Expression of embryonic lethal abnormal vision (ELAV)-like protein HuR and cyclooxygenase-2 (COX-2) in Ewing sarcoma.

AIMS AND BACKGROUND: HuR is a member of the family of ELAV (embryonic lethal abnormal vision)-like proteins that stabilize several cellular mRNAs by binding to AU-rich elements in the 3' untranslated region of the mRNA. Cyclooxygenase-2 (COX-2) is a well known enzyme that promotes tumor growth and metastasis. Recent studies have shown that HuR can stabilize the mRNA of COX-2, and cytoplasmic expression of HuR is associated with increased COX-2 expression in some cancers. The aim of this study was to investigate the correlation between COX-2 and HuR in Ewing sarcoma. METHODS: The expression patterns for HuR and COX-2 were assessed via immunochemical analysis of 70 Ewing sarcoma samples. RESULTS: Nuclear HuR expression was observed in 12 of 70 (17.1%) cases, but cytoplasmic expression was not observed. COX-2 expression was seen in 25 of 70 (35.7%) samples. Nuclear HuR and COX-2 were simultaneously expressed in 8 of 70 (11.4%) samples. The expression of nuclear HuR was significantly associated with COX-2 expression (P = 0.014). Neither HuR nor COX-2 expression showed a correlation with age or sex. CONCLUSIONS: COX-2 expression in Ewing sarcoma may not be directly related to mRNA stabilization by HuR. However, a correlation between COX-2 expression and nuclear HuR expression through indirect mRNA stabilization can be suggested.

Brachyury expression in extra-axial skeletal and soft tissue chordomas: a marker that distinguishes chordoma from mixed tumor/myoepithelioma/parachordoma in soft tissue.

Axial chordoma represents approximately 1% of malignant bone tumors. This tumor expresses cytokeratins, specifically cytokeratin 19, and commonly S100. More recently brachyury, a transcription factor important in mesodermal differentiation, including notochord development, has been detected by immunohistochemistry in axial chordomas and hemangioblastomas but not chondrosarcomas or other neoplasms. In this report, we describe 10 cases (6 men, 4 women: age 18 to 68 y; mean 44.6) of extra-axial tumors, 8 in bone and 2 in soft tissue, with morphologic and immunohistochemical features identical to those of axial chordoma. Imaging excluded metastases from axial chordoma. Three tumors occurred in the tibia, the others in the rib, metatarsal, ulna, femur, pubis: 2 intracortical, 6 intramedullary. Both soft tissue brachyury-positive tumors, one involving the thumb the other the wrist, were sited in the juxta-articular region. Seven of the tumors were widely excised and these patients are disease-free but of the 3 tumors that recurred, 1 was curetted, 1 was marginally excised, and 1 had a pathologic fracture on presentation. Metastases have not occurred in any of the patients. We also confirm the expression of brachyury in hemangioblastomas, and for the first time demonstrates its expression in spermatogonia and testicular germ cell tumors by immunohistochemistry. Brachyury was not detected in a wide range of tumors including carcinomas, lymphomas, and sarcomas. In conclusion, we describe the first series of extra-axial skeletal chordomas bringing the total number of such cases reported in the literature to 11, and present the first report of 2 soft tissue chordomas as defined by brachyury expression.

Macrophagic myofasciitis in childhood: the role of scanning electron microscopy/energy-dispersive spectroscopy for diagnosis.

Macrophagic myofasciitis (MMF) is an inflammatory myopathy related to aluminum-containing vaccines. Described in 1998, most cases were reported in adults, with only 22 cases being reported in children. Three children aged between 13 months and 3(1/2) years were investigated in our institution for neuromuscular symptoms. They underwent thorough clinical, familial, and laboratory investigations, electroneuromyography, muscle biopsy with transmission electron microscopy, scanning electron microscopy/energy dispersive spectroscopy (SEM/EDS), and, in one case, brain magnetic resonance imaging. They had received regular immunizations. Two patients were hypotonic and one presented with myotonia. Muscle biopsy of all patients presented macrophagic infiltrates with intracytoplasmic aluminum content as revealed by SEM/EDS analysis. Their diverse clinical picture does not support a direct relationship between local morphologic findings and systemic symptoms. The atypical clinical presentation of these children may not result from the superposition of MMF upon a background systemic neuromyopathy, suggesting instead that they are two coincident and independent conditions. Although the finding of macrophage infiltrates in muscle tissue is not new, the identification of aluminum content is recent. The use of tissue sections for aluminum detection and mapping by SEM/EDS is conclusive for, diagnosis; it has not been reported previously in a pathology journal, to the authors' knowledge.

Protein expression of KIT and gene mutation of c-kit and PDGFRs in Ewing sarcomas.

Ewing sarcoma is a highly malignant tumor of bone preferentially arising in children and young adults. Its 5-year survival rate is only 50% despite the use of multimodal therapeutic approaches, requiring a search for new therapeutic targets and the development of novel therapeutic modalities. KIT and PDGFRs are type III receptor tyrosine kinases, and activating mutations in c-kit (which encodes KIT) and PDGFRs have been reported as oncogenic events in many malignancies. Imatinib is a selective inhibitor of KIT, PDGFR, and ABL tyrosine kinase activity and exerts different anti-tumor effects according to the regions of mutations in c-kit and PDGFR genes. Thus, we evaluated the immunohistochemical expression of KIT protein and the mutational status of exons 9, 11, 13, and 17 of the c-kit gene, exons 12 and 18 of the PDGFRA gene, and exon 12 of the PDGFRB gene in 71 formalin-fixed, paraffin-embedded Ewing sarcomas to increase our understanding of the potential, if any, of imatinib treatment for this malignancy. Of the 71 samples, 27 (38%) were immunohistochemically positive for KIT; however, activating mutations in c-kit were found in only 2 of 71 Ewing sarcomas (2.6%) within exon 9. No activating mutations in the PDGFRA and PDGFRB genes were found, but pleomorphism was identified in exon 18 of the PDGFRA gene. Our results for KIT protein expression agree with those of previous studies. This is the largest series of c-kit mutational analysis in Ewing sarcoma to date, and the results definitively show that c-kit activating mutations are not coincident with KIT protein expression in Ewing sarcoma in most samples. These findings imply other mechanisms for KIT activity and leave open the question of whether imatinib would be efficacious in the treatment of Ewing sarcoma.

The function of proprioceptors in bone organization: a possible explanation for neurogenic heterotopic ossification in patients with neurological damage.

Neurogenic heterotopic ossification is characterized by the formation of extra osseous bone in soft tissue surrounding peripheral joints in neurological patients. It occurs in 25% of spinal cord injury patients, and in 20% of these the pathologic process is severe enough to cause limitations in joint motion. Vascular and metabolic changes resulting from autonomic nervous system impairment may play a role in the etiology of heterotopic ossification. Repetitive vigorous passive manipulation of the joint to preserve range of motion, in the presence of reduced defense mechanisms, may also traumatize soft tissue, thereby initiating the pathological process. Nerve terminals within ligaments and capsules that allow for proprioception have a determinant role in triggering on and off muscle contraction, permitting acceleration and deceleration during gait. The Sarah Network of Rehabilitation Hospitals has treated over 20,000 patients with spinal cord and brain injury in the past 20 years. Based on the observation of heterotopic ossification development in some of these patients, and its tendency to relapse, this present article speculates whether, after an interruption in the neural pathways: (1) altered proprioception can forge a different relationship between tissues; and (2) chaotic new bone formation can occur. We postulate that heterotopic ossification in patients with injury to the central nervous system (CNS) may be related to a dysfunction of proprioception. With interruption of the neural tract of a given limb, ligaments lose control and coordination of their proprioceptive function and begin to react to direct stimulus in an independent, isolated and haphazard way. Free of CNS control and directly stimulated by such independent signals, mesenchymal osteoprogenitor cells located in soft tissues begin to occasion tissue maturation and differentiation into bone: heterotopic bone.

Upregulation of the oncogenic helix-loop-helix protein Id2 in Ewing sarcoma.

AIMS AND BACKGROUND: Id helix-loop-helix proteins function as regulators of cell growth and differentiation. However, they can induce malignant transformation when overexpressed. The EWS/ETS chimeric proteins in Ewing sarcoma act as aberrant transcription factors leading to tumorigenic processes. An enhanced expression of the Id2 gene in Ewing sarcoma cells was previously shown by gene array techniques. We investigated the expression of Id2 at the protein and gene level in Ewing sarcoma. METHODS: We evaluated the expression of Id2 protein using immunohistochemistry in formalin-fixed, paraffin-embedded specimens from a total of 71 cases of Ewing sarcoma. Additionally, a Ewing sarcoma cell line was examined by real-time quantitative PCR. RESULTS: Id2 expression was observed in 65 cases (91.5%) of the 71 total cases examined and a high level of Id2 expression was observed in 45 of these cases (63.8%). In tumor cells, Id2 proteins displayed cytoplasmic as well as nuclear localization. The amplification of the Id2 gene was not noted in a Ewing sarcoma cell line using real-time quantitative PCR. The crossing points of Id2 in the Ewing sarcoma cell line, control fibroblast, and osteosarcoma cell line were 18.54 +/- 0.16, 18.25, and 18.34, respectively. CONCLUSIONS: Our data support a role for increased Id2 protein expression in Ewing sarcoma. However, this overexpression of the Id2 protein could not be confirmed by a corresponding change at the gene level in a Ewing sarcoma cell line.

Familial occurrence of osteoid osteoma.

Familial occurrence of osteoid osteoma is an exceedingly rare event. This paper describes the second report of this event, where two siblings presented with this lesion in the same location, the proximal left femur. They both presented at 6 years of age, but 3 years apart.

Osteocondromas da coluna vertebral: um diagnóstico a considerar nas síndromes de compressäo medular / Osteochondromas of the spine: a diagnosis to consider in spinal cord compression syndromes

Os autores realizaram revisao dos 312 casos de osteocondroma solitário e osteocondromatose múltipla, atendidos no Hospital SARAH do Aparelho Locomotor durante período de 13 anos - compreendido entre 1982 e 1994. Destes, foram selecionados seis casos de pacientes com lesao da coluna vertebral, correspondendo a 1,92 por cento do total de casos diagnosticados desta entidade. Os casos selecionados foram submetidos a propedêutica radiológica que envolveu radiografias simples, mielografia, tomografia computadorizada e, em um dos casos, ressonância magnética. Todos foram submetidos a procedimento cirúrgico descompressivo, com retirada das lesoes, as quais foram encaminhadas a análise histopatológica que confirmou a impressao diagnóstica inicial. Este estudo abrange ainda revisao dos possíveis mecanismos implicados na patogênese do processo.

Schwannoma intramedular: relato de caso / Intramedullary schwannoma: case report

A localizaçao intramedular de schwannoma é rara, correspondendo a O,3 por cento dos tumores nesta topografia. Os autores relatam o caso de uma paciente leucoderma de 52 anos, que apresentou sintomas de compressao devido à presença de schwannoma intramedular localizado em nível de C4 a C6. Nao foram encontrados sinais de neurofibromatose, enfermidade que tem sido associada ao desenvolvimento da lesao. Os exames de ressonância magnética nuclear e a biópsia transoperatória foram fatores decisivos no planejamento e na execuçao do tratamento, ao estabelecer as características, localizaçao e diagnóstico da lesao. Sua boa delimitaçao e sua localizaçao posterior facilitaram a exérese total. O exame histopatológico transoperatório permitiu a instituiçao de procediniento cirúrgico adequado. A célula de Schwann nao é normalmente encontrada no sistema nervoso central e sua presença neste local tem sido objeto de várias teorias expostas no texto deste trabalho, que aborda também revisao de aspectos clínicos, diagnóstico por imagem, patologia, diagnóstico diferencial e tratamento dos schwannomas. É provável que, com os métodos propedêuticos atualmente disponíveis, venha a ser encontrado maior número destas lesoes no futuro.