RESUMO
Extraskeletal myxoid chondrosarcoma is characterized by the reciprocal chromosomal translocation t(9;22) and the resultant fused gene EWS RNA-binding protein 1 and nuclear receptor subfamily 4, group A, member 3 (EWSR1-NR4A3). A second cytogenetic rearrangement t(9;17) involves the genes NR4A3 and TAF 15 RNA polymerase II, TATA box binding protein (TBP)-associated factor (TAF15). Less frequent fusion transcript variants of the NR4A3 gene, transcription factor 12 (TCF12)-NR4A3 and TRK-fused gene (TFG)-NR4A3, are associated with t(9;15) and t(9;3) respectively. The samples from 42 patients with extraskeletal myxoid chondrosarcoma were examined for the presence of EWSR1-NR4A3, TAF15-NR4A3, TCF12-NR4A3, and TFG-NR4A3 fusion transcripts by using RT-PCR. Fluorescence in situ hybridization was performed to analyze the status of EWSR1 and NR4A3 genes. The fusion transcripts were detected in 34 of 42 samples (81%); the presence of an EWSR1 or NR4A3 gene rearrangements were detected in 8 of 42 samples (19%) which had tested negative for all fusion transcripts detected by RT-PCR. Of the 34 samples evaluable for fusion transcripts, 23 yielded positive results for EWSR1-NR4A3, 10 for TAF15-NR4A3, and 1 for TCF12-NR4A3. The combination of RT-PCR and fluorescence in situ hybridization on frozen and paraffin-embedded tissue is a sensitive and specific method for molecular detection of recurrent translocations and is an important ancillary method to establish the diagnosis of extraskeletal myxoid chondrosarcoma.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Ligação a Calmodulina/genética , Condrossarcoma/diagnóstico , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/diagnóstico , Proteínas de Fusão Oncogênica/genética , Proteínas/genética , Proteínas de Ligação a RNA/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Condrossarcoma/genética , Feminino , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Proteína EWS de Ligação a RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Translocação GenéticaRESUMO
BACKGROUND: Angiosarcoma of bone is a rare high-grade malignant vascular tumor. The literature regarding treatment and outcome of patients with this tumor is limited.We performed a 2 institutional retrospective study to analyze treatment and survival of patients with angiosarcoma of bone. PATIENTS AND METHODS: We reviewed patients with the histologic diagnosis of primary angiosarcoma of bone treated from 1980 to 2009. Demographic details, histology, treatment, and survival were reviewed. RESULTS: A total of 38 men and 22 women (median age, 54 y) were recruited. Most lesions occurred in the femur and the pelvis. Metastatic disease at presentation was diagnosed in 24 patients (40%). Forty-three patients underwent surgery, with 30 of them achieving surgical complete remission (SCR). Radiotherapy was applied to 17 patients, and chemotherapy to 13/35 and 15/22 patients with localized and metastatic disease, respectively.The 5-year overall survival (OS) was 20%: 33% for patients with localized disease and 0% for metastatic patients. Higher 5-year OS was reported for patients who achieved SCR (46%) than for those who did not (0%). In nonmetastatic patients, a trend toward improved survival was observed after SCR and adjuvant chemotherapy based on cisplatin, doxorubicin, and ifosfamide.Fifteen patients received chemotherapy for metastases. Two RECIST partial responses of 13 evaluable patients were documented (paclitaxel [n=1] and doxorubicin [n=1]). Stable disease was observed in 2 patients. CONCLUSIONS: Complete surgical resection is essential for outcome. Survival of patients with metastatic or unresectable disease is very poor. Activity of taxanes and anthracycline was observed in the metastatic setting and merits further evaluation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/terapia , Hemangiossarcoma/terapia , Adolescente , Adulto , Idoso , Neoplasias Ósseas/patologia , Criança , Cisplatino/administração & dosagem , Estudos de Coortes , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Neoplasias Femorais/patologia , Neoplasias Femorais/terapia , Fêmur/patologia , Fêmur/cirurgia , Hemangiossarcoma/patologia , Humanos , Úmero/patologia , Úmero/cirurgia , Ifosfamida/administração & dosagem , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/administração & dosagem , Ossos Pélvicos/patologia , Ossos Pélvicos/cirurgia , Radioterapia , Radioterapia Adjuvante , Rádio (Anatomia)/patologia , Rádio (Anatomia)/cirurgia , Estudos Retrospectivos , Neoplasias Cranianas/patologia , Neoplasias Cranianas/cirurgia , Neoplasias da Coluna Vertebral/patologia , Neoplasias da Coluna Vertebral/cirurgia , Resultado do Tratamento , Ulna/patologia , Ulna/cirurgia , Adulto JovemRESUMO
Giant cell tumor (GCT) of bone is a histologically benign osteolytic tumor featuring prominent osteoclast-like giant cells, mononuclear osteoclast precursors, and spindle-shaped stromal cells (SCs). Thus far, most studies have identified SCs as truly transformed elements that are responsible for sustained giant cell formation via receptor activator of NF-κB ligand (RANKL) paracrine induction. However, we have previously shown that SCs are hyperplastic, rather than neoplastic, and able to induce giant cell formation similar to that of normal mesenchymal SCs; we hypothesized that other cell subsets of GCTs might be primarily relevant for the pathogenesis. In this study, we show that the nonproliferating CD14(+) cells of GCTs, exhibiting typical monoblast lineage features, secrete high amounts of RANKL, thereby activating a RANKL/RANK autocrine loop that determines sustained giant cell formation. Moreover, these cells also lack adequate negative feedback control of the RANKL signaling pathway, as determined by endogenous interferon ß. These data demonstrate that CD14(+) cells of GCTs are abnormally stimulated to limitless differentiation into multinucleated giant cells and provide useful suggestions for the development of novel therapies.
Assuntos
Comunicação Autócrina , Retroalimentação Fisiológica , Tumor de Células Gigantes do Osso/metabolismo , Tumor de Células Gigantes do Osso/patologia , Receptores de Lipopolissacarídeos/metabolismo , Osteoclastos/patologia , Osteogênese , Regulação Neoplásica da Expressão Gênica , Tumor de Células Gigantes do Osso/genética , Humanos , Interferon beta/genética , Interferon beta/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Modelos Biológicos , Osteoclastos/metabolismo , Osteoclastos/ultraestrutura , Ligante RANK/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/genéticaRESUMO
PURPOSE: The multikinase inhibitor sorafenib displays antitumor activity in preclinical models of osteosarcoma. However, in sorafenib-treated patients with metastatic-relapsed osteosarcoma, disease stabilization and tumor shrinkage were short-lived and drug resistance occurred. We explored the sorafenib treatment escape mechanisms to overcome their drawbacks. EXPERIMENTAL DESIGN: Immunoprecipitation, Western blotting, and immunohistochemistry were used to analyze the mTOR pathway [mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2)]. Cell viability, colony growth, and cell migration were evaluated in different osteosarcoma cell lines (MNNG-HOS, HOS, KHOS/NP, MG63, U-2OS, SJSA-1, and SAOS-2) after scalar dose treatment with sorafenib (10-0.625 µmol/L), rapamycin-analog everolimus (100-6.25 nmol/L), and combinations of the two. Cell cycle, reactive oxygen species (ROS) production, and apoptosis were assessed by flow cytometry. Nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice injected with MNNG-HOS cells were used to determine antitumor and antimetastatic effects. Angiogenesis and vascularization were evaluated in vitro by exploiting endothelial branching morphogenesis assays and in vivo in xenografted mice and chorioallantoic membranes. RESULTS: After sorafenib treatment, mTORC1 signaling was reduced (downstream target P-S6), whereas mTORC2 was increased (phospho-mTOR Ser2481) in MNNG-HOS xenografts compared with vehicle-treated mice. Combining sorafenib with everolimus resulted in complete abrogation of both mTORC1 [through ROS-mediated AMP-activated kinase (AMPK) activation] and mTORC2 (through complex disassembly). The sorafenib/everolimus combination yielded: (i) enhanced antiproliferative and proapoptotic effects, (ii) impaired tumor growth, (iii) potentiated antiangiogenesis, and (iv) reduced migratory and metastatic potential. CONCLUSION: mTORC2 activation is an escape mechanism from sorafenib treatment. When sorafenib is combined with everolimus, its antitumor activity is increased by complete inhibition of the mTOR pathway in the preclinical setting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Complexos Multiproteicos/metabolismo , Osteossarcoma/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Everolimo , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neovascularização Patológica/metabolismo , Neovascularização Patológica/prevenção & controle , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Osteossarcoma/irrigação sanguínea , Osteossarcoma/patologia , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacologia , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Sirolimo/farmacologia , SorafenibeRESUMO
PURPOSE: To describe the imaging features of soft tissue solitary fibrous tumors, with histopathological correlations and clinical outcome. MATERIAL AND METHODS: Twenty-seven patients with histologically proven SFTs were retrospectively evaluated. Imaging studies included six radiographs, five U/S studies, eighteen CT scans, fourteen MRI exams, and one angiography. RESULTS: On CT scans, two lesions were isodense and five were mildly hypodense compared to muscle while 11 lesions appeared heterogeneous-mixed of iso and hypodense areas. Heterogeneous enhancement was depicted in 13 lesions and four lesions enhanced homogeneously. Six lesions were partially calcified. On T1W MR images, seven lesions were isointense and one was slightly hyperintense relative to adjacent muscles while five lesions appeared heterogeneous-mixed of iso and hypointense areas. T2W images showed high SI in two cases and heterogeneous-mixed in seven cases. Enhancement was heterogeneous in six and homogeneous in four lesions. Patchy unenhanced areas (on CT and T1W MR images) along with patchy areas of low to markedly high SI on T2W images were depicted in 19 lesions. The enhanced portions correlated to areas of increased vascularity and cellularity. The four clinically more aggressive lesions could not be predicted on imaging. CONCLUSION: Typical soft tissue SFTs are deep masses made of isodense and isointense areas relative to adjacent muscles mixed with hypodense and hypointense areas on unenhanced CT and MR T1W respectively. Variable enhancement patterns and mixed to high signal intensities on MRT2W are attributed to tumor's cellularity, vascularity, collagen distribution and/or degeneration. Heterogeneity of SFTs affects imaging features on MRI and CT modalities. The biological behavior of soft tissue SFTs can not be predicted based solely either on histopathologic or imaging evaluation.
RESUMO
INTRODUCTION: There is no clear radiologic or pathologic agreement on the differences between enchondroma and conventional chondrosarcoma, which has huge therapeutic consequences. Microscopically, an enchondroma is composed of "islands of intramedullary hyaline cartilage surrounded by marrow fat", and a chondrosarcoma a "diffuse cartilaginous replacement (invasion) of the marrow which leads to complete 'trapping' of host lamellar bone trabeculae." The marrow around islands of cartilage should be detectable on magnetic resonance imaging (MR). Enchondroma may be the precursor of chondrosarcoma; benign cartilaginous islands are often seen microscopically at the periphery of chondrosarcoma. We attempted to detect these islands at the periphery of chondrosarcomas on MR and correlate them microscopically. MATERIALS AND METHODS: We examined our database for all patients with a chondrosarcoma of the long and flat bones between 1990 and 2007. Only those with a preoperative MR who underwent an en bloc resection were included, yielding 32 patients. We looked for low-signal islands surrounded by high (fat) signal on T1-weighted images, and high-signal islands surrounded by low signal on T2-weighted fat saturated images at the periphery of the main tumour mass. Microscopic correlation was performed in all cases. RESULTS: On microscopy, there were 23 conventional chondrosarcomas, nine dedifferentiated. Peripheral islands surrounded by fat were detected on MR in 19 cases, corresponding to benign cartilage in 18 cases and to the benign scar of a needle biopsy tract in one. There were no peripheral islands detected radiographically or microscopically in 13 cases. CONCLUSION: Cartilaginous islands microscopically detected at the periphery of some chondrosarcomas are easily and reliably diagnosed on MR.
Assuntos
Neoplasias Ósseas/patologia , Condroma/patologia , Condrossarcoma/patologia , Imageamento por Ressonância Magnética/métodos , Criança , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Osteosarcomas of hands or feet are rare, and seemingly these cases differ in presentation and behavior compared to those in usual locations. The clinico-pathological presentation of patients with osteosarcomas of the hand or foot was studied and compared with published cases. Forty osteosarcomas were identified among 4,221 cases, representing 0.95 % of all osteosarcomas. Thirty of these were well documented. Mean age at diagnosis was 43 years (hands) and 36 years (feet) and male-female ratio was 1.2:1 and 2.0:1, respectively. In the hand, 62 % of the osteosarcomas presented in the metacarpals and 23 % in the phalanges, and only two cases occurred in the carpal bones. Distribution in the foot was tarsal bones 56 %, metatarsal bones 33 %, and phalanges 11 %.Of the cases in the hand 54 % were of high grade and of those in the foot 71 %. Survival of osteosarcomas of the hand or foot was 81 %. Only patients with high-grade osteosarcoma died of the disease. Histological grade was the only significant variable related to survival. High-grade osteosarcoma of the hand or feet should be treated similar to those in conventional sites. Osteosarcomas of hands or feet are rare and in a relative high proportion are of low grade. Survival in high-grade cases is comparable to that in conventional sites.
Assuntos
Neoplasias Ósseas/patologia , Pé , Mãos , Osteossarcoma/patologia , Adolescente , Adulto , Idoso , Neoplasias Ósseas/mortalidade , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Osteossarcoma/mortalidade , Fatores Sexuais , Taxa de Sobrevida , Adulto JovemRESUMO
The question is not classic: which signs suggest a possible malignancy when faced with a solitary bone lesion? Usually radiologists try to identify the leave me alone lesions, for which nothing is needed. Here we consider the suspicious lesions. Clinical and radiological indicators are proposed, leading to a probability. Nowadays, a biopsy is nevertheless always requested before treating a malignant lesion, even if suspicion is very high. But histology should integrate with the radiological signs.
Assuntos
Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/patologia , Humanos , Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios XRESUMO
The classification of vascular bone tumors remains challenging, with considerable morphological overlap spanning across benign to malignant categories. The vast majority of both benign and malignant vascular tumors are readily diagnosed based on their characteristic histological features, such as the formation of vascular spaces and the expression of endothelial markers. However, some vascular tumors have atypical histological features, such as a solid growth pattern, epithelioid change, or spindle cell morphology, which complicates their diagnosis. Pathologically, these tumors are remarkably similar, which makes differentiating them from each other very difficult. For this rare subset of vascular bone tumors, there remains considerable controversy with regard to the terminology and the classification that should be used. Moreover, one of the most confusing issues related to vascular bone tumors is the myriad of names that are used to describe them. Because the clinical behavior and, consequently, treatment and prognosis of vascular bone tumors can vary significantly, it is important to effectively and accurately distinguish them from each other. Upon review of the nomenclature and the characteristic clinicopathological, radiographic and genetic features of vascular bone tumors, we propose a classification scheme that includes hemangioma, hemangioendothelioma, angiosarcoma, and their epithelioid variants.
Assuntos
Neoplasias Ósseas/classificação , Neoplasias Ósseas/diagnóstico , Diagnóstico por Imagem/métodos , Neoplasias de Tecido Vascular/classificação , Neoplasias de Tecido Vascular/diagnóstico , HumanosRESUMO
Malignant fibrous histiocytoma (MFH) and fibrosarcoma (FS) of bone are rare malignant tumours and contentious entities. Sixty seven cases labelled as bone MFH (57) and bone FS (10) were retrieved from five bone tumour referral centres and reviewed to determine whether recent advances allowed for reclassification and identification of histological subgroups with distinct clinical behaviour. A panel of immunostains was applied: smooth muscle actin, desmin, h-caldesmon, cytokeratin AE1-AE3, CD31, CD34, CD68, CD163, CD45, S100 and epithelial membrane antigen. Additional fluorescence in situ hybridisation and immunohistochemistry were performed whenever appropriate. All cases were reviewed by six bone and soft tissue pathologists and a consensus was reached. Follow-up for 43 patients (median 42 months, range 6-223 months) was available. Initial histological diagnosis was reformulated in 18 cases (26.8 %). Seven cases were reclassified as leiomyosarcoma, six as osteosarcoma, three as myxofibrosarcoma and one each as embryonal rhabdomyosarcoma and interdigitating dendritic cell sarcoma. One case showed a peculiar biphasic phenotype with epithelioid nests and myofibroblastic spindle cells. Among the remaining 48 cases, which met the WHO criteria for bone FS and bone MFH, we identified five subgroups. Seven cases were reclassified as undifferentiated pleomorphic sarcoma (UPS) and 11 as UPS with incomplete myogenic differentiation due to positivity for at least one myogenic marker. Six were reclassified as spindle cell sarcoma not otherwise specified. Among the remaining 24 cases, we identified a further two recurrent morphologic patterns: eight cases demonstrated a myoepithelioma-like phenotype and 16 cases a myofibroblastic phenotype. One of the myoepithelioma-like cases harboured a EWSR1-NFATC2 fusion. It appears that bone MFH and bone FS represent at best exclusion diagnoses.
Assuntos
Neoplasias Ósseas/diagnóstico , Fibrossarcoma/diagnóstico , Histiocitoma Fibroso Maligno/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , DNA de Neoplasias/análise , Diagnóstico Diferencial , Erros de Diagnóstico , Europa (Continente)/epidemiologia , Feminino , Fibrossarcoma/genética , Fibrossarcoma/metabolismo , Fibrossarcoma/mortalidade , Seguimentos , Histiocitoma Fibroso Maligno/genética , Histiocitoma Fibroso Maligno/metabolismo , Histiocitoma Fibroso Maligno/mortalidade , Humanos , Hibridização in Situ Fluorescente , Leiomiossarcoma/diagnóstico , Masculino , Pessoa de Meia-Idade , Mixossarcoma/diagnóstico , Osteossarcoma/diagnóstico , Rabdomiossarcoma Embrionário/diagnóstico , Adulto JovemRESUMO
Epithelial marker and adhesion molecule expression has been reported in Ewing's sarcoma family of tumors (ESFTs), although the prognostic significance has not been assessed systematically. We performed immunohistochemical analysis of epithelial cell adhesion molecule and epithelial mesenchymal transition markers on 415 genetically confirmed ESFTs. Survival analyses were performed in 217 patients. The atypical histological subtype expressed a high proportion of the epithelial markers compared with conventional and PNET variants. We observed that expression of desmoplakin (p < 0.001) and PI3K (p = 0.003) was higher in disseminated than in localized disease. Multivariate analysis showed that desmoplakin and pGSK3ß constitute independent good prognostic factors for progression free survival (PFS), while ZO-1 and Snail represent independent good prognostic factors for overall survival (OS). In contrast, CK8/18 represents an independent poor prognostic factor for OS and the radiotherapy treatment group demonstrated an independent poor prognostic factor for PFS and OS. Although the expression of pan-cytokeratin has been previously highlighted in a significant proportion of ESFT, its expression did not reveal prognostic significance in the present series. Considering the results of prognostic analysis herein reported, we strongly recommend a prospective validation of at least the immunomarkers with prognostic significance (desmoplakin, ZO-1, CK8/18, pGSK3ß, and Snail) in prospective series that include localized and disseminated tumors.
Assuntos
Antígenos de Neoplasias/metabolismo , Neoplasias Ósseas/metabolismo , Moléculas de Adesão Celular/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Sarcoma de Ewing/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/mortalidade , Desmoplaquinas/metabolismo , Intervalo Livre de Doença , Molécula de Adesão da Célula Epitelial , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Imuno-Histoquímica/métodos , Prognóstico , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/mortalidade , Espanha/epidemiologia , Taxa de SobrevidaRESUMO
STUDY DESIGN: Clinical case series. OBJECTIVE: To describe the clinical, radiological, and histological presentation of a series of patients presenting with benign notochordal tumors, and review the existing literature on the topic. SUMMARY OF BACKGROUND DATA: During the past decade, several authors have reported a spine tumor with benign clinical characteristics and histological resemblance to notochordal tissue. The prognosis and appropriate management remain controversial. METHODS: Description of clinical, radiological, and histological findings in 3 patients with benign notochordal tumors of the spine. RESULTS: All cases presented with subacute mild pain, without neurological deficit. Tumors developed at L3, S1, and S4, without canal involvement or apparent instability. The first 2 patients presented with classic imagenological findings were treated conservatively, showing no progression on follow-up. The last patient presented an atypical lytic pattern and contrast enhancement on magnetic resonance imaging, and underwent en bloc resection, with significant associated morbidity. Histopathology of the specimen revealed coexistent foci of incipient chordoma. CONCLUSION: Benign notochordal cell tumors represent a clinical entity derived from notochordal tissue, with characteristics distinct but closely related to the classic chordoma. Some radiological features may suggest the presence of chordoma precursors. Because its true potential for aggressiveness is still undetermined, a careful decision making must weigh the morbidity of en bloc procedures in the spine with uncertain natural history.
Assuntos
Cordoma/diagnóstico , Notocorda/patologia , Neoplasias da Coluna Vertebral/diagnóstico , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Radiografia , Sacro/diagnóstico por imagem , Neoplasias da Coluna Vertebral/cirurgiaRESUMO
PURPOSE: We compared two chemotherapy regimens that included methotrexate (MTX), cisplatin (CDP), and doxorubicin (ADM) with or without ifosfamide (IFO) in patients with nonmetastatic osteosarcoma of the extremity. PATIENTS AND METHODS: Patients age ≤ 40 years randomly received regimens with the same cumulative doses of drugs (ADM 420 mg/m(2), MTX 120 g/m(2), CDP 600 mg/m(2), and IFO 30 g/m(2)) but with different durations (arm A, 44 weeks; arm B, 34 weeks). IFO was given postoperatively when pathologic response to MTX-CDP-ADM was poor (arm A) or given in the primary phase of chemotherapy with MTX-CDP-ADM (arm B). End points of the study included pathologic response to preoperative chemotherapy, toxicity, and survival. Given the feasibility of accrual, the statistical plan only permitted detection of a 15% difference in 5-year overall survival (OS). RESULTS: From April 2001 to December 2006, 246 patients were enrolled. Two hundred thirty patients (94%) underwent limb salvage surgery (arm A, 92%; arm B, 96%; P = .5). Chemotherapy-induced necrosis was good in 45% of patients (48% in arm A, 42% in arm B; P = .3). Four patients died of treatment-related toxicity (arm A, n = 1; arm B, n = 3). A significantly higher incidence of hematologic toxicity was reported in arm B. With a median follow-up of 66 months (range, 1 to 104 months), 5-year OS and event-free survival (EFS) rates were not significantly different between arm A and arm B, with OS being 73% (95% CI, 65% to 81%) in arm A and 74% (95% CI, 66% to 82%) in arm B and EFS being 64% (95% CI, 56% to 73%) in arm A and 55% (95% CI, 46% to 64%) in arm B. CONCLUSION: IFO added to MTX, CDP, and ADM from the preoperative phase does not improve the good responder rate and increases hematologic toxicity. IFO should only be considered in patients who have a poor histologic response to MTX, CDP, and ADM.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Ifosfamida/administração & dosagem , Metotrexato/administração & dosagem , Osteossarcoma/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Fêmur/patologia , Humanos , Úmero/patologia , Masculino , Tíbia/patologiaRESUMO
BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a relatively common soft-tissue tumor. A more aggressive appearing fibrosarcoma may arise in DFSP, changing its biological behavior. CD34 and apolipoprotein-D are highly expressed in DFSP, but their prognostic significance is uncertain. METHODS: DFSP and fibrosarcomatous-DFSP (FS-DFSP) patients referred to our institute between 1982 and 2009 were identified. Fibrosarcomatous changes, expression of CD34 and apolipoprotein-D were evaluated. RESULTS: 40 patients, (median age 43 years, 55% males) were identified. Tumor was located in the limbs in 60%, in the trunk in 40%. Thirty-seven patients had localized and 3 had metastatic disease. Thirteen (32%) patients were FS-DFSP. All but one underwent surgery with adequate surgical margins in 72%. 7 FS-DFSP received also radiotherapy (RT). Chemotherapy was administered to 3 patients with FS-DFSP. With a median follow-up of 49 months, the 5-OS was 90%. Local recurrence rate was 23%: 42% FS-DFSP, 15% DFSP. Metastases developed in three FS-DFSP patients. The 5-year EFS was 70% in localized patients. Histology (DFSP 75% vs. FS-DFSP 52%, p = 0.002), surgical margins (adequate 74% vs. inadequate 55%, p = 0.02), site (limb 47% vs. trunk 100%), CD34 expression (CD34 positive: 70% vs. CD34 negative: 33%, p = 0.05), and apolipoprotein-D expression (Apo-D positive: 73% vs. Apo-D negative: 33%, p = 0.02) influenced the 5-year EFS, whereas sex, use of RT or number of previous surgical treatments did not. CONCLUSIONS: Patients with DFSP have a high survival probability. Site, adequate surgical margins, presence of the fibrosarcomatous component, lack of CD34 expression and apolipoprotein-D influence outcome.
RESUMO
AIMS AND BACKGROUND: Information is scarce on systemic treatment of pelvic osteosarcoma because most chemotherapy protocols for osteosarcoma include patients with extremity tumors and aged up to 30-40 years. METHODS: Data on patients <41 years of age with high-grade pelvic osteosarcoma were prospectively collected. Patients received two chemotherapy protocols consisting of methotrexate, cisplatin, doxorubicin (MAP) and standard-dose or high-dose ifosfamide. RESULTS: Forty patients between 11 and 36 years were included. The most frequent histological subtype was osteoblastic followed by chondroblastic (37.5%). Complete surgical remission was achieved in 65% of patients. Eighteen patients had MAP/standard-dose ifosfamide, 22 MAP/high-dose ifosfamide. Primary chemotherapy was given to 25 patients and 6 (24%) of them had a good histological response. Median follow-up was 32 months (range, 4-134). Five-year overall survival was 27.5%: 33% in localized and 0 in metastatic patients ( P = 0.02); 45% in patients with complete surgical remission and 0 for patients without complete surgical remission (P = 0.001). Local recurrence rate was 46%. In patients with complete surgical remission, 5-year overall survival was 32% with MAP/standard-dose ifosfamide and 59% with MAP/high-dose ifosfamide regimen (P = 0.3). CONCLUSIONS: Local control is the major issue in the treatment of pelvic osteosarcoma. Poor pathological response and high incidence of chondroblastic variant indicate different characteristics between pelvic and extremity osteosarcoma. Chemotherapy with MAP and high-dose ifosfamide might be beneficial in patients with pelvic osteosarcoma and warrants further investigation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/cirurgia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/cirurgia , Ossos Pélvicos , Adolescente , Adulto , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/patologia , Criança , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Seguimentos , Humanos , Ifosfamida/administração & dosagem , Estimativa de Kaplan-Meier , Masculino , Metotrexato/administração & dosagem , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/patologia , Ossos Pélvicos/efeitos dos fármacos , Ossos Pélvicos/patologia , Estudos Prospectivos , Radiografia , Indução de Remissão , Resultado do TratamentoRESUMO
Identification of factors to detect chemotherapy-resistant tumours at diagnosis is a first priority for risk-adapted therapy in the oncology of children and young adults, where more individualized, effective, and less toxic treatments are highly desirable. In this study, we analysed the miRNAs discriminating Ewing's sarcoma (EWS) patients with different clinical outcomes in order to identify new indicators of prognosis. miRNA expression was investigated in 49 primary EWSs by using the Agilent human miRNA microarray v.2 and/or qRT-PCR. Statistical power of the samples studied for miRNA expression was verified, indicating adequate sample size. Microarray analysis defined a signature of five miRNAs (miR-34a, miR-23a, miR-92a, miR-490-3p, and miR-130b) as an independent predictor of risk for disease progression and survival. Validation analysis in the extended sample set indicated that both miR-34a and miR-490-3p achieved sufficient statistical power to predict prognosis. Results were particularly robust for miR-34a, which appeared associated with either event-free or overall survival and emerged as a significant predictor also after multivariate analysis. Patients with the highest expression of miR-34a did not experience adverse events in 5 years; in contrast, patients with the lowest expression recurred within 2 years. High expression of miR34a can be detected also in paraffin-embedded tissues by in situ hybridization, thus contributing to an easy routine evaluation of this miRNA. Functional analysis of miR-34a in EWS cell lines indicated that when miR-34a expression was enforced, cells were less proliferative, less malignant, and sensitized to doxorubicin and vincristine. Expression of miR-34a could be increased in p53wt cells by treatment with nutlin-3a. Accordingly, nutlin-3a synergizes with doxorubicin. Overall, our data indicate that miR-34a expression is a strong predictor of outcome in EWS. Restoration of miR-34a activity may be useful to decrease malignancy and increase tumour sensitivity to current drugs, so sparing excessive long-term toxicity to EWS patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , MicroRNAs/metabolismo , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Humanos , Imidazóis/farmacologia , Hibridização In Situ , Concentração Inibidora 50 , Estimativa de Kaplan-Meier , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos , Inclusão em Parafina , Piperazinas/farmacologia , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Sarcoma de Ewing/genética , Sarcoma de Ewing/mortalidade , Sarcoma de Ewing/patologia , Fatores de Tempo , Transfecção , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Vincristina/farmacologiaRESUMO
To highlight possible similarities and differences in receptor tyrosine kinase (RTK) and downstream signalling activation profiles between clear-cell sarcomas (CCS) and metastatic melanomas (MM), frozen, and paired-matched fixed samples of six CCS with EWSR1 rearrangement (EWSR1+), five CCS without EWSR1 rearrangement (EWSR1-), and seven MM were investigated by means of biochemical, immunohistochemical, FISH, molecular analyses, and immunofluorescence confocal microscopy. Fixed samples of a further 10 CCS and 14 MM were investigated by means of sequencing for BRAF, NRAS, and KRAS mutations and FISH analyses for the gain of chromosomes 22 and 8. RTK analysis of all CCS/MM samples showed activation of short-form (sf) recepteur d'origine nantais (RON) RTK and of PDGFRB, MET, and HER3. Analysis of downstream signaling revealed consistent phosphorylation patterns of PI3K/AKT, RSK, and the mTOR targets S6 and 4EBP1. Analysis of frozen and fixed material from 21 CCS and 21 MM showed the presence of the V600E BRAF mutation in 2/12 EWSR1+ and 3/9 EWSR1- CCS and 9/21 MM and demonstrated a significant (P < 0.001) correlation between the gain of chromosomes 22 and 8 and EWSR1- CCS. Our results show that BRAF mutation can also be present in CCS and support the proposed aberration of chromosomes 22 and 8 as a possibly useful nonrandom hallmark of EWSR1- CCS. Besides, they broaden the spectrum of the similarities of RTK pathway activation between CCS and MM, thus suggesting that new drugs found to be active in melanoma and RON inhibitors could have a role in CCS treatment. © 2011 Wiley Periodicals, Inc.
Assuntos
Biomarcadores Tumorais/metabolismo , Melanoma/secundário , Receptores Proteína Tirosina Quinases/metabolismo , Sarcoma de Células Claras/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Biomarcadores Tumorais/genética , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a Calmodulina/metabolismo , Duplicação Cromossômica , Cromossomos Humanos Par 22 , Cromossomos Humanos Par 8 , Feminino , Expressão Gênica , Humanos , Metástase Linfática , Masculino , Melanoma/genética , Melanoma/metabolismo , Pessoa de Meia-Idade , Fosforilação , Proteína EWS de Ligação a RNA , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Receptores Proteína Tirosina Quinases/genética , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/patologia , Análise de Sequência de DNA , Trissomia , Adulto JovemRESUMO
Atypical lipomatous tumors/well-differentiated liposarcomas are low-grade malignant mesenchymal neoplasms with high propensity to local recurrence and potential to dedifferentiate to higher grades over time. However, the published risks of local recurrence and dedifferentiation vary, and no unified treatment and follow-up plan has been accepted. We performed a study to evaluate the long-term clinical behavior and proper treatment and follow-up strategy for these tumors. We retrospectively reviewed the files of 101 patients treated between 1990 and 2008 with the diagnosis of atypical lipomatous tumors/well-differentiated liposarcomas. For 67 of these patients, complete data and 2-year minimum follow-up were available and were included in the study; 47 patients (group A) had primary surgical treatment at our institution and 20 patients (group B) were referred after ≥1 local recurrences. Mean follow-up was 81 months (range, 24-229 months). The local recurrence rate of primary atypical lipomatous tumors/well-differentiated liposarcomas was 10.6% (5/47 group A patients). The local re-recurrence rate of the recurrent atypical lipomatous tumors/well-differentiated liposarcomas was 52% (13/67 group A and B patients). Recurrences developed as late as 140 months after diagnosis and treatment. The rate of dedifferentiation at recurrences was 4% (1/25 group A and B patients with recurrent tumors). No patients developed metastases. Atypical lipomatous tumors/well-differentiated liposarcomas are associated with an increased rate of local re-recurrence and low risk of dedifferentiation at recurrences. Long-term follow-up is recommended for early diagnosis and treatment of local recurrences.
Assuntos
Lipoma/patologia , Lipossarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Adulto , Idoso , Desdiferenciação Celular , Feminino , Humanos , Lipoma/cirurgia , Lipossarcoma/cirurgia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos Retrospectivos , Neoplasias de Tecidos Moles/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: The polycomb transcription factor Yin Yang 1 (YY1) overexpression can be causally implicated in experimental tumor growth and metastasization. To date, there is no clinical evidence of YY1 involvement in outcome of patients with osteosarcoma. Prognosis of osteosarcoma is still severe and only few patients survive beyond five years. We performed a prospective immunohistochemistry analysis to correlate YY1 immunostaining with metastatic development and survival in a selected homogeneous group of patients with osteosarcoma. METHODS: We studied 41 patients suffering from osteosarcoma (stage II-IVa). Multivariate analysis was performed using Cox proportional hazard regression to evaluate the correlation between YY1 expression and both metastasis development and mortality. RESULTS: YY1 protein is not usually present in normal bone; in contrast, a high number of patients (61%) showed a high score of YY1 positive cells (51-100%) and 39% had a low score (10-50% positive cells). No statistical difference was found in histology, anatomic sites, or response to chemotherapy between the two degrees of YY1 expression. Cox regression analysis demonstrated that the highest score of YY1 expression was predictive of both low metastasis-free survival (HR = 4.690, 95%CI = 1.079-20.396; p = 0.039) and poor overall survival (HR = 8.353, 95%CI = 1.863-37.451 p = 0.006) regardless of the effects of covariates such as age, gender, histology and chemonecrosis. CONCLUSION: Overexpression of YY1 in primary site of osteosarcoma is associated with the occurrence of metastasis and poor clinical outcome.
Assuntos
Neoplasias Ósseas/metabolismo , Proteínas de Neoplasias/metabolismo , Osteossarcoma/metabolismo , Fator de Transcrição YY1/metabolismo , Adulto , Análise de Variância , Neoplasias Ósseas/terapia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Osteossarcoma/secundário , Osteossarcoma/terapia , Prognóstico , Estudos ProspectivosRESUMO
Epithelial marker expression has been reported in Ewing's sarcoma family of tumors (ESFT). However, cytokeratin (CK), epithelial membrane antigen (EMA), and carcino embryonic antigen (CEA) prevalence has not been assessed thoroughly in a large series of genetically confirmed ESFT. The aim of the present study is to confirm the presence of epithelial markers in a large group of ESFT tested genetically for any of their specific gene fusions and the differential diagnosis with other small round cell tumors. To establish the prevalence of epithelial markers, we then performed immunohistochemical studies with antibodies CK (AE1/AE3), CK8/18, CK34ß12, EMA, E-cadherin, and CEA on 415 genetically confirmed ESFT. Immunoreactivity to cytokeratin, EMA, and CEA was present in 19.2%, 6.6%, and 20.8% of cases, respectively. There was no significant association between epithelial markers and histological subtypes, but the atypical variant of ESFT expressed these markers in a high proportion compared with the peripheral neuroectodermal tumors and the conventional variant. The present findings confirm that epithelial marker expression in ESFT, including EMA and CEA, does not rule out a diagnosis of ESFT, and the integration of clinical, radiological, histopathological, immunohistochemical, and molecular genetic findings should form the basis for the diagnosis of bone and soft tissue sarcomas, especially in tumors with atypical or unusual phenotype.