD, et al.
Malignant round cell tumor of bone with EWSR1-NFATC2 gene fusion.
Virchows Arch. 2014; 465(2):233-9 [PubMed] Related Publications
Gene rearrangements involving the Ewing sarcoma breakpoint region 1 (EWSR1) gene are seen in a broad range of sarcomas and some nonmesenchymal neoplasms. Ewing sarcoma is molecularly defined by a fusion of the EWSR1 gene (or rarely the related FUS gene) to a member of the E26 transformation-specific (ETS) family of transcription factors, frequently the EWSR1-FLI1 fusion. More recently, EWSR1 gene fusion to non-ETS family members, including the nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 2 (NFATC2) gene, has been reported in a histological variant of Ewing sarcoma. Here, we report a malignant round cell tumor of bone with an EWSR1-NFATC2 fusion gene. This report builds upon the unusual morphological and clinical presentation of bone neoplasms containing an EWSR1-NFATC2 fusion gene.

Related: Bone Cancers EWSR1 gene


Jing Z, Wen-Yi L, Jian-Li L, et al.
The imaging features of meningeal Ewing sarcoma/peripheral primitive neuroectodermal tumours (pPNETs).
Br J Radiol. 2014; 87(1041):20130631 [PubMed] Related Publications
OBJECTIVE: To explore the imaging features of meningeal Ewing sarcoma/peripheral primitive neuroectodermal tumours (pPNETs).
METHODS: The imaging features and pathological characteristics of eight cases of surgically and pathologically confirmed Ewing sarcoma/pPNET were analysed retrospectively in light of recent literature on the disease.
RESULTS: The peak age was between 10 and 20 years. The lesions tended to be spindle shaped and dural based, usually widely so. CT showed that the lesions had slightly uneven high density in five cases and iso-low mixed density in three cases; marked heterogeneous enhancement was seen in all cases after contrast injection. MRI of the lesions showed varying proportions of isointense and hypointense signal in all cases on unenhanced T1 weighted imaging and varying proportions of isointense and hyperintense signal on T2 weighted imaging. After contrast injection, marked heterogeneous enhancement was seen in all cases; three cases showed a short and nodular dural tail and five cases showed adjacent skull erosion and osteolysis. Pathological results included high cell density, haemorrhage and necrosis. The cells resembled lymphocytes and spindle cells with transparent cytoplasm. CD99 and vimentin were expressed by all tumour cells.
CONCLUSION: Features of meningeal Ewing sarcoma/pPNETs include peak incidence at 10-20 years of age, a broad connection to the meninges, a thick dural tail involved with tumour, skull and scalp erosion and early metastasis. Necrosis and cystic changes are the common histological findings.
ADVANCES IN KNOWLEDGE: The imaging features of meningeal Ewing sarcoma/pPNETs have not been reported. The study helps to identify meningeal Ewing sarcoma/pPNETs and meningioma.


Le Deley MC, Paulussen M, Lewis I, et al.
Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial.
J Clin Oncol. 2014; 32(23):2440-8 [PubMed] Related Publications
PURPOSE: Relative efficacy and toxicity of cyclophosphamide compared with ifosfamide are debatable. The Euro-EWING99-R1 trial asked whether cyclophosphamide may replace ifosfamide in combination with vincristine and dactinomycin (vincristine, dactinomycin, and cyclophosphamide [VAC] v vincristine, dactinomycin, and ifosfamide [VAI]) after an intensive induction chemotherapy containing vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in standard-risk localized disease (NCT00020566).
METHODS: Standard-risk Ewing sarcomas were localized tumors with either a good histologic response to chemotherapy (< 10% cells) or small tumors (< 200 mL) resected at diagnosis or receiving radiotherapy alone as local treatment. Patients entered the trial after six VIDE+1 VAI courses. Allocated treatment was either 7 VAC courses with 1.5 g/m(2) of cyclophosphamide or seven VAI-courses with 6 g/m(2) ifosfamide. The limit of noninferiority was set at -8.5% for the 3-year event-free survival rate (EFS), equivalent to 1.43 in terms of the hazard ratio of event (HR(event)).
RESULTS: This large international trial recruited 856 patients between February 2000 and March 2010 (n = 431 receiving VAC and n = 425 receiving VAI). With a median follow-up of 5.9 years, the 3-year EFSs were 75.4% and 78.2%, respectively, the 3-year EFS difference was -2.8% (91.4% CI, -7.8 to 2.2%), the HR(event) was 1.12 (91.4% CI, 0.89 to 1.41), and the HR(death) was 1.09 (91.4% CI, 0.84 to 1.42; intention-to-treat). The HR(event) was 1.22 (91.4% CI, 0.96 to 1.54) on the per-protocol population. Major treatment modifications were significantly less frequent in the VAC arm (< 1%) than in the VAI arm (7%), mainly resulting from toxicity. Patients experienced more frequent thrombocytopenia in the VAC arm (45% v 35%) but fewer grade 2 to 4 acute tubular toxicities (16% v 31%).
CONCLUSION: Cyclophosphamide may be able to replace ifosfamide in consolidation treatment of standard-risk Ewing sarcoma. However, some uncertainty surrounding the noninferiority of VAC compared with VAI remains at this stage. The ongoing comparative evaluation of long-term renal and gonadal toxicity is crucial to decisions regarding future patients.

Related: Bone Cancers Cyclophosphamide Dactinomycin Doxorubicin Etoposide Ifosfamide Vincristine


van der Ent W, Jochemsen AG, Teunisse AF, et al.
Ewing sarcoma inhibition by disruption of EWSR1-FLI1 transcriptional activity and reactivation of p53.
J Pathol. 2014; 233(4):415-24 [PubMed] Related Publications
Translocations involving ETS-transcription factors, most commonly leading to the EWSR1-FLI1 fusion protein, are the hallmark of Ewing sarcoma. Despite knowledge of this driving molecular event, an effective therapeutic strategy is lacking. To test potential treatment regimes, we established a novel Ewing sarcoma zebrafish engraftment model allowing time-effective, dynamic quantification of Ewing sarcoma progression and tumour burden in vivo, applicable for screening of single and combined compounds. In Ewing sarcoma the tumour-suppressor gene TP53 is commonly found to be wild-type, thus providing an attractive target for treatment. Here, we study TP53 wild-type (EW7, CADO-ES1 and TC32) and TP53-deleted (SK-N-MC) Ewing sarcoma cell lines to investigate the potentiating effect of p53 reactivation by Nutlin-3 on treatment with YK-4-279 to block transcriptional activity of EWSR1-FLI1 protein. Blocking EWSR1-FLI1 transcriptional activity reduced Ewing sarcoma tumour cell burden irrespective of TP53 status. We show that simultaneous YK-4-279 treatment with Nutlin-3 to stabilize p53 resulted in an additive inhibition of TP53 wild-type Ewing sarcoma cell burden, whilst not affecting TP53-deleted Ewing sarcoma cells. Improved inhibition of proliferation and migration by combinatorial treatment was confirmed in vivo by zebrafish engraftments. Mechanistically, both compounds together additively induced apoptosis of tumour cells in vivo by engaging distinct pathways. We propose reactivation of the p53 pathway in combination with complementary targeted therapy by EWSR1-FLI1 transcriptional activity disruption as a valuable strategy against p53 wild-type Ewing sarcoma.

Related: Bone Cancers Signal Transduction TP53


Qureshi SS, Kembhavi S, Bhagat M, et al.
Primary non-metastatic Ewing sarcoma of the jaw in children: results of surgical resection and primary reconstruction.
J Surg Oncol. 2014; 110(6):689-95 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: The rarity of Ewing sarcoma (ES) of the jaw coupled with the technical challenge of resection and associated functional and cosmetic impairment has resulted in deficient data on surgical management of these tumors. The purpose of this study is to describe the results of surgical excision and reconstruction of primary non-metastatic ES of the mandible and maxilla in children.
METHODS: Consecutive patients (mandible = 6, maxilla = 5) treated with surgery from August 2005 to January 2013 were selected. All patients received induction chemotherapy and were selected for surgical resection based on the presence of specific criteria for operability.
RESULTS: The median age was 11.5 years (range 5-16 years). Free fibular osteocutaneous flap was commonly used for reconstruction. There were no complications related to microvascular anastomosis or flap loss. Five patients had 100% tumor necrosis and did not receive radiotherapy. Teeth alignment, chewing, swallowing, and speech were normal in all and donor site morbidity occurred in one. The 5-year overall, event-free survival, and local control are 87.5%, 72.9%, and 90%, respectively.
CONCLUSION: In eligible patients, surgery with contemporary reconstruction results in optimal oncological and functional outcome. Surgery also has the added advantage of identifying patients who may not need radiotherapy.


Oliveira Filho Jd, Tebet AC, Oliveira AR, Nasser K
Primary cutaneous Ewing sarcoma--case report.
An Bras Dermatol. 2014 May-Jun; 89(3):501-3 [PubMed] Free Access to Full Article Related Publications
Ewing sarcoma is a primitive neuroectodermal tumor rarely occurs in the skin and sobcutaneous tissues. Generally Ewing's sarcoma is a primary bone tumor, but when present in soft tissues it characterizes an extremely uncommon clinical picture. It usually involves the deep subcutaneous tissue or muscles, and more rarely occurs like a primary skin cancer. Most patients are white, women, and in the second decade of life. The clinical features are a superficial mass, in average measuring 2-3 cm, of soft consistency, freely mobile and sometimes painful. The more affected locations are upper and lower extremities, trunk, head, neck or multiple lesions. The presence of metastases is very rare.

Related: Skin Cancer


Tanaka M, Yamazaki Y, Kanno Y, et al.
Ewing's sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors.
J Clin Invest. 2014; 124(7):3061-74 [PubMed] Free Access to Full Article Related Publications
Ewing's sarcoma is a highly malignant bone tumor found in children and adolescents, and the origin of this malignancy is not well understood. Here, we introduced a Ewing's sarcoma-associated genetic fusion of the genes encoding the RNA-binding protein EWS and the transcription factor ETS (EWS-ETS) into a fraction of cells enriched for osteochondrogenic progenitors derived from the embryonic superficial zone (eSZ) of long bones collected from late gestational murine embryos. EWS-ETS fusions efficiently induced Ewing's sarcoma-like small round cell sarcoma formation by these cells. Analysis of the eSZ revealed a fraction of a precursor cells that express growth/differentiation factor 5 (Gdf5), the transcription factor Erg, and parathyroid hormone-like hormone (Pthlh), and selection of the Pthlh-positive fraction alone further enhanced EWS-ETS-dependent tumor induction. Genes downstream of the EWS-ETS fusion protein were quite transcriptionally active in eSZ cells, especially in regions in which the chromatin structure of the ETS-responsive locus was open. Inhibition of β-catenin, poly (ADP-ribose) polymerase 1 (PARP1), or enhancer of zeste homolog 2 (EZH2) suppressed cell growth in a murine model of Ewing's sarcoma, suggesting the utility of the current system as a preclinical model. These results indicate that eSZ cells are highly enriched in precursors to Ewing's sarcoma and provide clues to the histogenesis of Ewing's sarcoma in bone.

Related: Bone Cancers CTNNB1 gene


Uziel O, Kanfer G, Beery E, et al.
The effects of erythropoietin signaling on telomerase regulation in non-erythroid malignant and non-malignant cells.
Biochem Biophys Res Commun. 2014; 450(1):274-82 [PubMed] Related Publications
Treatment with erythropoietin (EPO) in several cancers is associated with decreased survival due to cancer progression. Due to the major importance of telomerase in cancer biology we hypothesized that some of these effects may be mediated through EPO effect on telomerase. For this aim we explored the possible effects of EPO on telomerase regulation, cell migration and chemosensitivity in non-erythroid malignant and non-malignant cells. Cell proliferation, telomerase activity (TA) and cell migration increased in response to EPO. EPO had no effect on cancer cells sensitivity to cisplatinum and on the cell cycle status. The inhibition of telomerase modestly repressed the proliferative effect of EPO. Telomere shortening caused by long term inhibition of the enzyme abolished the effect of EPO, suggesting that EPO effects on cancer cells are related to telomere dynamics. TA was correlated with the levels of Epo-R. The increase in TA was mediated post-translationally through the Lyn-Src and not the canonical JAK2 pathway.

Related: Signal Transduction


Biswas B, Rastogi S, Khan SA, et al.
Outcomes and prognostic factors for Ewing-family tumors of the extremities.
J Bone Joint Surg Am. 2014; 96(10):841-9 [PubMed] Related Publications
BACKGROUND: There are few published studies describing the clinical results of patients uniformly treated for a Ewing-family tumor of an extremity.
METHODS: We performed a review of patients who had received uniform treatment consisting of neoadjuvant chemotherapy, surgery and/or radiation therapy as local treatment, and then adjuvant chemotherapy from June 2003 to November 2011 at a single institution.
RESULTS: There were 158 patients included in the study. The median age was fifteen years. Sixty-nine (44%) of the patients had metastatic disease at presentation. Fifty-seven patients underwent surgery, and forty-one received radical radiation therapy following neoadjuvant chemotherapy. After a median of 24.3 months (range, 1.6 to ninety-seven months) of follow-up, the five-year event-free survival, overall survival, and local control rates (and standard error) were 24.1% ± 4.3%, 43.5% ± 6%, and 55% ± 6.8%, respectively, for the entire cohort and 36.4% ± 6.2%, 57.6% ± 7.4%, and 58.2% ± 7.9%, respectively, for patients without metastases. In the multivariate analysis, metastases predicted inferior event-free survival (p = 0.02) and overall survival (p = 0.03) rates in the entire cohort, whereas radical radiation therapy predicted an inferior local control rate in the entire cohort (p = 0.001) and in patients without metastases (p = 0.04). In the group with localized disease, there was no difference between the patients who received radical radiation therapy and those who underwent surgery with regard to tumor diameter (p = 0.8) or post-neoadjuvant chemotherapy response (p = 0.1). A white blood cell count (WBC) of >11 × 109/L predicted inferior event-free survival (p = 0.005) and local control (p = 0.02) rates for patients without metastases.
CONCLUSIONS: To our knowledge, this is the largest study on extremity Ewing-family tumors treated with uniform chemotherapy and either surgical resection or radical radiation therapy in Asia. All possible efforts should be made to resect a primary tumor after neoadjuvant chemotherapy, as radical radiation therapy alone results in a poor local control rate despite a good post-neoadjuvant chemotherapy response. Patients without metastases but with a high WBC had inferior event-free survival and local control rates and may require more aggressive therapy.
LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

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Brasme JF, Chalumeau M, Oberlin O, et al.
Time to diagnosis of Ewing tumors in children and adolescents is not associated with metastasis or survival: a prospective multicenter study of 436 patients.
J Clin Oncol. 2014; 32(18):1935-40 [PubMed] Related Publications
PURPOSE: The time to diagnosis (TtD) of Ewing tumors is one of the longest among pediatric tumors. Its precise consequences, however, have not been studied well. We analyzed the distribution of TtD for Ewing tumors in children and adolescents and its association with clinical features, tumor characteristics, surgical outcome, and long-term survival.
PATIENTS AND METHODS: We analyzed prospectively collected data from two multicenter clinical trials of patients younger than 21 years old who had Ewing bone tumors treated in France between 1988 and 2000. Clinical and tumoral features, TtD, and outcome associations were studied by univariable and multivariable analyses.
RESULTS: The median TtD for the 436 patients was 70 days (interquartile range, 27 to 146 days), with no significant decrease during the study period (P > .2). The factors associated with long TtD were older age and some tumor sites (pelvis, extremities of limbs). Increased tumor volume and decreased histologic response to chemotherapy were associated with long TtD on univariable analysis (P < .05) but not after adjustment. Presence of a nerve or spinal-cord compression at diagnosis, presence or site of metastasis, surgical treatment, mutilating surgery, complete resection, or survival were not associated with TtD.
CONCLUSION: TtD of Ewing tumors was long, especially for adolescents and for certain tumor sites, and did not improve over time. But TtD was not associated with metastasis, surgical outcome, or survival. These findings could be used to comfort parents at diagnosis and in expert testimony produced for malpractice claims.

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Yildiz I, Sen F, Ekenel M, et al.
Survival and prognostic factors in adult patients with recurrent or refractory ewing sarcoma family tumours: a 13-years retrospective study in Turkey.
In Vivo. 2014 May-Jun; 28(3):403-9 [PubMed] Related Publications
AIM: The aim of the present study was to evaluate the results of treatment and prognostic factors in adult patients with recurrent or refractory Ewing's sarcoma family tumors (ESFT).
PATIENTS AND METHODS: We retrospectively evaluated treatment outcomes of 54 consecutive patients with ESFT (aged 15 years or more) with complete medical records, who were treated with multimodal therapies after recurrence at the Istanbul University, Institute of Oncology.
RESULTS: The commonly used chemotherapy regimens at relapse were ifosfamide and etoposide (IE), ifosfamide and etoposide plus carboplatin (ICE), and oral etoposide. The median progression-free survival and overall survival for the entire group were 6.3 (95% confidence interval, 3.08-9.60) and 8.6 (95% confidence interval CI, 4.7-12.4) months, respectively. Multivariate analysis using a Cox proportional hazards model showed that non-IE/ICE chemotherapy regimens (p=0.003, hazard ratio=2.38) and the presence extrapulmonary metastases (p=0.045, hazard ratio=2.15) were associated with worse overall survival.
CONCLUSION: In primary refractory or relapsed ESFT, the presence of extrapulmonary metastases and treatment with salvage regimens other than ifosfamide and etoposide and/or carboplatin correlate with a poor prognosis.

Related: Bone Cancers


Bledsoe KL, McGee-Lawrence ME, Camilleri ET, et al.
RUNX3 facilitates growth of Ewing sarcoma cells.
J Cell Physiol. 2014; 229(12):2049-56 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Ewing sarcoma is an aggressive pediatric small round cell tumor that predominantly occurs in bone. Approximately 85% of Ewing sarcomas harbor the EWS/FLI fusion protein, which arises from a chromosomal translocation, t(11:22)(q24:q12). EWS/FLI interacts with numerous lineage-essential transcription factors to maintain mesenchymal progenitors in an undifferentiated state. We previously showed that EWS/FLI binds the osteogenic transcription factor RUNX2 and prevents osteoblast differentiation. In this study, we investigated the role of another Runt-domain protein, RUNX3, in Ewing sarcoma. RUNX3 participates in mesenchymal-derived bone formation and is a context dependent tumor suppressor and oncogene. RUNX3 was detected in all Ewing sarcoma cells examined, whereas RUNX2 was detected in only 73% of specimens. Like RUNX2, RUNX3 binds to EWS/FLI via its Runt domain. EWS/FLI prevented RUNX3 from activating the transcription of a RUNX-responsive reporter, p6OSE2. Stable suppression of RUNX3 expression in the Ewing sarcoma cell line A673 delayed colony growth in anchorage independent soft agar assays and reversed expression of EWS/FLI-responsive genes. These results demonstrate an important role for RUNX3 in Ewing sarcoma.

Related: RUNX3 FLI1 gene


Puls F, Niblett A, Marland G, et al.
BCOR-CCNB3 (Ewing-like) sarcoma: a clinicopathologic analysis of 10 cases, in comparison with conventional Ewing sarcoma.
Am J Surg Pathol. 2014; 38(10):1307-18 [PubMed] Related Publications
BCOR-CCNB3 fusion transcripts resulting from an X-chromosomal paracentric inversion were recently identified in a series of unclassifiable soft tissue and bone sarcomas with Ewing sarcoma-like morphology. The morphologic and clinical features of these sarcomas are, as yet, not well characterized. Here we describe the clinicopathologic features of 10 cases of BCOR-CCNB3 sarcoma and compare their clinical course with typical Ewing sarcoma. Nine of 10 patients were male, and all were 11 to 18 years of age. Seven tumors were located in the bone and 3 in the deep soft tissues. The histomorphologic spectrum was quite wide, with 7 tumors predominately showing small primitive cell morphology with angulated nuclei simulating so-called atypical Ewing sarcoma and 3 predominately showing spindle cell morphology. Recurrent and metastatic lesions showed increased cellularity and marked pleomorphism. Immunohistochemistry showed expression of CCNB3 (100%), bcl2 (90%), CD99 (60%), and CD117 (60%). Reverse transcription polymerase chain reaction for BCOR-CCNB3 fusion transcripts was positive in all 9 cases, which yielded sufficient extracted RNA. Five- and 10-year survival rates were 75% and 56%, respectively. BCOR-CCNB3 sarcomas located in axial skeleton and soft tissues showed a significantly shorter survival. The Ewing sarcoma overall survival was not statistically different, although there was a trend for longer survival of patients with BCOR-CCNB3 sarcomas in the extremities. In conclusion, this study provides a detailed description of the histologic spectrum, immunohistochemical features, and clinical characteristic of BCOR-CCNB3 sarcoma justifying distinction from Ewing sarcoma with its typical EWS/FUS-ETS translocations. Ideally immunohistochemistry is used in combination with reverse transcription polymerase chain reaction for definitive diagnosis.

Related: Bone Cancers BCOR gene


Casey DL, Wexler LH, LaQuaglia MP, et al.
Favorable outcomes after whole abdominopelvic radiation therapy for pediatric and young adult sarcoma.
Pediatr Blood Cancer. 2014; 61(9):1565-9 [PubMed] Related Publications
BACKGROUND: Current Children's Oncology Group (COG) guidelines recommend 24 Gy whole abdominopelvic radiation therapy (WAP-RT) for pediatric patients with sarcoma with peritoneal dissemination and/or malignant ascites. However, WAP-RT has never been described for pediatric sarcoma excluding desmoplastic small round-cell tumor (DSRCT). The objective of this study was to evaluate feasibility, outcomes, and toxicity of WAP-RT in children with sarcoma and peritoneal dissemination.
PROCEDURE: Detailed records of all 10 pediatric patients with sarcoma (excluding DSRCT) treated with WAP-RT from 2001 to 2013 were reviewed.
RESULTS: Median age was 9.9 years (range, 1.7-33.8). Seven patients had rhabdomyosarcoma, 2 embryonal undifferentiated sarcoma of the liver, and 1 Ewing sarcoma. Patients received a median dose of 24 Gy with intensity-modulated radiation therapy (IMRT) to the whole abdomen and pelvis. Two patients did not complete treatment, one due to transfusion-resistant pancytopenia and one due to moderate acute gastrointestinal toxicity. At a median follow-up of 4.0 years, both relapse-free survival and overall survival were 100%. Acute hematologic toxicities were common, with 40% of patients developing a grade 4 hematologic toxicity. Most acute gastrointestinal toxicities were grade 1 and managed appropriately with anti-diarrheals and anti-emetics. Late effects varied, and half of patients are without long-term sequelae.
CONCLUSIONS: All patients remain free of disease, both locally and distantly. Although WAP-RT was associated with acute and late toxicity, treatment was feasible with supportive care. Given the excellent rates of tumor control, we recommend that all providers give WAP-RT with IMRT to patients with pediatric sarcoma and peritoneal dissemination and/or malignant ascites.

Related: Bone Cancers Liver Cancer Childhood Liver Cancer Rhabdomyosarcoma


Pappo AS, Vassal G, Crowley JJ, et al.
A phase 2 trial of R1507, a monoclonal antibody to the insulin-like growth factor-1 receptor (IGF-1R), in patients with recurrent or refractory rhabdomyosarcoma, osteosarcoma, synovial sarcoma, and other soft tissue sarcomas: results of a Sarcoma Alliance for Research Through Collaboration study.
Cancer. 2014; 120(16):2448-56 [PubMed] Related Publications
BACKGROUND: Insulin-like growth factor-1 receptor (IGF-1R) is implicated in the pathogenesis of rhabdomyosarcoma (RMS), osteosarcoma (OS), and synovial sarcoma (SS). The authors conducted a multi-institutional phase 2 trial of the monoclonal antibody R1507 in patients with various subtypes of recurrent or refractory sarcomas.
METHODS: Eligibility criteria included age ≥ 2 years and a diagnosis of recurrent or refractory RMS, OS, SS, and other soft tissue sarcomas. Patients received a weekly dose of 9 mg/kg R1507 intravenously. The primary endpoint was the best objective response rate using World Health Organization criteria. Tumor imaging was performed every 6 weeks × 4 and every 12 weeks thereafter.
RESULTS: From December 2007 through August 2009, 163 eligible patients from 33 institutions were enrolled. The median patient age was 31 years (range, 7-85 years). Histologic diagnoses included OS (n = 38), RMS (n = 36), SS (n = 23), and other sarcomas (n = 66). The overall objective response rate was 2.5% (95% confidence interval, 0.7%-6.2%). Partial responses were observed in 4 patients, including 2 patients with OS, 1 patient with RMS, and 1 patient with alveolar soft part sarcoma. Four additional patients (3 with RMS and 1 with myxoid liposarcoma) had a ≥ 50% decrease in tumor size that lasted for <4 weeks. The median progression-free survival was 5.7 weeks, and the median overall survival was 11 months. The most common grade 3/4 toxicities were metabolic (12%), hematologic (6%), gastrointestinal (4%), and general constitutional symptoms (8%).
CONCLUSIONS: R1507 is safe and well tolerated but has limited activity in patients with recurrent or refractory bone and soft tissue sarcomas. Additional studies to help identify the predictive factors associated with clinical benefit in selected histologies such as RMS appear to be warranted.

Related: Monoclonal Antibodies Bone Cancers IGF1R


Gilg MM, Wibmer C, Andreou D, et al.
Paley's multiplier method does not accurately predict adult height in children with bone sarcoma.
Clin Orthop Relat Res. 2014; 472(8):2506-13 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: The majority of patients with osteosarcoma and Ewing's sarcoma are diagnosed before skeletal maturity. Paley's multiplier is used for height prediction in healthy children, and has been suggested as a method to make growth predictions for children with osteosarcoma and Ewing's sarcoma when considering limb salvage options. To our knowledge, no evaluation of this method in this particular patient group has been performed, but a temporary growth deficit has been observed in children undergoing chemotherapy.
QUESTIONS/PURPOSES: We asked whether (1) Paley's formula reliably predicts growth in children who received polychemotherapy; (2) chemotherapy impairs growth velocity; and (3) final adult height is impaired in these patients.
METHODS: Retrospectively, data for 94 patients with osteosarcoma and Ewing's sarcoma were retrieved from databases of two sarcoma centers. Onset before 14 years of age in girls and 16 years in boys and a minimum followup until 18 years were required (mean, 67 months; range, 31-124 months) criteria. Exclusion criteria were the intake of growth hormones or no chemotherapy. Thirty-three patients (35%) fulfilled all inclusion criteria. Predicted adult heights were compared with actual adult height. The development of a growth deficit was evaluated for 23 children (without chemotherapy for recurrence) using age- and gender-specific standard deviation scores for height (WHO Z-scores).
RESULTS: Height prediction using Paley's method showed a high percentage of false predictions (outside ± 1 SD, 70%; outside ± 2 SD, 61%). On average, the mean total height of the patients was overestimated (2.3 cm). The median absolute error of prediction was 5.0 cm (range, -17 to 8). Patients with osteosarcoma and Ewing's sarcoma showed a significant growth impairment during polychemotherapy. A catchup phase in growth before skeletal maturity was observed in patients with osteosarcoma but not with Ewing's sarcoma.
CONCLUSIONS: Owing to its lack of reliability in this patient group, methods other than Paley's should be evaluated to predict adult height. Although limited by a small number of patients, our study results indicate a decreased adult height in patients with bone sarcoma after chemotherapy.
LEVEL OF EVIDENCE: Level III, therapeutic study. See the Instructions for Authors for complete description of levels of evidence.

Related: Bone Cancers Osteosarcoma


Grimsby GM, Harrison CB
Ewing sarcoma of the scrotum.
Urology. 2014; 83(6):1407-8 [PubMed] Related Publications
Nonosseous Ewing sarcoma commonly occurs in the extremities or deep soft tissues. However, cutaneous and subcutaneous locations have been reported. A 3-year-old boy presented with a 2-year history of a painless, slowly growing mid-scrotal mass. Pathology after surgical excision revealed the lesion to be Ewing sarcoma. The patient is free of metastatic disease and is currently undergoing chemotherapy. Soft-tissue malignancies must be kept in the differential diagnosis of any solid paratesticular mass in a child. Although rhabdomyosarcoma is the most common, as this case demonstrates, other rare sarcomas are also possible.

Related: Testicular Cancer


Marrero Barrera PA, Marrero Ortiz PV
Ewing sarcoma superimposed on a previous osteochondroma in multiple osteochondromatosis.
Orthopedics. 2014; 37(4):e403-6 [PubMed] Related Publications
It has been reported that patients with hereditary multiple exostoses (called multiple osteochondromatosis by the World Health Organization) are at increased risk for malignant transformation of osteochondromas to secondary chondrosarcomas. A review of the literature found 14 cases showing transformation of osteochondromas into osteosarcomas; however, Ewing sarcoma has never been reported superimposed on an osteochondroma. This article presents the case of a boy who underwent biopsy of a previously existent osteochondroma for which the pathology report showed cytologic and immunohistochemical properties consistent with Ewing sarcoma. A 13-year-old boy with hereditary multiple exostoses (multiple osteochondromatosis) presented to an orthopedic clinic because of waxing and waning pain superficial to a previous osteochondroma on the lateral aspect of the right leg, below the knee, of 1 month's duration. On examination, inflammation was noted over a bony mass associated with tenderness to palpation of the affected area. There was no evidence of penetrating injury or trauma, and the patient reported no constitutional symptoms, including fever. Radiographs showed marked osteolysis and signs of periosteal reaction. Magnetic resonance imaging showed evidence of cortical bone erosion and extension of the mass into soft tissue. Malignant transformation was suspected, and the patient underwent biopsy. The pathology findings were consistent with Ewing sarcoma. The highly uncommon presentation of this malignancy must serve as a red flag to other physicians who treat patients with hereditary multiple exostoses. Ewing sarcoma tends to be of higher grade and have a worse prognosis than other malignancies that are more commonly seen in these patients.

Related: Bone Cancers Multiple Hereditary Exostoses


Vanhapiha N, Knuutila S, Vettenranta K, Lohi O
Burkitt lymphoma and Ewing sarcoma in a child with Williams syndrome.
Pediatr Blood Cancer. 2014; 61(10):1877-9 [PubMed] Related Publications
Williams syndrome (WS) is a relatively rare multisystem neurodevelopmental disorder caused by a hemizygous deletion of contiguous genes on chromosome 7q11.23. Although WS does not predispose carriers to cancers, alterations of chromosome 7 are common in several human neoplasms. We report here a patient with WS and two different cancers, Burkitt lymphoma and Ewing sarcoma. Array-CGH analysis of the patient blood revealed a constitutive 1.4 million base pair deletion at 7q11.23, compatible with WS diagnosis.

Related: CGH FISH


Villasante A, Marturano-Kruik A, Vunjak-Novakovic G
Bioengineered human tumor within a bone niche.
Biomaterials. 2014; 35(22):5785-94 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Monolayer cultures of tumor cells and animal studies have tremendously advanced our understanding of cancer biology. However, we often lack animal models for human tumors, and cultured lines of human cells quickly lose their cancer signatures. In recent years, simple 3D models for cancer research have emerged, including cell culture in spheroids and on biomaterial scaffolds. Here we describe a bioengineered model of human Ewing's sarcoma that mimics the native bone tumor niche with high biological fidelity. In this model, cancer cells that have lost their transcriptional profiles after monolayer culture re-express genes related to focal adhesion and cancer pathways. The bioengineered model recovers the original hypoxic and glycolytic tumor phenotype, and enables re-expression of angiogenic and vasculogenic mimicry features that favor tumor adaptation. We propose that differentially expressed genes between the monolayer cell culture and native tumor environment are potential therapeutic targets that can be explored using the bioengineered tumor model.

Related: Bone Cancers


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