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Primary thoracic sarcomas.

Primary sarcomas of the thorax are rare. The diagnosis is established only after sarcomalike primary lung malignancies and metastatic disease have been excluded. Primary sarcomas of the thorax are classified according to their histologic features and constitute a large group of tumors that occur in the lung, mediastinum, pleura, and chest wall. Angiosarcoma, leiomyosarcoma, rhabdomyosarcoma, and mesothelioma (sarcomatoid variant) are the most common primary intrathoracic sarcomas. Ewing sarcoma, primitive neuroectodermal tumor, chondrosarcoma, malignant fibrous histiocytoma, osteosarcoma, synovial sarcoma, and fibrosarcoma usually arise in the chest wall. Although primary thoracic sarcomas commonly manifest as large, heterogeneous masses, they have a wide spectrum of radiologic manifestations, including solitary pulmonary nodules, central endobronchial tumors, and intraluminal masses within the pulmonary arteries. The different histologic types of sarcomas are frequently indistinguishable at radiologic analysis. However, differences in clinical presentation and the location of the tumor, as well as morphologic features such as calcification within the mass and rib involvement, can be useful in suggesting the appropriate diagnosis. For example, a large rib mass in a child with fever and malaise indicates a Ewing sarcoma, a mass with a calcified matrix is likely a chondrosarcoma or osteosarcoma, and a pulmonary artery mass is likely a leiomyosarcoma.

Adult↗

Extraosseous Ewing's sarcoma.

Extraosseous Ewing's sarcoma is an undifferentiated round-cell sarcoma that is indistinguishable histologically from Ewing's sarcoma of bone. Despite this similarity, it has been accepted as a distinct clinicopathologic entity. The authors describe a 53-year-old man who presented with extraosseous Ewing's sarcoma of the left subcostal chest wall. The lesion was demonstrated by radiography and computed tomography and confirmed by pathological examination.

Humans↗

Cutaneous extraskeletal Ewing's sarcoma.

Extraskeletal Ewing's sarcoma has been recognized as being histologically indistinguishable from Ewing's sarcoma of bone. Although the occurrence of extraosseous Ewing's sarcoma in deep soft tissues has been well described, such cutaneous lesions are rare. We report the clinical history, histopathologic findings, and results of ultrastructural study of this rare variant occurring in a 12-year-old girl. She presented with a dermal and subcutaneous tumor of the left third toe, without osseous involvement. The lesion was composed of masses of round-oval cells, with perilobular fibrosis, focal hemorrhage, ill-defined pale cytoplasm containing glycogen, and absent pericellular reticulin. Ultrastructural study showed a monotonous cell population, with focal thickening of apposing membranes, high nuclear/cytoplasmic ratio, copious intracytoplasmic glycogen, and paucity of organelles except mitochondria. We present this case along with discussion of the literature and problems concerning differential diagnosis of small cell malignancies in the skin.

Bone Neoplasms↗

Extraskeletal Ewing's sarcoma.

BACKGROUND: Ewing's sarcoma usually is identified as a primary malignancy of bone affecting children and young adults. Extraskeletal Ewing's sarcoma is rare, and very few data are available addressing optimal surgical and oncologic treatment modalities. METHODS: The authors chose to review retrospectively 24 patients with extraskeletal Ewing's sarcoma treated at the study institution with modern multimodality therapies. Anatomic location, tumor size, patient age at diagnosis, stage of disease at the time of diagnosis, surgical margins, radiation dose, and the type and dose of chemotherapy were documented for every patient. Follow-up averaged 64 months for surviving patients. RESULTS: The overall 5-year survival rate was 61% and the disease free survival rate was 54%. A multivariate analysis found that younger age at the time of diagnosis was associated with improved 5-year survival and disease free survival (P = 0.008 and P = 0.005, respectively). Patients who underwent wide resection and less-than-wide resection had better overall survival (P = 0.001 and P = 0.015, respectively) and disease free survival (P = 0.002 and P = 0.024) compared with those who underwent no attempt at surgical resection. Patients who underwent a wide resection had an improved overall survival compared with those who underwent a less-than-wide resection (P = 0.045). The size of the lesion (P = 0.277) and the presence of metastatic disease at the time of diagnosis (P = 0.219) were not found to be significant prognostic factors. CONCLUSIONS: Age and surgical treatment were found to be important prognostic variables in the treatment of extraskeletal Ewing's sarcoma. No other variables, such as tumor size, tumor location, stage of disease, or radiation therapy, were found to improve survival. Surgical resection should be considered for all patients with extraskeletal Ewing's sarcoma.

Adolescent↗

Isolated maxillary sinus Ewing's sarcoma.

Extraskeletal Ewing's sarcoma is rarely found arising in the head and neck region. Only six cases of extraskeletal Ewing's sarcoma invading the nasal cavity or paranasal sinuses have been reported in the literature. The first described case of that Ewing's sarcoma located in isolated maxillary sinus extending into the orbita without involving the nose is presented. A 16-year-old woman presented with swelling in her right cheek. The nasal examination was normal. A computed tomography (CT) and magnetic resonance imaging (MRI) of the sinuses revealed a large mass in the right maxillary sinus with extension to the orbita. Under general anesthesia biopsies were taken. Based on histopathological analysis, a diagnosis of extraskeletal Ewing's sarcoma was made. The patient did not accept the surgical therapy. The patient was treated with combined chemotherapy and radiotherapy. The patient has done without evidence of recurrence or metastasis for one year.

Adolescent↗

Constraints to DNA unwinding near radiation-induced strand breaks in Ewing's sarcoma cells.

Ewing's sarcoma cell lines were compared to other cell lines for induction of DNA strand breaks by ionizing radiation and their ability to repair those breaks. The alkali-unwinding assay and alkaline sucrose gradient analysis were used for these studies. The alkali-unwinding assay revealed that the amount of DNA unwound per strand break in Ewing's sarcoma cells was less than for other cells and was not influenced by high-salt denaturation conditions. Ewing's sarcoma cells had similar induction and repair rates for strand breaks compared with other cell lines. The kinetics of unwinding suggests there are constraints to DNA unwinding in the chromatin of Ewing's sarcoma cells, possibly related to high levels of poly(ADP-ribose) polymerase in these cells.

Cell Line↗

Radiation therapy as local treatment in Ewing's sarcoma. Results of the Cooperative Ewing's Sarcoma Studies CESS 81 and CESS 86.

The Cooperative Ewing's Sarcoma Studies, CESS 81 and CESS 86, are multiinstitutional trials with more than 80 participating institutions from Germany, the Netherlands, Austria, and Switzerland. Treatment consists of four courses of multiagent chemotherapy and local therapy. Local therapy was not randomized and was either radical surgery or resection plus postoperative irradiation or definitive radiation therapy. Here results according to local therapy have been analyzed for 93 protocol patients with localized Ewing's sarcoma (ES) who have been recruited in CESS 81 from January 1981 to February 1985 and 122 protocol patients recruited in CESS 86 from January 1986 to November 1989. The 3-year relapse-free survival (RFS) was 55% in CESS 81 and 62% in CESS 86. In CESS 81, the RFS was better for surgically treated than for irradiated patients. In this study there was an extremely high incidence of local failures (50%) after definitive irradiation. In CESS 86, however, the results after radiation therapy have been improved markedly (3-year RFS 67% after radiation therapy, 65% after surgery, and 62% after resection plus irradiation). Possible explanations for the improvement of radiotherapeutic results are as follows: selections for patients for radiation therapy, start of local therapy, and quality of radiation therapy. In CESS 86, irradiated patients were randomized to receive either conventionally fractionated irradiation with less intense chemotherapy or hyperfractionated irradiation with simultaneous chemotherapy. There was no difference in treatment results at the time of analysis. The authors conclude that selection of patients for local treatment modalities and quality of treatment performance has an impact on local and overall treatment results in ES.

Antineoplastic Combined Chemotherapy Protocols↗

Primary cranial Ewing's sarcoma.

Primary Ewing's sarcoma of the cranium is extremely rare, with only 17 cases reported so far. We describe a further case with involvement of the frontotemporal region and the orbit. The patient, an adult male, was admitted with headache and papilloedema, and later developed localised swelling and proptosis. He was treated with surgery, radiotherapy and chemotherapy, and was free from metastases during a follow-up of 14 months. The prognosis of Ewing's sarcoma is improving with radiotherapy and chemotherapy. Further cases are needed to study the biological behaviour of primary cranial Ewing's sarcoma.

Adult↗

Fine-needle aspiration cytology of extraskeletal Ewing's sarcoma.

Extraskeletal Ewing's sarcoma (EES) is a round-cell malignancy that manifests most commonly in the paravertebral and intercostal regions. It occurs predominantly in adolescents and young adults, between the ages of 10 and 30 yr, and follows an aggressive course with a high recurrence rate. Distant metastasis is also common. The tumor is often confused with other round, small-cell neoplasms, including primitive neuroectodermal tumor, neuroblastoma, embryonal rhabdomyosarcoma, and lymphoma. This report pertains to a fine-needle aspiration cytologic diagnosis of EES, supported by clinicopathologic and fine structural correlations in a 56-yr-old man who presented with a rapidly growing, massive, right groin mass. The smears showed a diffuse cellular population of malignant round cells composed of two types: one group of larger cell exhibiting a thin-rim, pale cytoplasm, less hyperchromatic nuclei, nucleoli, and diffusely dispersed chromatinic nuclear details; and the second group of smaller and darker cells with highly hyperchromatic and almost smudged nuclei. These are chief cells and dark cells, respectively. Special studies revealed significant intracytoplasmic glycogen and positive vimentin and HBA-71 immunostaining. Cytogenetic findings of chromosomal 11;22 translocation is also supportive of the diagnosis of EES.

Antigens, Neoplasm↗

Biologic characteristics of four Ewing's sarcomas.

Four Ewing's sarcomas were examined for chromosomal characteristics, growth in cell culture, tumorigenicity in nude mice, and presence of beta-adrenergic receptors. Three tumors were from untreated patients (one obtained directly from the patient and two after growth in nude mice) and one was a metastatic lesion obtained after treatment. All four tumors were diploid or near-diploid, with one or more structural rearrangements. In the metastatic lesion, 21 abnormalities were seen. No specific chromosome aberration was found to be common to all four tumors, although a t(1,16) was observed in two and a t(11;22) in two. Abnormalities involving chromosomes #1, #3, #11, #13, #16, and #22 were each found in two of four tumors. All four tumors were tumorigenic in nude mice; two grew well in cell culture, one of which became an established line, and all four expressed high concentrations of beta-adrenergic receptors.

Adolescent↗

Association of EWS-FLI1 type 1 fusion with lower proliferative rate in Ewing's sarcoma.

The Ewing's sarcoma (ES) family of tumors, including peripheral neuroectodermal tumor (PNET), is defined genetically by specific chromosomal translocations resulting in fusion of the EWS gene with a member of the ETS family of transcription factors, either FLI1 (90-95%) or ERG (5-10%). A second level of molecular genetic heterogeneity stems from the variation in the location of the translocation breakpoints, resulting in the inclusion of different combinations of exons from EWS and FLI1 (or ERG) in the fusion products. The most common type of EWS-FLI1 fusion transcript, type 1, is associated with a favorable prognosis and appears to encode a functionally weaker transactivator, compared to other fusion types. We sought to determine whether the observed covariation of structure, function, and clinical course correlates with tumor cell kinetic parameters such as proliferative rate and apoptosis, and with expression of the receptor for insulin-like growth factor I (IGF-1R). In a group of 86 ES/PNET with defined EWS-ETS fusions (45 EWS-FLI1 type 1, 27 EWS-FLI1 non-type 1, 14 EWS-ERG), we assessed proliferation rate by immunostaining for Ki-67 using MIB1 antibody (n = 85), apoptosis by TUNEL assay (n = 66), and IGF-1R expression by immunostaining with antibody 1H7 (n = 78). Ki-67 proliferative index was lower in tumors with EWS-FLI1 type 1 than those with non-type 1 EWS-FLI1, whether analyzed as a continuous (P = 0.049) or categorical (P = 0.047) variable. Logistic regression analysis suggests that this association was secondary to the association of type 1 EWS-FLI1 and lower IGF-1R expression (P = 0.04). Comparing EWS-FLI1 to EWS-ERG cases, Ki-67 proliferative index was higher in the latter (P = 0.01, Mann-Whitney test; P = 0.02, Fisher's exact test), but there was no significant difference in IGF-1R. TUNEL results showed no significant differences between groups. Our results suggest that clinical and functional differences between alternative forms of EWS-FLI1 are paralleled by differences in proliferative rate, possibly mediated by differential regulation of the IGF-1R pathway.

Adolescent↗

PTPL1 is a direct transcriptional target of EWS-FLI1 and modulates Ewing's Sarcoma tumorigenesis.

Ewing's Sarcoma family tumors (ESFT) are characterized by a translocation t(11:22) forming an aberrant transcription factor EWS-FLI1. Protein tyrosine phosphatase L1 (PTPL1) was identified as a gene upregulated by EWS-FLI1 in transfected cells by microarray. Our results show that PTPL1 is a transcriptional target of EWS-FLI1 both by chromatin immunoprecipitation and promoter activation studies. We demonstrate that PTPL1 is highly expressed in ESFT cells and patient tumors compared with normal tissues, with a trend towards higher expression in metastatic versus primary tumors. Reduction of PTPL1 protein in ESFT cells correlated with a significant reduction in both monolayer and soft-agar cell growth. In addition, these PTPL1-reduced cells were more sensitive to etoposide-induced apoptosis than the controls. We therefore report a novel transcriptional activation of a phosphatase involved in the oncogenesis of ESFT. Increasing interest in specific phosphatase inhibitors would allow PTPL1 to be evaluated as a therapeutic target in ESFT.

Animals↗

Enhanced poly(adenosine diphosphate ribose) polymerase activity and gene expression in Ewing's sarcoma cells.

Ewing's sarcoma (ES) is a highly malignant childhood bone tumor and is considered curable by moderate doses of radiotherapy. The addition of chemical inhibitors of the activity of the nuclear enzyme poly(adenosine diphosphate ribose) [poly(ADPR)] polymerase to ES cells in culture results in increased cell killing, a phenomenon called "inhibitor sensitization." Since poly(ADPR) polymerase is thought to be associated with DNA repair, it has been suggested that ES cells and other inhibitor-sensitized cells may have a reduced capacity for polymer synthesis resulting in deficient postirradiation recovery. We present here the unexpected observation that in comparison to other cell lines tested, ES cells exhibit a high enzyme activity, higher constitutive levels of the protein, and elevated levels of its mRNA transcript for poly(ADPR) polymerase. No gross amplifications or rearrangements of the gene were observed; however, regulation of poly(ADPR) polymerase in these tumor cells takes place at the level of the gene transcript.

Blotting, Northern↗

Esophageal extraskeletal Ewing's sarcoma.

Extraskeletal Ewing's sarcoma is a rare tumor. The most common sites of occurrence are on the trunk, extremities, and retroperitoneum. This type of tumor is well characterized by recurrent chromosomal translocation such as t (11;22) (q24;q12) (EWSR1/FLI1) or t (21;22) (q22;q12) (EWSR1/ERG) and overexpression of MIC2/CD99 on tumor cell membrane. We describe the first reported case of an esophageal extraskeletal Ewing's sarcoma with confirmation from immunohistochemical and molecular diagnoses. A 56-year-old man developed a polypoid tumor located in the lower part of the esophagus. The tumor was composed of small-sized round cells showing prominent fibrillar cytoplasmic processes. Intracytoplasmic glycogen was detected in all the tumor cells. Immunoreactivity for MIC2/CD99 was positive on the membrane of all tumor cells. A reverse transcriptase-polymerase chain reaction followed by sequencing revealed an EWSR1/ERG chimeric transcript, which combined EWSR1 exon 10 with ERG exon 6. The present report added a new entity of esophageal small round cell tumor.

12E7 Antigen↗

Periosteal Ewing's sarcoma.

Periosteal Ewing's sarcoma is an uncommon, but well documented origin of this malignant condition with radiographic signs, different from intramedullary growing tumours. Imaging modalities like CT or MRI supply proof of macroscopically intact endosteal cortical surface and free medullary cavity in long bones affected by this periosteal type of malignancy. Definite confirmation is valid after a careful microscopic investigation of the resected specimen. The prognosis of this type of Ewing's sarcoma may be more favourable than that of the central type. Early diagnosis and therapy are thus essential. A clinical survey of six observations is given.

Bone Neoplasms↗

Poly(ADP-ribose) polymerase turnover alterations do not contribute to PARP overexpression in Ewing's sarcoma cells.

Ewing's sarcoma (EWS) cells contain significantly higher levels of poly(ADP-ribose) polymerase (PARP) mRNA, protein and enzymatic activities than any other eukaryotic cells. Evidence from our laboratory showed that increased transcription, rather than mRNA stability, contributes to the elevated PARP levels. It has been proposed that alterations in the normal turnover rate of PARP may also contribute to the total cellular PARP content as well as to the apoptotic response of Ewing's sarcoma cells to ionizing radiation. To address this possibility, we compared the turnover of PARP in EWS cells (A4573), which contain high PARP and are relatively radiosensitive, with that in laryngeal squamous cell carcinoma cells (SQ-20B), which have low PARP and are radioresistant. Results showed that PARP turnover parameters are nearly identical in both cells types. These data conclusively demonstrate that PARP turnover is not a determinant of either the elevated PARP content or the radiation response of EWS cells.

Bone Neoplasms↗