Primary Ewing Sarcoma Family Of Tumors Research Articles

Primary orbital Ewing sarcoma family of tumors: a study of 12 cases.

PurposeThe purpose of this study is to discuss the clinical presentation, management, and outcomes of patients with primary orbital Ewing sarcoma family of tumors (ESFTs).Patients and methodsRetrospective study of 12 patients with biopsy-proven primary orbital ESFT.ResultsThe mean age at presentation of primary orbital ESFT was 12 years (median, 8 years; range, 5 months to 28 years). There were seven (58%) females and five (42%) males. The presenting complaints included proptosis (n=10; 83%) and swelling in the upper eyelid (n=2; 17%). The mean duration of symptoms was 9 weeks (median, 5 weeks; range, 2-24 weeks). Tumor epicenter was located in the superior orbit (n=6; 50%), lateral orbit (n=3; 25%), inferior orbit (n=2; 17%), and medial orbit (n=1; 8%). Computed tomography of the orbits revealed predominant bony lesion (n=10; 83%) or isolated soft tissue/extraosseous lesion (n=2, 17%). At presentation, extraorbital extension was noticed in 10 patients including intra cranial extension (n=7; 58%), extension into temporal fossa (n=4; 33%), nasal cavity (n=2; 17%), maxillary sinus (n=2; 17%), and ethmoid sinus (n=1, 8%). Systemic metastases at presentation was detected in five (42%) patients involving the bone marrow (n=4; 33%), kidney (n=1; 8%), and retroperitoneal lymphnode (n=1; 8%). Multi-modal treatment including a combination of neoadjuvant chemotherapy, excision biopsy/debulking, and/or radiotherapy was given. Over a mean follow-up period of 21 months (median, 7 months; range, 1-152 months), disease-related death occurred in 11 (92%) cases.ConclusionPrimary orbital ESFT is aggressive at presentation and is associated with poor prognosis.

Kidney Cancers in Adolescents & Young Adults

Kidney Cancers in Adolescents & Young Adults

Potential Role of FDG PET Imaging in Predicting Metastatic Potential and Assessment of Therapeutic Response to Neoadjuvant Chemotherapy in Ewing Sarcoma Family of Tumors

The aim of this study was to retrospectively correlate FDG uptake in primary Ewing sarcoma family of tumors (ESFT) with tumor behavior, and to evaluate whether FDG PET can be used to predict response to neoadjuvant chemotherapy (NACT) in this patient group. Out of the total 54 patients of recently diagnosed ESFT who underwent pretreatment FDG PET imaging, group I included patients without metastasis at presentation (n = 34) and group II included those with metastasis at presentation (n = 20). Fourteen of these patients had undergone FDG PET after 4 cycles of induction chemotherapy and surgical resection of primary tumor. In this subgroup of 14 patients, maximum standardized uptake value (SUVmax) of primary tumor was estimated before and after 4 cycles of induction chemotherapy and was correlated with the histopathological response in terms of necrosis in the tumor specimen. Mean SUVmax in the primary tumor in group I patients was 6.84 and in group II patients, it was 11.31. The difference between mean SUVmax of these 2 groups was significant by Wilcoxon test analysis, with P < 0.01. In group II patients, SUVmax in metastasis with maximum FDG uptake was consistently lower as compared with that of primary tumor. In subgroup of 14 patients, Pearson correlation analysis showed that percentage change in SUVmax of primary tumor correlated well with percentage necrosis on histopathological examination (P < 0.01). FDG uptake in primary ESFT reflected its metastatic potential and hence the aggressive behavior. The significant correlation between change in metabolic activity of the primary tumor and histopathological response after neoadjuvant chemotherapy suggests that FDG PET may be an ideal noninvasive method to assess tumor behavior and response to therapy in ESFT.

Abstract 1949: Positive feedback regulation between EWS-FLI1 and miR-145 in Ewing's sarcoma

Abstract The EWS-FLI1 chimeric protein is a potent tumor specific transcriptional regulator and the molecular cause of Ewing's sarcoma family of tumors (ESFT). We had previously hypothesized that, since EWS-FLI1 is the major driver of aberrant gene expression in ESFT, there should be an inverse correlation between the changes in gene expression observed in ESFT cell lines in response to RNAi-mediated EWS-FLI1 knockdown and the corresponding gene expression in primary tumors relative to the tissue of origin. We found that mesenchymal progenitor cells (MPC) fit this assumption best and established an ESFT specific EWS-FLI1 transcriptional signature on the mRNA level. Following the same approach, we now studied the EWS-FLI1 dependent regulation of microRNAs (miRNAs) in ESFT. Genome-wide miRNA analysis was performed after shRNA-mediated stable (5 cell lines) and inducible (1 cell line) EWS-FLI1 knockdown, as well as in 6 primary ESFT and 6 MPC samples using the stem-loop reverse transcription quantitative PCR platform. Among miRNAs consistently affected by EWS-FLI1 silencing and inversely expressed in primary tumors compared to MPCs was hsa-miR-145 which we found upregulated upon EWS-FLI1 silencing. Since several target sites exist for this miRNA within the FLI1 3′UTR, we asked if hsa-miR-145 is capable of modulating EWS-FLI1 expression in ESFT cells. Upon ectopic expression of pri-miR-145 in wildtype p53 ESFT cells, strong modulation of EWS-FLI1 protein levels, but not RNA levels, was observed. In p53 mutant cell lines this effect was less pronounced consistent with a recently reported role of p53 in miR-145 maturation. Preliminary studies suggest that hsa-miR-145 is indirectly regulated by EWS-FLI1 by a mechanism that may involve the NOTCH signaling pathway. Our results identify a positive feed-back loop between EWS-FLI1 and hsa-miR-145 expression in ESFT. Supported by the 6th framework program of the European Commission, (STREP “E.E.T. Pipeline“ contract LSHC-CT-2006-037260) and grant P20665-B12 of the Austrian Science Fund FWF. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1949.

Primary Ewing sarcoma of the tentorium presenting with intracranial hemorrhage in a child

Spontaneous intracerebral hemorrhage in children is usually related to cerebrovascular conditions. Brain tumors presenting with spontaneous bleeding account for approximately 10% of intracranial hemorrhages in children. The occurrence of primitive central nervous system lesions in the Ewing sarcoma family of tumors (ESFT) not related to bone or metastatic disease is a rare condition. The authors report on a child who presented with intracranial bleeding secondary to a nonmetastatic tentorial ESFT confirmed by detection of the fusion gene EWS-ERG. A detailed review of the literature reveals that most primary intracranial ESFT had a meningeal attachment, and that almost half of them presented at diagnosis with hemorrhage. Distinguishing between ESFT and other intracranial neoplasms is essential because the treatment and prognosis differ remarkably from that of other tumors, namely central primitive neuroectodermal tumors (PNETs). Whereas adjuvant treatment for ESFT consists of local or regional radiotherapy and chemotherapy containing alkylating agents, central PNETs are generally treated with whole neuraxis radiation and platinum-based chemotherapy. Additionally, the prognosis for intracranial ESFT might be better than the one for nonpineal central PNETs.

Concurrent Ewing Sarcoma Family of Tumors and Fibrous Dysplasia: Possible Diagnostic Pitfall

We present 2 patients with synchronous Ewing sarcoma family of tumors (ESFTs) and fibro-osseous lesion in the independent sites, possibly causing misjudgment in staging. Each patient showed another activity apart from the primary ESFT lesion on gallium and/or thallium scintigraphy at initial presentation. Of note is that such lesions showed no obvious radiologic change even though the primary ESFT lesions were mildly shrunken during chemotherapy. The biopsies confirmed fibrous dysplasia (FD) in the first patient and fibro-osseous lesion, possibly FD in the second patient. As far as we know, concurrent ESFT and FD in independent sites have never been described. However, this unusual combination emphasized the possibility of concurrent FD mimicking metastasis in a patient with malignancy and the view that exploratory biopsy should be performed in a critical case to make staging. Further investigation will be required about whether the co-occurrence of ESFD and FD in our patients is coincidence or genetic linkage.

Suppression of KCMF1 by constitutive high CD99 expression is involved in the migratory ability of Ewing's sarcoma cells

High CD99 expression levels and rearrangements of the EWS gene with ETS transcription factor genes characterize the Ewing's sarcoma family of tumors (ESFT). CD99 is a cell surface glycoprotein whose engagement has been implicated in cell proliferation as well as upregulation and transport of several transmembrane proteins in hematopoietic cells. In ESFT, antibody ligation of CD99 induces fast homotypic cell aggregation and cell death although its functional role in these processes remains largely unknown. Here, using an RNAi approach, we studied for the first time the consequences of modulated CD99 expression in six different ESFT cell lines, representing the most frequent variant forms of EWS gene rearrangement. CD99 suppression resulted in growth inhibition and reduced migration of ESFT cells. Among genes whose expression changes in response to CD99 modulation, the potassium-channel modulatory factor KCMF1 was consistently upregulated. In a series of 22 primary ESFT, KCMF1 expression levels inversely correlated with CD99 abundancy. Cells forced to express ectopic KCMF1 showed a similar reduction in migratory ability as CD99 silenced ESFT cells. Our results suggest that in ESFT, high CD99 expression levels contribute to the malignant properties of ESFT by promoting growth and migration of tumor cells and identify KCMF1 as a potential metastasis suppressor gene downregulated by high constitutive CD99 expression in ESFT.

Primary Ewing??s Sarcoma Family of Tumors Arising from the Broad Ligament

We report a case of a primary Ewing's sarcoma family of tumors (ESFT) that was an incidental finding in the broad ligament of a 53-year-old woman. ESFT now includes tumors previously described as Askin tumor, neuroepithelioma, extraskeletal Ewing's sarcoma, and peripheral primitive neuroectodermal tumor. This is because of the discovery that all of the above tumors contain a specific gene rearrangement involving chromosome 22q12. On microscopic examination, the tumor was composed of small, round cells with mild nuclear pleomorphism and scant eosinophilic cytoplasm. There were large areas of tumor necrosis and numerous mitoses. Immunohistochemically, there was strong membrane staining for CD99 and weak focal staining for CD56 and neuron specific enolase. Fluorescence in situ hybridization revealed a separation of the breakapart probe on chromosome 22q12 consistent with the presence of a gene rearrangement, supporting the diagnosis of ESFT. We believe the importance of recognizing the existence of a primary ESFT in the broad ligament as some primary tumors of the gynecological tract and of other systems may resemble it histologically. To the best of our knowledge, our case is the second case of extraskeletal Ewings sarcoma arising from the broad ligament but the first case that is confirmed by strong CD99 positivity and supported by fluorescence in situ hybridization.

Fas Ligand Is Present in Tumors of the Ewing's Sarcoma Family and Is Cleaved into a Soluble Form by a Metalloproteinase

Fas ligand (FasL) exists in transmembrane and soluble forms and induces apoptosis on cross-linking with the Fas receptor. We evaluated the biological significance of FasL and Fas in 61 tumor tissues and 9 cell lines of the Ewing's sarcoma family of tumors (ESFT). FasL was present in 62.5% and Fas in 79.4% of primary ESFT. Metastatic tumors had higher expression of FasL (95%), suggesting association with a metastatic phenotype. FasL was detected in the cytoplasm and membrane of ESFT cells by immunofluorescence. Western blotting revealed transmembrane and soluble FasL in cytosolic extracts and soluble FasL in conditioned media. Both transmembrane and soluble FasL induced apoptosis of Fas-sensitive Jurkat cells in co-culture experiments with ESFT cells or their media. Treatment with phenanthroline and the synthetic metalloproteinase inhibitor BB-3103 reduced the levels of soluble FasL in the media, suggesting that in ESFT, FasL is processed by a metalloproteinase and released in the extracellular milieu. The released soluble FasL may serve to attack cells of the immune system and/or interfere with the binding of transmembrane FasL with Fas, and results in down-regulation of transmembrane FasL. Synthetic metalloproteinase inhibitors may modify the ratio of transmembrane to soluble FasL.