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PubMed1999

Pelvic Ewing sarcoma: a retrospective analysis of 241 cases.

BACKGROUND: This article reports on 241 patients each with pelvic Ewing sarcoma registered for studies in Germany, Austria, and the Netherlands from January 1, 1981, until January 31, 1994. One hundred sixty-four patients had localized disease and 87 had metastases at diagnosis (PMP). Eighty-four patients with localized disease were entered on protocol (PP) and 80 were followed (FP). METHODS: Statistics included an analysis of event free survival by the Kaplan-Meier method and a Cox regression analysis of factors influencing prognosis. RESULTS: In the Kaplan-Meier analysis, on February 1, 1995, the event free survival (EFS) rate was 32% at 12 years for all patients, 54% for PP, 25% for FP, and 13% for PMP. Cox regression analysis showed that response to chemotherapy, initial metastases, and less intense therapy were significant prognostic factors. Among patients who had surgery for local control, the histologic response to chemotherapy was analyzed in the surgical specimen and had a significant influence on survival: EFS 69% for PP with good response compared with 47% (P = 0.11) for patients with poor response, and for FP 56% versus 13% (P = 0.002). All PP with small tumors had relapse free survival, compared with 69% of patients with medium-sized tumors and 36% of patients with tumors larger than 200 mL (P = 0.006). The initial tumor volume was a significant predictor of survival. CONCLUSIONS: Combined modality treatment has resulted in definitive improvement of prognosis for patients with localized pelvic Ewing sarcoma. However, the results for patients with metastases at diagnosis are still discouraging, and their treatment requires new approaches. Tumor load, responsiveness to chemotherapy, and adequate surgical margins are the major factors influencing the prognosis of patients with localized Ewing sarcoma of the pelvis.

Adolescent↗

PubMed2007

Dose response and local control using radiotherapy in non-metastatic Ewing sarcoma.

BACKGROUND: To determine prognostic factors for local control in the radiotherapeutic management of non-metastatic Ewing sarcoma. PROCEDURE: Forty patients with localized Ewing sarcoma (ES) were treated with primary site RT at one institution. Median RT dose was 55.8 Gy (range, 25.5-76 Gy). Chemotherapy was given to 34 patients (85%) with the most common regimen being vincristine, dactinomycin, cyclophosphamide, doxorubicin alternating with ifosfamide and etoposide (VACA + IE) in 10. Median follow-up for surviving patients was 12.3 years (range, 1.7-26.4 years). RESULTS: The 5- and 10-year local control rate was 78.2%. On multivariate analysis, RT dose was the only prognostic factor to impact on local control. The 5- and 10-year local control rate was 88.7% for RT dose >or=49 Gy and was 37.5% for <49 Gy (P = 0.0002, log-rank test). For tumors or=49 Gy and 50.0% for RT dose <49 Gy (P = 0.01, log-rank test). For tumors >8 cm, the 5- and 10-year local control rate was 85.7% for RT dose >or=54 Gy and 26.7% for RT dose <54 Gy (P = 0.006, log-rank test). CONCLUSIONS: Radiotherapy dose was found to influence local control in ES. In particular, patients who received RT doses >or=49 Gy for tumor size or=54 Gy for tumor size >8 cm had improved local control.

Adolescent↗

PubMed1998

Abnormalities of the FHIT transcripts in osteosarcoma and Ewing sarcoma.

In a study of FHIT gene abnormalities by reverse transcription-polymerase chain reaction (RT-PCR) and sequence analysis of the PCR products, we found normal and abnormal PCR products in 11 osteosarcomas, one osteosarcoma cell line and 3 Ewing sarcomas, and a normal PCR product only in 5 osteosarcomas and 8 Ewing sarcomas. Sequence analysis of the abnormal PCR products revealed 7 osteosarcomas lacking exons 4 to 6, 7, 8 or 9, two lacking exons 5 to 7 or 10, and two lacking exons 6 to 8 or 10. In the aberrant transcripts of the 11 osteosarcomas, fusion had occurred in the exon/intron junctions in 2 tumors, between a segment within an exon and a complete exon in 3, and between segments within exons in 6. The 3 Ewing sarcomas had lost exon 4 or 5 to exon 6 or 10, and fusion had occurred in the exon/intron junction in one, and between segments within exons in 2. These findings suggest that both abnormal or variant splicing and other mechanisms such as genomic instabilities in the FHIT locus may have resulted in the expression of aberrant transcripts. One osteosarcoma and one cell line established from this osteosarcoma showed different abnormal FHIT transcripts, indicating that the tumor cells with the initial aberrant transcripts may not have had a selective advantage for proliferation. The FHIT abnormalities did not seem to be correlated with lung metastasis or a poor clinical outcome in our patients with osteosarcoma or Ewing sarcoma.

Acid Anhydride Hydrolases↗

PubMed1999

Clinical correlations of genetic changes by comparative genomic hybridization in Ewing sarcoma and related tumors.

Our previous comparative genomic hybridization (CGH) study of Ewing sarcoma and related tumors showed that DNA sequence copy number increases of 1q21-q22 and of chromosomes 8 and 12 were associated with trends toward poor survival (Armengol et al., Br J Cancer 1997, 75, 1403-1409). These trends were not statistically significant. In the present study, we analyzed 28 primary Ewing sarcomas and related tumors by CGH to study whether these (or other) changes have prognostic value in these tumors. Twenty-one tumors (75%) had changes with a mean of 1.9 changes per tumor. The most frequent aberration was gain of chromosome 8 in 10 tumors (36%). Five tumors (18%) had copy number increases at 1q21-22 and 5 had gain of 7q. Copy number increase of 6p21.1-pter, gain of chromosome 12, and loss of 16q were seen in 11%. Copy number increases of 1q21-q22 and of chromosomes 8 and 12 were associated with trends toward worse outcome, but the differences did not reach statistical significance. A novel finding is the association of copy number increase at 6p with worse distant disease-free (P = 0.04) and overall survival (P = 0.004). To confirm this finding and to see whether copy number increases of 1q21-q22 and of chromosomes 8 and 12 have definite prognostic value, a larger number of cases needs to be studied.

Adolescent↗

PubMed2008

Hematometrocolpos in an adolescent female treated for pelvic Ewing sarcoma.

Radiation therapy is often used to achieve local control of pelvic Ewing sarcoma in children. The effects of radiation on the female reproductive tract have been well documented in adults with gynecological malignancies, but the long-term consequences of pelvic radiation in pre-pubertal or adolescent girls are not as well described. We report a case of hematometrocolpos developing in an adolescent previously treated with chemotherapy and radiation therapy for pelvic Ewing sarcoma. We describe the clinical presentation, radiographic features, gross pathology, treatment strategies, outcome, as well as putative predisposing factors and preventative interventions.

Bone Neoplasms↗

PubMed2003

Primitive neuroectodermal tumor and extraskeletal Ewing sarcoma arising primarily around the spinal column: report of four cases and a review of the literature.

STUDY DESIGN: Report of four cases and a review of the literature. OBJECTIVES: To study the clinical features and prognosis of primitive neuroectodermal tumor or extraskeletal Ewing sarcoma arising around the spinal column. SUMMARY OF BACKGROUND DATA: Primitive neuroectodermal tumor or extraskeletal Ewing sarcoma that originates around the spinal column is very rare, and its prognosis is very poor. METHODS: Four patients were diagnosed and underwent treatment. RESULTS: Although all the patients received high-dose chemotherapy with or without radiotherapy after surgery, three patients died of the disease. Only one patient who received en bloc resection of the tumor combined with multiagent chemotherapy followed by high-dose chemotherapy with peripheral blood stem cell transplantation remains alive and continues to be disease free. CONCLUSION: The prognosis of the patients with primitive neuroectodermal tumor or extraskeletal Ewing sarcoma around the spinal column is very poor. Multiagent chemotherapy combined with en bloc resection and radiation therapy is the preferred treatment for patients with primitive neuroectodermal tumor or extraskeletal Ewing sarcoma around the spinal column.

Adolescent↗

PubMed1996

Is the EWS/FLI-1 fusion transcript specific for Ewing sarcoma and peripheral primitive neuroectodermal tumor? A report of four cases showing this transcript in a wider range of tumor types.

The presence of t(11;22)(q24;q12) is often considered diagnostic of Ewing sarcoma and peripheral primitive neuroectodermal tumor. We report four cases, all of which possessed this translocation as detected by reverse transcriptase polymerase chain reaction and confirmed by sequencing with or without fluorescent in situ hybridization, but none of which were Ewing sarcoma or peripheral primitive neuroectodermal tumor by histological criteria. Two were polyphenotypic tumors and two were mixed embryonal and alveolar rhabdomyosarcomas. Only one case was positive for MIC2 by immunohistochemistry and only in a rare cell. Two cases (one polyphenotypic tumor and one rhabdomyosarcoma) had double minute chromosomes with > 100 copies of the MDM2 gene. The presence of the t(11;22)(q24;ql2) translocation should probably not be considered diagnostic of Ewing sarcoma and peripheral primitive neuroectodermal tumor in the absence of supporting histological evidence. The presence of this translocation in Ewing sarcoma and peripheral primitive neuroectodermal tumor has been taken as evidence that these two tumors are related. Extending this relationship to include some polyphenotypic tumors and some rhabdomyosarcomas may not be justified unless additional evidence is gathered. Pathologists and oncologists will need to decide whether treatment regimens for tumors are better based on phenotype rather than genotype when these two profiles are seemingly in conflict.

Abdominal Neoplasms↗

PubMed1997

[Cervical extraosseous Ewing sarcoma].

A case of extraosseous Ewing's sarcoma is presented. The clinical, morphological and imaging characteristics of this rare neoplasm are briefly discussed.

Adult↗

PubMed2001

Primary Ewing sarcoma of the orbit.

PURPOSE: To report the clinicopathologic features of a 17-year-old patient with primary Ewing sarcoma of the orbit. METHODS: The patient was evaluated clinically before surgery with computed tomography scans of the orbit. After surgery, the patient was staged with computed tomography scans and bone scan and was treated with systemic chemotherapy and radiation therapy to the orbit. The orbital biopsy was evaluated with conventional light microscopy and immunohistochemistry. RESULTS: Clinical evaluation revealed proptosis and limited upgaze. Computed tomography scans disclosed a mass involving the superior orbit, anterior cranial fossa, and temporal fossa. Microscopic examination revealed small, poorly differentiated cells with medium-sized nuclei containing finely granular chromatin and small nucleoli. The cytoplasmic borders of the cells were indistinct. A PAS stain revealed modest glycogen in many of the tumor cells. The tumor stained positive for O-13 and vimentin and was negative for neural, skeletal, and lymphoid cell markers. Computed tomography scan, bone scan, and blood chemistries revealed no other site of involvement. After treatment, the clinical symptoms and signs resolved, and there has been no evidence of residual orbital tumor or metastasis. CONCLUSIONS: Primary Ewing sarcoma of the orbit should be considered in the differential diagnosis of children or young adults with proptosis, diplopia, or periorbital swelling. Immunohistochemistry is essential to distinguish Ewing sarcoma from other small round cell tumors.

Adolescent↗

PubMed2003

Adult soft tissue Ewing sarcoma or primitive neuroectodermal tumors: predictors of survival?

BACKGROUND: Ewing sarcoma (ES) is the second most common primary osseous malignancy in childhood and adolescence. The improvement in survival is primarily associated with the combination of surgery and chemotherapy. HYPOTHESIS: Little is known about the outcome of adults with soft tissue ES or primitive neuroectodermal tumors (PNET). Certain prognostic factors from soft tissue sarcomas (tumor size, tumor location, margin status, and initial presentation) in adults (>16 years) with ES/PNET will help to identify factors associated with outcome. METHODS: Between July 1, 1982, and June 30, 2000, we identified 59 adult patients with primary soft tissue ES/PNET. Clinicopathologic factors were correlated with the end points studied: patient factors, tumor factors, pathologic factors, status of surgical margins, adjuvant chemotherapy, and radiation therapy. RESULTS: There were 41 male and 18 female patients, with a median age of 27 years (range, 16-72 years). Median tumor size was 8 cm, with all lesions being high grade. The most common site was the trunk (n = 22), with an even distribution of retroperitoneal, pelvis, buttock, and lower extremity (all n = 5). The median follow-up was 29 months (range, 6-222 months), with local recurrence identified in 13 patients (22%), with a median time to recurrence of 15 months (range, 5-200 months). Overall 5-year survival was 60%. Initial presentation was the only predictor of long-term survival, with primary tumor-only presentation having a 5-year survival of 60% (median not reached) compared with primary tumor plus metastatic disease having a 5-year survival of 33% (median, 17 months) (P =.02). CONCLUSION: Initial presentation of disease represents the only predictor of survival identified in this small group of adult patients with ES/PNET.

Adolescent↗

PubMed2000

Busulfan, melphalan, and thiotepa with or without total marrow irradiation with hematopoietic stem cell rescue for poor-risk Ewing-Sarcoma-Family tumors.

BACKGROUND: Survival following metastatic or recurrent Ewing sarcoma family tumors (ESFT) remains <25%. Myeloablative therapy with hematopoietic stem cell transplantation (HSCT) may improve survival for poor-risk ESFT. We describe the toxicity and efficacy of a myeloablative chemotherapy regimen, followed by a second myeloablative radiotherapy regimen as consolidation treatment for poor-risk ESFT. PROCEDURE: Sixteen patients with poor-risk ESFT were treated with myeloablative therapy followed by HSCT. All patients received busulfan, melphalan, and thiotepa (BuMelTT) as chemotherapy conditioning. Nine patients received total marrow irradiation (TMI) as a second myeloablative therapy, also followed by HSCT. Seven patients were excluded from TMI because of inadequate peripheral blood stem cell harvest, extensive prior radiation therapy, early disease progression, orpatient refusal. The disease status prior to my eloablative therapy was first complete response (CR1) in three patients, CR2 in nine, second partial response (PR2) in one, CR3 in one, and progressive disease (PD) in two. RESULTS: One patient died of regimen-related toxicity, one from late pulmonary toxicity, and one following allogeneic transplantation for myelodysplasia. Eight developed recurrent disease (median time to progression 6.8 months). Six survive without relapse from 27 to 66 months following BuMelTT (median follow-up 42 months), all of whom received both BuMelTT and TMI patients (3-year event-free survival 36%). CONCLUSIONS: Dual myeloablative therapy with BuMelTT and TMI was a feasible and promising treatment approach for patients with poor-risk ESFT. Inability to collect sufficient PBSC and extensive previous radiation therapy limit the ability to deliver TMI as a second HSCT conditioning regimen.

Adolescent↗

PubMed2000

Prognostic impact of INK4A deletion in Ewing sarcoma.

BACKGROUND: The primary genetic alteration in > 95% of Ewing sarcomas (ES) is a specific fusion of EWS with FLI1 or ERG. Secondary genetic alterations possibly involved in progression of ES are not well understood. A recent study found loss of the negative cell cycle regulator gene INK4A in 8 of 27 ES samples (30%). To confirm these findings and evaluate their prognostic significance, the authors studied INK4A deletion in 41 ES samples from 39 patients. METHODS: Using Southern blot analysis with an INK4A p16 cDNA probe, the intensity of the INK4A bands in ES DNA samples was normalized to that of a control probe and compared with nondeleted control DNA; > 50% signal reduction was scored as evidence of deletion. All ES tumor DNA samples previously were confirmed to have EWS rearrangements on the same Southern blots, using a cDNA probe spanning the EWS breakpoint region. RESULTS: Tumors from 7 patients (18%) showed INK4A deletion independent of disease stage (localized or metastatic) or sample source (primary tumor or metastasis). INK4A was a strong negative factor for disease specific survival in univariate analysis (P = 0.001) and in multivariate analysis including stage (relative risk = 6; P = 0.001). CONCLUSIONS: INK4A deletions appear to be the most frequent secondary molecular genetic alteration found to date in ES. Their possible clinical usefulness in identifying a subset of ES patients with poor prognosis merits systematic prospective analysis. [See related article on pages 783-92.]

Adult↗

PubMedDate not supplied

Hematologic abnormalities and acute myeloid leukemia in children and adolescents administered intensified chemotherapy for the Ewing sarcoma family of tumors.

PURPOSE: Current treatment of the Ewing sarcoma family of tumors (ESFT) includes intensive multiagent chemotherapy with topoisomerase II inhibitors, alkylating agents, and granulocyte colony-stimulating factor (G-CSF). This treatment approach has been associated with myelodysplasia and acute myeloid leukemia. Because macrocytosis and thrombocytopenia are distinctive features of myelodysplasia, the authors evaluated a cohort of patients treated for ESFT to determine the degree and duration of macrocytosis and thrombocytopenia and their relation with the development of therapy-related hematologic malignancies. PATIENTS AND METHODS: The study group consisted of 73 patients with ESFT treated on two consecutive protocols (EW92 and EW87). Both chemotherapy regimens incorporated the same agents but differed in cumulative drug dose, dose per course, and the use of G-CSF. Platelet counts and the mean corpuscular volume (MCV) of erythrocytes were determined at diagnosis and during follow-up visits after completion of treatment. RESULTS: Patients in the EW92 group had significantly greater MCVs after treatment than did the less intensively treated EW87 group. These changes persisted throughout the 40-month observation period. Patients in the EW92 group also had lesser mean platelet counts after treatment than those in the EW87 group. MCV differences (from baseline) were inversely related to platelet counts. The cumulative incidence of treatment-related acute myeloid leukemia was 7.8%+/-4.7% at 4 years in the EW92 group and zero in the EW87 group. CONCLUSION: Patients treated for ESFT with intensive chemotherapy that includes large doses of alkylators, topoisomerase II inhibitors, and G-CSF characteristically have persistently elevated MCVs and decreased platelet counts after completion of therapy. These hematologic abnormalities may represent stem cell damage, predisposing patients to myelodysplasia and acute myeloid leukemia, but further study is needed to establish this relation.

Adolescent↗

PubMed1994

MR imaging findings in recurrent primary osseous Ewing sarcoma.

The objective of this study was to determine the value of magnetic resonance (MR) imaging in diagnosing local recurrence of Ewing sarcoma. We retrospectively reviewed radiographs, Tc99m-methylene diphosphonate (MDP) skeletal scintigraphy, computed tomography scans, and MR studies of 11 patients who had local recurrences of osseous Ewing sarcoma following initial responses to chemotherapy and local radiation. The MR images were compared to those of a control group of nine patients who had no evidence of relapse. T1- and T2-weighted MR images identified 9 of the 11 recurrences. Computed tomography was diagnostic in 4 of 6 cases evaluated, Tc99m-MDP bone scintigraphy in 4 of 11 cases, and plain radiographs in 2 of 10. MR findings at relapse included changes in signal intensity, increased extent of abnormal marrow signal on T1- and T2-weighted images, and identification of a new soft tissue mass. These findings suggest that MR imaging is valuable in the routine follow-up of primary osseous Ewing sarcoma.

Adolescent↗

PubMed1991

Molecular localization of the t(11;22)(q24;q12) translocation of Ewing sarcoma by chromosomal in situ suppression hybridization.

Chromosome translocations are associated with a variety of human leukemias, lymphomas, and solid tumors. To localize molecular markers flanking the t(11;22) (q24;q12) breakpoint that occurs in virtually all cases of Ewing sarcoma and peripheral neuroepithelioma, high-resolution chromosomal in situ suppression hybridization was carried out using a panel of cosmid clones localized and ordered on chromosome 11q. The location of the Ewing sarcoma translocation breakpoint was determined relative to the nearest two cosmid markers on 11q, clones 23.2 and 5.8, through the analysis of metaphase chromosome hybridization. By in situ hybridization to interphase nuclei, the approximate physical separation of these two markers was determined. In both Ewing sarcoma and peripheral neuroepithelioma, cosmid clone 5.8 is translocated from chromosome 11q24 to the derivative chromosome 22 and a portion of chromosome 22q12 carrying the leukemia inhibitory factor gene is translocated to the derivative chromosome 11. The physical distance between the flanking cosmid markers on chromosome 11 was determined to be in the range of 1000 kilobases, and genomic analysis using pulsed-field gel electrophoresis showed no abnormalities over a region of 650 kilobases in the vicinity of the leukemia inhibitory factor gene on chromosome 22. This approach localizes the Ewing sarcoma breakpoint to a small region on chromosome 11q24 and provides a rapid and precise technique for the molecular characterization of chromosomal aberrations.

Cell Line↗

PubMed2002

Arrangement of chromosome 11 and 22 territories, EWSR1 and FLI1 genes, and other genetic elements of these chromosomes in human lymphocytes and Ewing sarcoma cells.

Standard and repeated fluorescence in situ hybridization and high-resolution cytometry were used to study topographical parameters of chromosome 11 and 22 territories, EWSR1 and FLI1 genes, and other genetic elements of these chromosomes in human lymphocytes and Ewing sarcoma cells. HSA 11 and its elements (BCL1, FLI1, centromere) were found, on average, more peripherally in comparison with HSA 22 and investigated elements (BCR, EWSR1, centromere). After the elimination of fluctuations of chromosome territories in nuclear volume, it was found that genetic elements in most cases adhered to their territories. The investigated genetic elements of HSA 11 were found close to each other relative to the large molecular lengths among them. This finding indicates a higher degree of chromatin condensation of at least a part of HSA 11 compared with HSA 22. In general, there is no correlation between the physical and molecular distance of two loci of the same chromosome territory. The topographical parameters of the EWSR1 and FLI1 genes do not differ substantially for G(0)-lymphocytes, stimulated lymphocytes and Ewing sarcoma cells. The fusion genes pertaining to both derivative chromosomes 11 and 22 in Ewing sarcoma cell nuclei are shifted to the midway position between the native EWSR1 and FLI1 genes. Comparing results obtained for the EWSR1/FLI1 and ABL1/BCR genes in samples of patients suffering from Ewing sarcoma or chronic myelogenous leukaemia, it can be concluded that the mean positions of the fusion genes are determined by the final structure of the chimeric chromosomes and do not depend on the location of the translocation event.

Cell Nucleus↗

PubMed2025

p300/CBP is an essential driver of pathogenic enhancer activity and gene expression in Ewing sarcoma.

The t(11;22) translocation encodes the EWS::FLI1 fusion oncoprotein which is the primary driver of Ewing sarcoma. EWS::FLI1 creates unique, de novo pathogenic enhancers that drive gene expression and are a central mechanism of oncogenesis. Which chromatin regulatory proteins are critical to this mechanism is understudied. Here, we perform a comparative analysis of the function of the chromatin complexes MLL3/4 and p300/CBP in EWS::FLI1-mediated gene regulation. Using EWS::FLI1 degradation models, we define a subset of EWS::FLI1-sensitive enhancers whose activity correlates with p300/CBP function. We perturb both chromatin complexes to establish that in contrast to MLL3/4, p300/CBP is a critical regulator of EWS::FLI1-driven enhancer activity and downstream gene expression. We also show that p300/CBP small-molecule inhibition decelerates tumor growth in vivo. Our work highlights the context-dependent nature of chromatin protein activity at oncogenic enhancers and reveals p300/CBP as an important regulator of Ewing sarcoma.

Sarcoma, Ewing↗

PubMed1990

Primary Ewing sarcoma: follow-up with Ga-67 scintigraphy.

While avid accumulation of gallium-67 citrate and technetium-99m methylene diphosphonate (MDP) occurs initially in most cases of primary Ewing sarcoma, uptake after therapy is less well defined. Thirty patients with Ewing sarcoma who underwent Ga-67 and bone scintigraphy at diagnosis, at completion of therapy, and at relapse from 1978 to 1988 were evaluated. All 30 patients showed less primary site Ga-67 activity following therapy. Twenty-three of 28 patients who underwent corresponding bone scintigraphy showed less uptake, but residual activity was usually more intense than with Ga-67. Avid reaccumulation of Ga-67 occurred in four of five patients with primary site relapse, while patients who underwent bone scintigraphy showed less change. It was concluded that a greater decrease in Ga-67 than in Tc-99m MDP uptake often occurs in patients successfully treated for primary Ewing sarcoma. Information obtained at Ga-67 scintigraphy is most likely to be helpful if results of bone scintigraphy remain abnormal or if occult relapse is suspected.

Adolescent↗