[Rare intrathoracic malignant tumors: reticulum cell sarcoma, Ewing sarcoma or smallcell extrapulmonary carcinoma].
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Animals↗
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"Secondary cancers after Ewing sarcoma and Ewing sarcoma as second malignant neoplasm".
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Bone Neoplasms↗
Absence of detectable EWS/FLI1 expression after therapy-induced neural differentiation in Ewing sarcoma.
Ewing sarcoma and other peripheral primitive neuroectodermal tumors (pPNETs) display limited neural differentiation and are thought to have a neural crest origin Greater than 95% of these tumors share common t(11;22)(q24;q12) ort(21;22)(q22;q12) chromosomal translocations leading to ES/FLI1 or EWS/ERG gene fusions, respectively. The resulting chimeric oncoproteins seem to function as aberrant transcription factors. However, whether these molecules contribute to the limited neural differentiation observed in pPNETs or actually inhibit differentiation remains unclear. We report a Ewing sarcoma case from the forearm of a 10-year-old girl which expressed EWS/FLI1 fusion transcripts. The tumor was treated with surgery, chemotherapy, and local radiation, but residual tumor was detected within a year as a well-differentiated peripheral neural tumor lacking detectable EWS/FLI1 expression. Further studies suggested that the primary and residual tumors were clonally related. This association between apparent therapy-induced differentiation in Ewing sarcoma and absence of detectable fusion transcripts in the residual tumor provides presumptive evidence that EWS/FLI1 expression may inhibit differentiation in tumour cells.
Bone Neoplasms↗
Cytogenetic and molecular cytogenetic studies of a variant of t(21;22), ins(22;21)(q12;q21q22), with a deletion of the 3' EWSR1 gene in a patient with Ewing sarcoma.
Ewing sarcoma is the second most common malignant bone tumor in children and young adults. Cytogenetic analysis to identify a common t(11;22)(q23;q12) or less frequently a t(21;22)(q22;q12) or t(7;22)(p22;q12) plays an important role in the confirmation of the clinical diagnosis. We report a case of a 10-year-old female who had extraskeletal Ewing sarcoma. Conventional cytogenetic analysis revealed that 11 out of 20 cells had a derivative chromosome 22, possibly due to an insertion of the long arm of the 21q21 approximately q22. This finding was confirmed by fluorescence in situ hybridization (FISH) utilizing whole chromosome paint probes specific for chromosomes 21 and 22. Hybridization utilizing LSI EWSR1, dual-color break-apart rearrangement probe unexpectedly revealed that the 3' EWSR1 gene was lost on the derivative chromosome 22. This finding suggests that the insertion of chromosome 21 is another mechanism that could lead to EWS-ERG gene fusion. To our knowledge, this is the first case report of an insertion of a segment of 21q21 approximately q22 into the long arm of 21q12 with a loss of a DNA segment around the breakpoint on the derivative chromosome 22 in Ewing sarcoma.
Calmodulin-Binding Proteins↗
Massive pleural effusion in an 18-year-old girl with Ewing sarcoma.
Ewing sarcoma is a bone tumour that commonly appears between ages five and 10 in the diaphysis of the long bones and predominantly presents with pain and swelling. The case of an 18-year-old girl who presented with back pain, cough, dyspnea, weakness and fever is described. Chest radiograph showed a homogenous density in the middle and inferior zones of the right hemithorax. Thoracic computed tomography revealed a diffuse pleural effusion and a 6.99 cm x 4.45 cm solid mass composed of lobulated, small cystic lesions and calcifications in the right hemithorax. Biochemical analysis of pleural fluid showed hemorrhagic effusion and exudate. A pleural needle biopsy demonstrated solid uniform tumour cells with narrowed cytoplasm, round nuclei and uncertain nucleoli. All of the tumour cell cytoplasms stained with CD99. The pathological examination supported Ewing sarcoma. Three-phase Tc-99m methylene diphosphonate scintigraphy of the whole body showed pathological tracer uptake in a broad area of the eighth costal bone and in smaller areas of the ninth and 10th costal bones. This case is reported because Ewing sarcoma is a rare cause of pleural effusion in clinical practice among younger adults.
Adolescent↗
Circulating IGF2BP3 enables risk stratification and predicts treatment response in Ewing sarcoma.
Ewing sarcoma (EWS), the second most common pediatric bone tumor, presents with a markedly heterogeneous clinical spectrum and optimal risk stratification is therefore crucial for improving treatment outcomes. The RNA-binding protein IGF2BP3 is a critical oncogenic driver of EWS malignancy. This study evaluates the clinical utility of circulating IGF2BP3 as a biomarker to predict treatment response and risk of disease progression in patients with EWS. Plasma samples from 60 patients with EWS diagnosed and treated at the IRCCS Rizzoli Orthopedic Institute (Bologna, Italy) were collected at diagnosis before treatment initiation and/or after induction chemotherapy. For 51 of these patients, blood was collected at diagnosis, prior to any treatments. For 25 patients, blood samples were available at diagnosis and before surgical intervention, allowing longitudinal analysis in the same patient. For 9 patients, blood was collected only after preoperative chemotherapy, before surgical intervention. Circulating IGF2BP3 levels were quantified using a highly specific and sensitive ELISA assay. Plasma samples from healthy donors served as controls. IGF2BP3 plasma levels were correlated with IGF2BP3 tumor tissue expression, established clinical risk factors, and cumulative incidence of relapse using univariable and multivariable analyses. Plasma IGF2BP3 levels were significantly elevated in patients with EWS compared with healthy controls, with a subset of patients (22/51, 43.2%) exhibiting clinically relevant concentrations. Circulating IGF2BP3 levels reflected tumor expression of the molecule and provided additional prognostic information beyond standard clinicopathologic features. The prognostic impact of circulating IGF2BP3 was primarily observed in patients with localized disease, in whom elevated levels were identified as a significant adverse prognostic factor for disease-specific survival (hazard ratio, 10.63; 95% CI, 1.27-88.62; P = 0.029). Longitudinal monitoring demonstrated that persistence of IGF2BP3 in plasma after induction chemotherapy was a strong predictor of poor clinical outcomes. Circulating IGF2BP3 represents a valuable biomarker for early risk stratification in EWS, particularly in patients with localized disease. Although this is single-marker assay, the expression of the molecule may impact on the fate of many mRNAs. We present an accurate, simple, cost-effective and easy clinical applicable tool to support risk-adapted therapeutic interventions. The limited number of employed patients warrants the need of larger cohorts for validation.
Humans↗
Frequency and implications of chromosome 8 and 12 gains in Ewing sarcoma.
Ewing sarcoma (ES) is the second most common primary malignant tumor of bone in children and young adolescents. Most ES contain a pathognomonic translocation t(11;22)(q24;q12) that is likely a pivotal event in the tumorigenesis of these neoplasms. Many ES also contain nonrandom, numerical chromosomal aberrations, the most common of which are trisomies 8 and 12. In this study we evaluated the hypothesis that these trisomies might occur during neoplastic progression and might be associated with differences in biologic behavior. We tested this hypothesis using a combined cytogenetic and dual color fluorescence in situ hybridization approach to determine chromosome 8 and 12 copy number in 52 ES. Relative gains, primarily trisomies, of chromosomes 8 and 12 were found in 24 (46%) and 17 (33%) cases, respectively. Trisomy 8 and trisomy 12 were independent events acquired in a flexible order during ES genetic progression. Our preliminary findings also suggest a higher frequency of trisomies 8 and 12 in relapses than in primary tumors. Prospective studies will be required to determine whether either trisomy is prognostic in newly-diagnosed ES.
Adolescent↗
[Pathology of Ewing sarcoma].
Ewing's sarcoma is a very rare tumor which has, however, attracted much oncological interest since the dramatic improvement of its prognosis under chemotherapy. Its histogenesis has been discussed controversially for a long time, including a possible origin in immature reticulum, myogenous, endothelial and undifferentiated mesenchymal cells. Repeated reports have also suggested a possible neuroectodermal genesis. Convincing arguments, however, have only been brought forward during recent years, since it was found that Ewing's sarcoma and malignant peripheral neuroectodermal tumor share a common chromosome translocation 11;22. In the meantime this hypothesis has been strengthened by numerous cell biological analyses. There seems to be no clear border between Ewing's sarcoma and malignant peripheral neuroectodermal tumors with definite neural differentiation. Histological differential diagnosis of Ewing's sarcoma has been improved by immunohistological methods. In most cases, they can be distinguished from lymphoma (leucocyte common antigen, B and T markers) and embryonal rhabdomyosarcoma (muscle specific actin, desmin) without problems. Apart from that, it is possible nowadays to obtain antibodies against the MIC 2-protein, which is preferably expressed in Ewing sarcoma. The diagnostics of Ewing's sarcoma and the malignant peripheral neuroectodermal tumor have considerably been enriched by the fact that the specific chromosome translocation t(11;22) can be proved molecular biologically. In contrast to the cytogenetic evidence, it is not necessary to establish cell cultures.
Biomarkers, Tumor↗
Disruption of Microhomology-mediated End-joining in Ewing Sarcoma.
Ewing sarcoma (EwS) is a group of bone and soft tissue cancers in children and young adults. Since EwS cells have pronounced sensitivity to radiation and chemotherapy-induced DNA damage, the role of the oncoprotein, EWS-FLI1, in DNA repair is likely. Here, we demonstrate that EWS-FLI1 causes a defect in microhomology-mediated end-joining (MMEJ) repair. EWSR1 is a splicing factor that promotes the faithful splicing of the POLQ pre-mRNA, required for the expression of POLΘ, a critical protein in the MMEJ pathway. Expression of EWS-FLI1, or loss of EWSR1, causes exon 25 skipping of the POLQ transcript, decreased POLΘ expression, impaired MMEJ, and cellular sensitivity to inhibitors of the Fanconi Anemia (FA), NHEJ, or HR pathways, through the mechanism of synthetic lethality. Knockdown of EWS-FLI1 expression restores POLΘ mitotic foci and increases MMEJ activity. Inhibitors of the FA, NHEJ, or HR therefore may provide a targeted therapy for patients with EwS.
Alternative end-joining↗
Detection and molecular cytogenetic characterization of a novel ring chromosome in a histological variant of Ewing sarcoma.
Ewing sarcoma/peripheral primitive neuro-ectodermal tumor (PNET) is a round-cell sarcoma that may show varying degrees of neuro-ectodermal differentiation. These tumors are identified by a characteristic round-cell morphology and immunohistochemical profile, as well as by specific translocations involving the EWS gene on chromosome 22 and the 3' portion of the E26 transformation-specific family of transcription factors. These translocations result in fusion proteins that act as aberrant transcription factors. The majority of Ewing sarcoma cases are characterized by a balanced t(11;22). Specific chromosomal abnormalities often correlate with distinct morphologic or phenotypic subtypes of tumors and play an important role in prognosis. Here we describe the molecular cytogenetic investigation of a case of Ewing sarcoma in the proximal humerus of a 39-year-old male using COBRA (combined binary ratio labelling) fluorescent in situ hybridization karyotyping, array comparative genomic hybridization, and EWS-gene specific fluorescence in situ hybridization. Multiple chromosomal aberrations were identified, including a der(22)r(20;22), resulting in an amplification of the proximal region of the EWS gene. This is the first time that both translocation and amplification involving the EWS gene and an unidentified gene are described. This case adds to the spectrum of both morphology and genetic rearrangements in Ewing sarcoma, and shows the importance of combined molecular cytogenetic approaches in identifying uncommon rearrangements in sarcomas.
Adult↗
Pattern of endogenous lectins of a human sarcoma (Ewing's sarcoma) reveals differences to human normal tissues and tumors of epithelial and germ cell origin.
A human sarcoma, Ewing's sarcoma, contains activities of endogenous lectins. Fractionation of salt and detergent extracts by affinity chromatography on columns with immobilized sugars or glycoproteins results in the pattern of endogenous lectins for alpha- and beta-galactosides, alpha-mannosyl- and alpha-fucosyl-moieties. Whereas some lectins are known from normal, non-malignant human tissues or from a human epithelial tumor or a human germ cell tumor, a Ca2+-independent alpha- and beta-galactoside-binding protein at apparent molecular weight of 58 kilodaltons has so far not been characterized from any human source. The patterns for the tumors and human normal tissues reveal various differences in comparison between each other. These differences, documented for the first human sarcoma, human tumors of different histogenetic lineage and normal tissues are a first step to a lectin-based diagnosis and therapy of certain human cancer types.
Apudoma↗
[Interdisciplinary therapy of Ewing sarcoma].
Ewing's sarcoma is the most common bone tumor in children under ten years of age. It represents a highly malignant tumor that usually arises in bone, but occasionally occurs in soft tissues. Most patients with Ewing's sarcoma present with what appears to be localized disease, but surgery and radiotherapy alone is unlikely to be curative due to the presence of micrometastases. Consequently chemotherapy has become increasingly effective in eliminating these cells, as well as assisting in obtaining local control. The goal of the optimal integration of the three modalities of therapy is to eradicate all tumor while preserving as much function as possible. The extent of the disease determines the aggressiveness of treatment. Diagnostic evaluation includes modern radiologic imaging, immunochemical and cytogenetic techniques. The outlook has dramatically changed in case of nonmetastatic disease, achieving local control of the tumor in 80%, and producing 5-year disease-free survival in two thirds of the patients.
Adolescent↗
The Role of Radiation Therapy in Localized Ewing' Sarcoma.
Ewing's sarcoma is a radiosensitive tumor that has historically been treated primarily with radiation therapy (RT). With the introduction of effective systemic therapy in the early 1970s, RT remained the primary local control modality until recently. With the concern about second tumors in the irradiated field and improved surgical techniques, surgical resection is currently playing a more important role in the management of these tumors. There have been no randomized trials comparing radiation with surgery, and in most series, patients with smaller tumors in accessible sites are treated with surgical resection. Retrospective reviews typically show a greater advantage to the use of surgery than do prospective trials. Although there may be slight local control advantage to surgery, the survival advantage is not great. Since the mid-1980s, fields tailored to the tumor volume have been recommended and the use of whole-bone irradiation has been abandoned. Local control has not been adversely effected. The intergroup trials for Ewing's sarcoma have recommended 45 Gy to a larger volume followed by a 10 Gy boost since 1978. Data from other studies suggest that the dose may be decreased in selected situations. Older studies of functional outcome report significant late effects related to radiation, but these seem to be reduced in more recent series.
Journal Article↗
The role of ifosfamide in the treatment of adult soft tissue sarcomas, Ewing's sarcoma, and osteosarcoma: a review.
Ifosfamide is an analogue of cyclophosphamide that has been extensively investigated in sarcomas. Like doxorubicin and dacarbazine, it belongs to the class of drugs active against advanced soft tissue sarcomas; its optimal use in combination regimens has not been identified. In the treatment of osteosarcoma and Ewing's sarcoma, ifosfamide has been identified as an effective drug. Nonetheless, in these diseases, too, its optimal place in combination therapy has not yet been determined.
Antineoplastic Combined Chemotherapy Protocols↗
Procholecystokinin as marker of human Ewing sarcomas.
PURPOSE: Ewing sarcoma is a rapidly growing mesenchymal tumor in young adults. Although it was shown previously to express the cholecystokinin (CCK) gene, it is unknown whether CCK gene expression is detectable at protein level in Ewing sarcoma tumor cell lines, in tumor tissue, and in plasma from Ewing sarcoma patients, and, if so, whether CCK peptides might play a role as tumor markers. EXPERIMENTAL DESIGN: CCK gene expression was evaluated with in situ hybridization or reverse transcription-PCR in tumor tissue. CCK precursors and bioactive CCK were measured with specific RIAs in tumor tissue, in cell culture medium, and in plasma of Ewing sarcoma patients before and after chemotherapy as well as after tumor recurrence. RESULTS: CCK mRNA was identified in 12 Ewing sarcoma biopsies sampled in two series and in four Ewing sarcoma cell lines but not in unrelated neoplasia. Immunoreactive proCCK was identified in the culturing medium of all Ewing sarcoma cell lines but not in the media from unrelated tumor cell lines. Moreover, in plasma from Ewing sarcoma patients, precursors and mature forms of CCK, in particular proCCK, were detected; several fold elevation of the total proCCK product was found in plasma from patients before treatment and after tumor recurrence, whereas successful chemotherapy reduced proCCK to basal concentrations. Plasma concentrations of proCCK paralleled the respective tumor size. CONCLUSIONS: This is the first study that consistently documents an altered CCK metabolism in human cancer; Ewing sarcomas synthesize and secrete proCCK that can be identified in plasma as circulating tumor marker.
Biomarkers, Tumor↗
Outcome of Ewing sarcoma in children and adolescents with Ewing sarcoma: a five-year survival from a single institution.
Ewing sarcoma, together with neuroblastoma and central nervous system tumors, has got the lowest percentage of complete cure among all malignant diseases in children. From 1993 to 2003, 26 patients with Ewing sarcoma were treated in Pediatric Hematology and Oncology Department, Medical University in Lublin, Poland. In this study the character and time of the clinical symptoms to making the diagnosis, the abnormalities of laboratory tests, and the primary site of tumor were analyzed. The prognosis and results of treatment in children and adolescents were evaluated.
Adolescent↗
Evaluation of prognostic factors in a tumor volume-adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience. Cooperative Ewing Sarcoma Study.
BACKGROUND: The Cooperative Ewing Sarcoma Study (CESS 86), conducted by the German Society of Pediatric Oncology and Hematology (GPOH), was planned on the basis of the results of the preceding CESS 81 study. The prognostic significance of tumor volume in localized Ewing sarcoma of bone was well documented in the CESS 81 trial. As a consequence, the treatment intensity was adapted to volume in the follow-up CESS 86 trial: the four-drug combination used in CESS 81 was amended for patients with large tumor volume (> or = 100 ml), where ifosfamide was substituted for cyclophosphamide. PROCEDURE: From January 1986 to June 1991, 177 protocol patients with localized Ewing sarcoma of bone were registered in CESS 86. The prognostic implication of tumor volume and several covariates was evaluated using Kaplan-Meier life table analysis and Cox's proportional hazard model. RESULTS: The estimated 5- and 8-year event-free survival (EFS) rates were both 59%. Age, gender, tumor site, and a tumor volume of 100 ml did not distinguish groups of patients with different prognosis. However, the prognosis of patients with tumors >200 ml (8-year EFS rate: 42%) was significantly inferior compared to patients with tumors both of 100 to 200 ml (70%) and of <100 ml (63%). In contrast to CESS 81, the histological response to chemotherapy was no longer a significant prognostic factor (EFS: 64% for good and 50% for poor responders, respectively). CONCLUSIONS: Despite risk-adapted treatment intensity, tumor volume retained its prognostic significance; the cut point, however, was shifted toward larger volumes.
Adolescent↗
Radiographic appearance of Ewing sarcoma of the hands and feet: report from the Intergroup Ewing Sarcoma Study.
Review of current data from the Intergroup Ewing Sarcoma Study (IESS) shows that Ewing sarcoma is rare in bones of the hands and feet. The 12 patients from the IESS protocols with hand or foot Ewing sarcoma are comparable to those already reported in the literature. With the exception of lesions in the calcaneus, the prognosis for disease-free survival is excellent. The radiographic features of hand and foot Ewing sarcoma are generally those of classic Ewing sarcoma: permeation, soft-tissue mass, and, often, associated sclerotic reaction. However, with the exception of sclerosis, features suggesting bone reaction and slow tumor growth in these patients were distinctly uncommon compared with Ewing sarcoma in general. Those radiographic features suggesting aggressive behavior were slightly more common than in the general Ewing population. Even so, neither the radiographic appearance nor the greatest dimension of the radiographic lesion can be shown to contribute significantly to prognostication in these patients. Apparently location of the lesion is important, since in the reported cases in the literature and in this series, lesions of the calcaneus fared poorly. The importance of this set of patients therefore relates to awareness and early recognition of an unusual appearance and location of Ewing sarcoma.
Adolescent↗