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Small-cell osteosarcoma: correlation of in vitro and clinical radiation response.

Small-cell osteosarcoma is an entity which shares some clinical and pathological features with both classic osteosarcoma and Ewing's sarcoma of bone. While noted to be "not radiosensitive" when first described, a retrospective review the National Cancer Institute experience of five patients with small-cell osteosarcoma treated with radiation therapy following biopsy (three pts) or limited excision (two pts) showed local control in all five patients with two long-term disease-free survivors (12, 18 years). This compares to three patients treated with surgery alone where one patient failed locally and one patient is a long-term disease-free survivor (7 years). We have studied the in vitro radiation response of a recently established small-cell osteosarcoma cell line (TC-252) and compared its response with that of a classic osteosarcoma cell line (U2-OS) and an Ewing's sarcoma cell line (5838). The small-cell osteosarcoma line responded with a similar Do and extent of PLDR compared to the Ewing's line and was different from the in vitro radiation response of classic osteosarcoma. Based on this small clinical series and the in vitro radiation studies, we conclude that small-cell osteosarcoma is a radioresponsive tumor. Definitive radiation therapy or conservative surgery plus radiation therapy are effective alternative therapeutic options, compared to ablative surgery, for the local treatment of this uncommon bone tumor of children and young adults.

Adolescent↗

Primary lymphoma of the endometrium. A report of two cases diagnosed on cervicovaginal smears.

BACKGROUND: Primary lymphomas of the endometrium are extremely rare. Diagnosis is difficult, especially when the neoplasm is originally evaluated on a cervicovaginal smear. When lymphomas involve the endometrium, the cervix is three times more likely to be the primary site rather than the endometrium. Two of the symptoms of primary lymphoma of the endometrium are abnormal vaginal bleeding and an abdominal or pelvic mass. CASES: Case 1 was a 36-year-old, obese, black female with an abdominal mass and recent onset of ascites. The second case was a 31-year-old, obese, black female with a history of menometrorrhagia. The cytologic findings in both cases revealed an individual cell population, high nuclear/cytoplasmic ratio, small nucleoli and coarsely granular chromatin with some chromatin clearing. Endometrial currettings showed a histologic pattern of malignant non-Hodgkin's lymphoma, diffuse, large cell type. Immunoperoxidase staining was positive for leukocyte common antigen. CONCLUSION: Two cases of lymphoma of the endometrium were diagnosed first by a cervical cytologic smear, supported by a positive body cavity fluid in one case and histology in both. The differential diagnoses included various inflammatory lesions, small cell carcinoma, endometrial stromal sarcoma and granulocytic sarcoma.

Adult↗

The comparative roles of electron microscopy and immunohistochemistry in the diagnosis of soft tissue tumours.

Electron microscopy has contributed to the diagnosis of soft tissue tumours for four decades, and immunohistochemistry for two. Because of its relative ease of use and interpretation, the latter technique has become extensively and routinely applied to identify lines of differentiation in benign soft tissue tumours and in sarcomas. The use of electron microscopy has declined but retains a role because few antibodies are wholly specific or fully sensitive, some tumours are polyphenotypic or divergent in differentiation, and others have no specific antigens. Immunohistochemistry is superior in diagnosis of smooth muscle tumours, small round cell tumours, sarcomas with epithelioid morphology, and most synovial sarcomas. Electron microscopy is of particular value for peripheral nerve sheath tumours, marker-negative synovial sarcomas, pleomorphic sarcomas and mesotheliomas. As with all adjunctive techniques, immunohistochemistry and electron microscopy should be used in a complementary fashion according to the nature of the diagnostic problem.

Diagnosis, Differential↗

ET-743: more than an innovative mechanism of action.

Ecteinascidin-743 (ET-743), an anti-tumor agent derived from the marine tunicate, Ecteinascidia turbinata, is active against various solid tumor cell lines, including soft tissue sarcoma, breast, ovarian, non-small-cell lung and prostate cancers and melanoma, and has a broad spectrum of anti-cancer activity in vivo. For reasons as yet unclear, sarcoma cell lines are exquisitely sensitive to ET-743. The drug has a unique mechanism of action that makes it a novel anti-tumor agent. ET-743 is a DNA-binding agent that covalently interacts with the minor groove of the DNA double helix to bend the molecule towards the major groove. Defects in DNA repair pathways have paradoxical effects on the anti-tumor activity of ET-743: loss of mismatch repair does not affect its toxicity; loss of DNA-dependent protein kinase activity enhances its toxicity; defects in transcription-coupled nucleotide excision repair confer resistance to ET-743. As a DNA repair capability appears to be necessary for at least one mechanism of ET-743-mediated cytotoxicity, the drug may interact with the DNA repair machinery to induce lethal strand breaks. One of the most novel aspects of ET-743 is its effect on RNA polymerase II-mediated gene transcription. ET-743 selectively inhibits activation of the multidrug resistance gene, while leaving constitutive gene expression relatively unaffected. Preliminary studies of other genes and transcriptional inducers indicate that ET-743 may be a more general inhibitor of activated, but not basal, transcription.

Antineoplastic Agents, Alkylating↗

Characteristics of proteoglycans associated with cell membrane of ascites Tawa sarcoma cells.

We investigated the biochemical characteristics of cell membrane-associated proteoglycans extracted from ascites Tawa sarcoma cells. Proteoglycans were extracted with 4 M Gdn-HCl, and purified by DEAE-Sephacel. The extract sample was fractionated into two proteoglycan fractions, TC-I and TC-II, and eluted at salt concentrations of approximately 0.35 M and 0.45 M NaCl, respectively, by HPLC ion exchange chromatography using a Bio-Scale DEAE 5 column in 7 M urea. After HPLC gel filtration using a TSK gel G 6000 PW column, the fractions were further analysed by hydrophobic interaction chromatography on Octyl-Sepharose in 4 M Gdn-HCl. Since TC-I displayed hydrophobic properties while TC-II was non-hydrophobic, the former was regarded as the proteoglycan associated with the cell membrane. Cellulose acetate membrane electrophoresis confirmed that both TC-I and TC-II contained only heparan sulfate as a sugar chain, and that the degree of sulfation of TC-I and TC-II was lower than that for normal tissue. Immunoblotting with monoclonal antibody HepSS-1 showed that TC-I and TC-II contained two heparan sulfate proteoglycans with Mr of about 30 kDa and 45 kDa, respectively. These results indicate that the proteoglycan associated with the cell membrane of ascites Tawa sarcoma cells is a small and undersulfated-heparan sulfate proteoglycan.

Animals↗

Oral vinzolidine as therapy for Kaposi's sarcoma and carcinomas of lung, breast, and colon/rectum.

Vinzolidine, a semisynthetic vinca alkaloid, was studied as oral therapy in 30 patients with Kaposi's sarcoma, non-small cell lung cancer, colorectal cancer, and breast cancer. Substantial variations in morbidity were observed among the patients, some patients receiving doses up to 45 mg/m2 without toxicity while others had severe hematologic toxicity at doses as low as 25 mg/m2. Nausea/vomiting and diarrhea also occurred. Responses were seen in two of 11 patients with Kaposi's sarcoma but not in other patients. Unpredictable severe hematologic toxicity led to early closure of this study. The heterogeneity of patient tolerance may relate to variable oral drug bioavailability, and it is conceivable that vinzolidine could be administered more safely by the IV route.

Administration, Oral↗

"Dedifferentiated" chordoma: a case report of the cytomorphologic findings on fine-needle aspiration.

Chordomas are relatively rare neoplasms occurring at both ends of a neuro axis. The majority follow an indolent course of multiple local recurrences, ultimately leading to the patient's death. Rare examples have been associated with sarcomatous components, usually resembling malignant fibrous histiocytoma, fibrosarcoma, or osteosarcoma. These tumors have followed a more aggressive course, with poor response to treatment and death following a relatively short time course. Cytologic material from a single case obtained by fine-needle aspiration revealed a high-grade malignancy composed of short atypical spindle cells containing modest amounts of granular cytoplasm. Physaliphorous cells were absent, and myxoid material was not a significant component of the smears. Rare polygonal cells with foamy cytoplasm were identified. Histologic study revealed a high-grade spindle-cell sarcoma in which were scattered small aggregates of vacuolated cells resembling physaliphorous cells. Anaplastic giant cells were present, and the overall appearance of the neoplasm resembled a malignant fibrous histiocytoma. Despite the radiographic appearance of a conventional chordoma in this case, the cytologic findings were indicative of a high-grade sarcoma consistent with a dedifferentiated chordoma.

Adult↗

A sinonasal primary Ewing's sarcoma.

Nasal fractures are a common complaint familiar to all otolaryngologists. Sinonasal primary Ewing's sarcomas are extremely rare. The case of a 9-year-old boy is presented whose nasal fracture and subsequent lateral nasal wall hematoma revealed an underlying Ewing's sarcoma. There are several unusual features in the history and clinical course of this patient. Following biopsies, immunohistochemistry proved essential in distinguishing a Ewing's sarcoma from other small cell tumours. It is important that a seemingly common condition can be the first presentation of a less common, more sinister pathology.

Biopsy, Fine-Needle↗

Malignant rhabdoid tumour of soft tissue. An ultrastructural and immunohistological study of a pelvic tumour.

A case of extrarenal malignant rhabdoid sarcoma arising in the pelvic soft tissues of a 12-year-old girl is described. By routine light microscopy the tumour resembled, in some areas, an embryonal rhabdomyosarcoma and, in other areas, a neuroblastoma. Electron microscopy revealed characteristic cytoplasmic aggregates of intermediate filaments, often with central clusters of organelle membranes surrounded by these filaments. Immunohistochemical stains showed strong cytoplasmic reactivity for vimentin. Staining for cytokeratin, myoglobin, desmin, neurofilaments, neurone specific enolase, S-100 protein and leucocyte common antigen was negative. A histogenetic origin from primitive mesenchymal cells is favoured. We strongly support the use of electron microscopy for the definitive diagnosis of small round cell undifferentiated sarcomas of childhood.

Child↗

Extracellular matrix of small round cell tumors of childhood: an immunohistochemical study of 67 cases.

Sixty-seven childhood tumors were studied immunohistochemically for the extracellular matrix element type IV collagen, laminin, and fibronectin. Tumors included Ewing's sarcoma, primitive neuroectodermal tumor, small cell osteosarcoma, neuroblastoma or ganglioneuroblastoma, rhabdomyosarcoma, and lymphoma. It was found that small cell osteosarcoma was often positive for fibronectin but not type IV collagen or laminin, a new observation. In the lymphomas, matrix proteins were rarely found. Ewing's sarcoma was variably positive for type IV collagen and laminin, but fibronectin was absent. Extracellular laminin and fibronectin were found in one of two cases of primitive neuroectodermal tumor. In neuroblastoma and ganglioneuroblastoma, the matrix components were rarely found. These results, discrepant with findings in cultured cells, may reflect the altered capacity of tumors to produce these proteins in vitro, which suggests that caution should be exercised in drawing conclusions regarding the nature or histogenesis of tumors from data obtained with cultured tumor cells. Embryonal rhabdomyosarcoma frequently contained all matrix elements in the extracellular space and in a dotlike pattern in the cytoplasm; alveolar rhabdomyosarcoma rarely contained these proteins and never exhibited the dotlike pattern. The frequent finding of matrix proteins in embryonal rhabdomyosarcoma but only rarely in alveolar rhabdomyosarcoma and the unique immunostaining pattern in embryonal rhabdomyosarcoma may prove to be a useful adjunct in the diagnosis of childhood tumors.

Adolescent↗

The ultrastructure of small-cell osteosarcoma, with a review of the light microscopy and differential diagnosis.

Small-cell osteosarcoma is a rare form of osteosarcoma and often poses difficulty in differential diagnosis when tissue samples do not include any diagnostic osteoid. By light microscopy, it may be difficult to distinguish small-cell osteosarcoma from other small-cell neoplasms, especially Ewing's sarcoma and mesenchymal chondrosarcoma. Relatively little has been reported about the ultrastructural characteristics of small-cell osteosarcoma, whereas electron microscopic examination has proven very useful in the diagnosis of most other small-cell neoplasms. We have studied four proven small-cell osteosarcomas in detail at the electron microscopic level and found their common features to be a high nucleocytoplasmic ratio, poorly differentiated cytoplasm, numerous free ribosomes and mitochondria as the next most prevalent organelle, small junctions, and envelopment of individual and groups of cells by matrix. Beyond these characteristics, cytoplasmic organelles and nuclear features varied, and no single pathognomonic ultrastructural picture was observed. However, within the range of possible ultrastructure of small-cell osteosarcoma, most small-cell neoplasms can be ruled out. Only certain examples of Ewing's sarcoma and mesenchymal chondrosarcoma may be indistinguishable from it when osteoid is not present in the sample.

Adolescent↗

[Special diagnostic problems in primary malignant bone tumors].

The diagnosis of primary malignant bone tumors, which only account for 1% of malignancies in humans, represents quite a challenge for the pathologist. Apart from the often overlapping morphology between different entities, heterogeneity within one and the same tumor has to be kept in mind. Furthermore, in most cases the diagnosis must be established based on small biopsy specimens and occasionally even on frozen sections. In this context detailed clinical information including the patient's age and exact localization of the tumor, as depicted by X-ray or MRI, are essential requirements for a correct diagnosis. In addition, multiple biopsies from different tumor sites may be of help. For example, 25% of osteogenic sarcomas (OSA) are chondroplastic. Others may contain areas similar to fibrosarcoma (FSA) or malignant fibrous histiocytoma (MFH). Since 90% of OSA occur in the second decade of life whereas chondrosarcomas, FSA and MFH usually manifest after the age of 40 years, a biopsy solely composed of malignant chondromatous tissue obtained from a tibial lesion of a 10-year-old child should most likely be considered as part of an OSA. In the differential diagnosis of the so-called small, round cell tumors, which include Ewing sarcoma, malignant lymphoma and small-cell OSA, immunohistochemical staining of the paraffin-embedded material and a molecular biological/genetic work-up of frozen material are most helpful. In this paper the histomorphological characteristics and criteria for differential diagnosis of the most common primary malignant bone tumors are discussed.

Bone Neoplasms↗

Detection of endometrial stromal sarcoma in cervicovaginal smears: reports of three cases.

Although the small neoplastic cells of pure endometrial stomal sarcoma do not usually exfoliate readily, they are sometimes detected in cervicovaginal smears. In three cases, constituting half the patients with histologically confirmed endometrial stromal sarcoma from 1971 through 1979 at the University of Texas Medical Branch at Galveston, cervicovaginal smears also contained malignant or suspicious cells. All three had certain common features: mostly rounded, small malignant cells with occasional tapered "comet" forms, discernible nucleoli and a tumor diathesis.

Adult↗

Small-cell osteosarcoma of the mandible. Case report.

A case of small-cell osteosarcoma of the mandible in an 8-year-old girl is reported. This unusual variant may simulate Ewing's sarcoma and other small-cell neoplasms affecting jaws in children. The correct recognition of this type of tumor may be important for an appropriate choice of treatment.

Child↗

Development of Ewing's sarcoma from primary bone marrow-derived mesenchymal progenitor cells.

Ewing's sarcoma is a member of Ewing's family tumors (EFTs) and the second most common solid bone and soft tissue malignancy of children and young adults. It is associated in 85% of cases with the t(11;22)(q24:q12) chromosomal translocation that generates fusion of the 5' segment of the EWS gene with the 3' segment of the ETS family gene FLI-1. The EWS-FLI-1 fusion protein behaves as an aberrant transcriptional activator and is believed to contribute to EFT development. However, EWS-FLI-1 induces growth arrest and apoptosis in normal fibroblasts, and primary cells that are permissive for its putative oncogenic properties have not been discovered, hampering basic understanding of EFT biology. Here, we show that EWS-FLI-1 alone can transform primary bone marrow-derived mesenchymal progenitor cells and generate tumors that display hallmarks of Ewing's sarcoma, including a small round cell phenotype, expression of EFT-associated markers, insulin like growth factor-I dependence, and induction or repression of numerous EWS-FLI-1 target genes. These observations provide the first identification of candidate primary cells from which EFTs originate and suggest that EWS-FLI-1 expression may constitute the initiating event in EFT pathogenesis.

Animals↗