RESUMO
O rabdomiossarcoma embrionário, variante botrioide, é uma neoplasia maligna dos tecidos moles que deriva de células musculares mesenquimais embrionárias. Alguns fatores de risco genéticos são conhecidos, mas a doença geralmente se apresenta de forma esporádica. É raro manifestar-se em adolescentes, assim como é raro ser primário do colo uterino. Cursa com a presença de pólipos e até massas que se sobressaem na vagina com casos de sangramento vaginal anormal. O diagnóstico é realizado essencialmente pela história e exame anatomopatológico. Quanto maior o tempo para confirmação do diagnóstico, pior o prognóstico. Há várias modalidades de tratamento que deve ser individualizado e envolver uma equipe multidisciplinar , que, basicamente, incluem quimioterapia, radioterapia e cirurgia. Os resultados geralmente são menos favoráveis em adolescentes, quando comparados com os de crianças com a mesma neoplasia.(AU)
Embryonic rhabdomyosarcoma, a botryoid variant, is a malignant neoplasm of soft tissues that derives from embryonic mesenchymal muscle cells. Some genetic risk factors are known, but the disease usually presents itself sporadically. It's rarely manifested in adolescents, just as it is rare to be primary in the cervix. It occurs with the presence of polyps and even masses that protrude in the vagina with cases of abnormal vaginal bleeding. The diagnosis is made essentially by history and anatomopathological examination. The longer the time to confirm the diagnosis, the worse the prognosis. There are several treatment modalities involving a multidisciplinary team that must be individualized and basically include chemotherapy, radiotherapy and surgery. The results are generally less favorable in adolescents, when compared with those of children with the same neoplasia.(AU)
Assuntos
Humanos , Feminino , Adolescente , Neoplasias do Colo do Útero , Rabdomiossarcoma Embrionário/etiologia , Rabdomiossarcoma Embrionário/patologia , Rabdomiossarcoma Embrionário/diagnóstico por imagem , Rabdomiossarcoma Embrionário/cirurgia , Rabdomiossarcoma Embrionário/tratamento farmacológicoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transtornos Cromossômicos/diagnóstico , Ciclofosfamida/administração & dosagem , Dactinomicina/administração & dosagem , Rabdomiossarcoma Embrionário/tratamento farmacológico , Neoplasias Vaginais/tratamento farmacológico , Vincristina/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transtornos Cromossômicos/complicações , Ciclofosfamida/uso terapêutico , Dactinomicina/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Lactente , Recém-Nascido , Mosaicismo , Rabdomiossarcoma Embrionário/diagnóstico , Rabdomiossarcoma Embrionário/etiologia , Neoplasias Vaginais/diagnóstico , Neoplasias Vaginais/etiologia , Vincristina/uso terapêuticoRESUMO
Costello syndrome (CS) arises from a typically paternally derived germline mutation in the proto-oncogene HRAS, and is considered a rasopathy. CS results in failure-to-thrive, intellectual disabilities, short stature, coarse facial features, skeletal abnormalities, congenital heart disease, and a predisposition for cancer, most commonly embryonal rhabdomyosarcoma (ERMS). The goal of this study was to characterize CS ERMS at the molecular level and to determine how divergent it is from sporadic ERMS. We characterized eleven ERMS tumors from eight unrelated CS patients, carrying paternally derived HRAS c.34G>A (p.Gly12Ser; 6) or c.35G>C (p.Gly12Ala; 2) mutations. Loss of heterozygosity (LOH) was evaluated in all CS ERMS by microarray and/or short tandem repeat (STR) markers spanning the entire chromosome 11. Eight CS ERMS tumors displayed complete paternal uniparental disomy of chromosome 11 (pUPD11), whereas two displayed UPD only at 11p and a second primary ERMS tumor showed UPD limited to 11p15.5, the classical hallmark for ERMS. Three sporadic ERMS cell lines (RD, Rh36, Rh18) and eight formalin fixed paraffin embedded (FFPE) ERMS tumors were also analyzed for RAS mutations and LOH status. We found a higher than anticipated frequency of RAS mutations (HRAS or NRAS; 50%) in sporadic ERMS cell lines/tumors. Unexpectedly, complete uniparental disomy (UPD11) was observed in five specimens, while the other six showed LOH extending across the p and q arms of chromosome 11. In this study, we are able to clearly demonstrate complete UPD11 in both syndromic and sporadic ERMS. © 2016 Wiley Periodicals, Inc.
Assuntos
Síndrome de Costello/genética , Perda de Heterozigosidade/genética , Rabdomiossarcoma Embrionário/genética , Dissomia Uniparental/genética , Adolescente , Criança , Pré-Escolar , Cromossomos Humanos Par 11/genética , Síndrome de Costello/complicações , Síndrome de Costello/patologia , Feminino , Genótipo , Mutação em Linhagem Germinativa/genética , Humanos , Lactente , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas p21(ras)/genética , Rabdomiossarcoma Embrionário/etiologia , Rabdomiossarcoma Embrionário/patologia , Dissomia Uniparental/patologiaRESUMO
Embryonic rhabdomyosarcoma (ERMS) is the most common soft-tissue tumor in children. Here, we report the identification of the minor groove DNA-binding factor high mobility group AT-hook 2 (HMGA2) as a driver of ERMS development. HMGA2 was highly expressed in normal myoblasts and ERMS cells, where its expression was essential to maintain cell proliferation, survival in vitro, and tumor outgrowth in vivo. Mechanistic investigations revealed that upregulation of the insulin-like growth factor (IGF) mRNA-binding protein IGF2BP2 was critical for HMGA2 action. In particular, IGF2BP2 was essential for mRNA and protein stability of NRAS, a frequently mutated gene in ERMS. shRNA-mediated attenuation of NRAS or pharmacologic inhibition of the MAP-ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) effector pathway showed that NRAS and NRAS-mediated signaling was required for tumor maintenance. Taken together, these findings implicate the HMGA2-IGFBP2-NRAS signaling pathway as a critical oncogenic driver in ERMS.
Assuntos
GTP Fosfo-Hidrolases/fisiologia , Proteína HMGA2/fisiologia , Proteínas de Membrana/fisiologia , Proteínas de Ligação a RNA/fisiologia , Rabdomiossarcoma Embrionário/etiologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Humanos , Camundongos , Mioblastos/química , Rabdomiossarcoma Embrionário/patologia , Transdução de SinaisRESUMO
Rhabdomyosarcoma (RMS) is an aggressive skeletal muscle-lineage tumor composed of malignant myoblasts that fail to exit the cell cycle and are blocked from fusing into syncytial muscle. Rhabdomyosarcoma includes two histolopathologic subtypes: alveolar rhabdomyosarcoma, driven by the fusion protein PAX3-FOXO1 or PAX7-FOXO1, and embryonal rhabdomyosarcoma (ERMS), which is genetically heterogeneous. Here, we show that adipocyte-restricted activation of Sonic hedgehog signaling through expression of a constitutively active Smoothened allele in mice gives rise to aggressive skeletal muscle tumors that display the histologic and molecular characteristics of human ERMS with high penetrance. Our findings suggest that adipocyte progenitors can be a cell of origin for Sonic hedgehog-driven ERMS, showing that RMS can originate from nonskeletal muscle precursors.
Assuntos
Adipócitos/citologia , Linhagem da Célula , Rabdomiossarcoma Embrionário/etiologia , Tecido Adiposo/metabolismo , Animais , Inibidor p16 de Quinase Dependente de Ciclina/fisiologia , Modelos Animais de Doenças , Proteínas Hedgehog/fisiologia , Humanos , Camundongos , Fator de Transcrição PAX7/fisiologia , Rabdomiossarcoma Embrionário/patologia , Transdução de Sinais , Células-Tronco/citologiaRESUMO
We report on two very similar cases of vaginal embryonal RMS, botryoid variant, that relapsed 9 and 10 years after initial diagnosis, a few months after the menarche in both cases. A possible causal association with estrogen hormones is hypothesized, particularly for the second case described, in which estrogen receptors were negative in the primary tumor specimen and positive in the relapsing tumor specimen.
Assuntos
Rabdomiossarcoma Embrionário/terapia , Neoplasias Vaginais/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Feminino , Humanos , Lactente , Receptores de Estrogênio/deficiência , Recidiva , Rabdomiossarcoma Embrionário/diagnóstico , Rabdomiossarcoma Embrionário/etiologia , Resultado do Tratamento , Neoplasias Vaginais/diagnóstico , Neoplasias Vaginais/etiologiaRESUMO
Embryonal rhabdomyosarcoma (ERMS) is a highly malignant tumor in children and adolescents. It rarely occurs in adults. A 47-year-old patient presented with ERMS of the muscle flap transplant 20 years after an open type III-comminuted fracture of the lower leg. The affected leg was amputated. The patient refused adjuvant chemotherapy and one year after surgery remains disease-free and in good general condition.
Assuntos
Fraturas Cominutivas/complicações , Fraturas Expostas/complicações , Neoplasias Musculares/etiologia , Neoplasias Pós-Traumáticas/etiologia , Rabdomiossarcoma Embrionário/etiologia , Fraturas da Tíbia/complicações , Amputação Cirúrgica , Fixação Interna de Fraturas , Fraturas Cominutivas/cirurgia , Fraturas Expostas/cirurgia , Humanos , Perna (Membro) , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias Musculares/diagnóstico , Neoplasias Musculares/cirurgia , Neoplasias Pós-Traumáticas/diagnóstico , Neoplasias Pós-Traumáticas/cirurgia , Rabdomiossarcoma Embrionário/diagnóstico , Rabdomiossarcoma Embrionário/cirurgia , Fraturas da Tíbia/cirurgia , Fatores de TempoRESUMO
Spindle cell rhabdomyosarcoma (RMS), a variant of embryonal RMS, is a rare tumour, especially in adults. Imaging techniques are used to evaluate the extent of the tumour whereas a biopsy is required to make the final diagnosis. In this article we describe a case of mandibular Spindle cell RMS in a previously irradiated field in a 56-year-old male, and discuss the clinicopathologic and imaging findings. Although the aetiology is still unclear, this case suggests that previous radiation therapy can be a causal factor.
Assuntos
Neoplasias Mandibulares/etiologia , Neoplasias Induzidas por Radiação/etiologia , Segunda Neoplasia Primária/etiologia , Radioterapia/efeitos adversos , Rabdomiossarcoma Embrionário/etiologia , Carcinoma de Células Escamosas/radioterapia , Humanos , Masculino , Neoplasias Mandibulares/patologia , Neoplasias Mandibulares/cirurgia , Pessoa de Meia-Idade , Soalho Bucal , Neoplasias Bucais/radioterapia , Recidiva Local de Neoplasia , Neoplasias Induzidas por Radiação/patologia , Neoplasias Induzidas por Radiação/cirurgia , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/cirurgia , Rabdomiossarcoma Embrionário/patologia , Rabdomiossarcoma Embrionário/cirurgiaRESUMO
Embryonal rhabdomyosarcoma (ERMS) is a devastating cancer with specific features of muscle differentiation that can result from mutational activation of RAS family members. However, to date, RAS pathway activation has not been reported in a majority of ERMS patients. Here, we have created a zebrafish model of RAS-induced ERMS, in which animals develop externally visible tumors by 10 d of life. Microarray analysis and cross-species comparisons identified two conserved gene signatures found in both zebrafish and human ERMS, one associated with tumor-specific and tissue-restricted gene expression in rhabdomyosarcoma and a second comprising a novel RAS-induced gene signature. Remarkably, our analysis uncovered that RAS pathway activation is exceedingly common in human RMS. We also created a new transgenic coinjection methodology to fluorescently label distinct subpopulations of tumor cells based on muscle differentiation status. In conjunction with fluorescent activated cell sorting, cell transplantation, and limiting dilution analysis, we were able to identify the cancer stem cell in zebrafish ERMS. When coupled with gene expression studies of this cell population, we propose that the zebrafish RMS cancer stem cell shares similar self-renewal programs as those found in activated satellite cells.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Genes ras/fisiologia , Rabdomiossarcoma Embrionário/genética , Peixe-Zebra/genética , Adenosina Desaminase/genética , Animais , Animais Geneticamente Modificados , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Transformação Celular Neoplásica , Células Cultivadas , Proteínas de Ligação a DNA/genética , Embrião não Mamífero/citologia , Embrião não Mamífero/metabolismo , Perfilação da Expressão Gênica , Humanos , Hibridização In Situ , Rim/citologia , Rim/metabolismo , Rim/patologia , Microinjeções , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas de Ligação a RNA , Rabdomiossarcoma Embrionário/etiologia , Rabdomiossarcoma Embrionário/patologia , Peixe-Zebra/metabolismoRESUMO
BACKGROUND: Secondary malignant neoplasms (SMN) in CNS tumor survivors has become problem of increasing concern over the last 20 years. These tumors usually occur in a different site from the primary brain tumor several years after treatment. CASE REPORT: We report secondary cranial malignant neoplasms in three patients who were treated with irradiation and chemotherapy for their primary brain tumors. The first case is a male survivor of an orbital rhabdomyosarcoma who developed a meningioma 8 years later. The other two cases are female survivors of ependymomas who were irradiated at the age of 3 and developed secondary gliomas 8 and 17 years after therapy respectively. CONCLUSION: Patients carry a risk of developing SMNs many years later since irradiation is still an important part of the treatment. An SMN may have a benign course, as in meningioma, or be a dilemma for the patient, as in glioblastoma.
Assuntos
Meningioma/etiologia , Radioterapia/efeitos adversos , Rabdomiossarcoma Embrionário/etiologia , Adulto , Anticorpos Antinucleares/metabolismo , Anticorpos Monoclonais/metabolismo , Criança , Pré-Escolar , Desmina/metabolismo , Ependimoma/etiologia , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Glioblastoma/etiologia , Glioblastoma/metabolismo , Humanos , Imuno-Histoquímica/métodos , Antígeno Ki-67/metabolismo , Masculino , Radioterapia/métodos , Rabdomiossarcoma Embrionário/metabolismo , Proteínas S100/metabolismoRESUMO
Malignant tumors arising within dysrhaphic malformations are very rare and are mostly teratomas; so far, only one rhabdomyosarcoma has been reported in this context. We report another case of a girl with lipomyelomeningocele who developed a lumbar rhabdomyosarcoma 2 years after birth and primary closure of the neural tube defect. We present clinical, radiological and pathological findings, discuss possible mechanisms of malignant transformation and review the literature.
Assuntos
Meningomielocele/complicações , Rabdomiossarcoma Embrionário/etiologia , Neoplasias da Medula Espinal/etiologia , Pré-Escolar , Feminino , Humanos , Vértebras Lombares , Rabdomiossarcoma Embrionário/diagnóstico , Rabdomiossarcoma Embrionário/cirurgia , Sacro , Neoplasias da Medula Espinal/diagnóstico , Neoplasias da Medula Espinal/cirurgiaRESUMO
Rhabdomyosarcoma (RMS) is a common paediatric soft tissue sarcoma that resembles developing foetal skeletal muscle. Tumours of the alveolar subtype frequently harbour one of two characteristic translocations that juxtapose PAX3 or PAX7, and the forkhead-related gene FKHR (FOXO1A). The embryonal subtype of RMS is not generally associated with these fusion genes. Here, we have quantified the relative levels of chimaeric and wild-type PAX transcripts in various subtypes of RMS (n=34) in order to assess the relevance of wild-type PAX3 and PAX7 gene expression in these tumours. We found that upregulation of wild-type PAX3 is independent of the presence of either fusion gene and is unlikely to contribute to tumorigenesis. Most strikingly, upregulated PAX7 expression is almost entirely restricted to cases without PAX3-FKHR or PAX7-FKHR fusion genes and may contribute to tumorigenesis in the absence of chimaeric PAX transcription factors. Furthermore, as myogenic satellite cells are known to express PAX7, this pattern of PAX7 expression suggests this cell type as the origin of these tumours. This is corroborated by the detection of MET (c-met) expression, a marker for the myogenic satellite cell lineage, in all RMS samples expressing wild-type PAX7.
Assuntos
Regulação da Expressão Gênica , Proteínas de Homeodomínio/biossíntese , Músculo Esquelético/citologia , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/patologia , Células Satélites de Músculo Esquelético , Animais , Proteínas de Ligação a DNA/biossíntese , Modelos Animais de Doenças , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead , Humanos , Camundongos , Proteínas Musculares , Proteínas do Tecido Nervoso , Fator de Transcrição PAX3 , Fator de Transcrição PAX7 , Fatores de Transcrição Box Pareados , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rabdomiossarcoma Embrionário/etiologia , Fatores de Transcrição/biossíntese , Células Tumorais Cultivadas , Regulação para CimaRESUMO
Although an increased incidence of de novo malignancies is reported in transplant recipients, rhabdomyosarcoma, an aggressive mesenchymal tumor typical of childhood, is not considered a neoplasm commonly related to immunosuppression. A 21-year-old woman presented with unilateral diplopia and proptosis 16 months after liver transplantation for fulminant hepatic failure. A tumoral mass originating from the medial rectus muscle was partially removed and diagnosed as being an embryonal rhabdomyosarcoma. Since the patient refused complete orbital excision, one course of radiotherapy and six courses of chemotherapy were administered, while immunosuppression was re-modulated, without interruption of the administration of cyclosporine. Complete control of tumor growth was achieved, while no alterations of graft function were observed throughout the treatment period.
Assuntos
Transplante de Fígado/efeitos adversos , Neoplasias Orbitárias/etiologia , Rabdomiossarcoma Embrionário/etiologia , Adulto , Feminino , Humanos , Terapia de Imunossupressão/efeitos adversos , Fígado/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Neoplasias Orbitárias/diagnóstico , Neoplasias Orbitárias/tratamento farmacológico , Neoplasias Orbitárias/radioterapia , Reoperação , Rabdomiossarcoma Embrionário/diagnóstico , Rabdomiossarcoma Embrionário/tratamento farmacológico , Rabdomiossarcoma Embrionário/radioterapia , Resultado do TratamentoRESUMO
We report a case of rhabdomyosarcoma which occurred in a mediastinal teratoma in a 44-year-old man. Presentation symptoms were chest pain, hoarseness and a cough. Diagnosis was fortuitous, performed by the histological and immunohistochemical study of a mediastinal tumour biopsy specimen that showed embryonal carcinoma and yolk sac tumour components associated with the rhabdomyosarcoma. After cisplatin-based chemotherapy (bleomycin-etoposide-cisplatin), surgical resection of the residual mediastinal tumour was performed. Histological and immunohistochemical study of this tumour confirmed the presence of mature teratoma and embryonal rhabdomyosarcoma. Evolution was marked by a local extension of the mediastinal tumour, occurrence of multiple metastases and bone marrow involvement. The patient died 8 months after diagnosis despite chemotherapy and radiotherapy. A review of the literature reveals that the development of rhabdomyosarcoma in primary mediastinal teratomas is unusual in adults. The diagnostic, therapeutic and prognostic implications of such an association are reviewed.
Assuntos
Neoplasias do Mediastino/complicações , Rabdomiossarcoma Embrionário/etiologia , Teratoma/complicações , Adulto , Humanos , MasculinoRESUMO
A 10-month-old boy presented with a 6-week history of abdominal pain. The pain was due to a large, stage IV embryonal rhabdomyosarcoma of the urinary bladder. The rhabdomyosarcoma was found in association with neurofibromatosis 1 (NF1) manifesting multiple café au lait spots and bowing of the right calf. The diagnosis of NF1 had not been made before presentation. This case report is intended to heighten the awareness of the manifestations of NF1 and the possibility of developing a nonneuroectodermal tumor as a concomitant of NF1, and to emphasize the importance of timely diagnosis and treatment of such an NF1-associated malignancy. Reports of the epidemiologic evidence for rhabdomyosarcoma in children with NF1 are reviewed.
Assuntos
Neurofibromatose 1/complicações , Rabdomiossarcoma Embrionário/etiologia , Neoplasias da Bexiga Urinária/etiologia , Humanos , Lactente , Masculino , Rabdomiossarcoma Embrionário/terapia , Neoplasias da Bexiga Urinária/terapiaAssuntos
Síndrome do Nevo Basocelular/etiologia , Fator de Crescimento Insulin-Like II/biossíntese , Proteínas de Membrana/genética , Rabdomiossarcoma Embrionário/etiologia , Anormalidades Múltiplas , Animais , Síndrome do Nevo Basocelular/complicações , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Modelos Biológicos , Receptores Patched , Receptores de Superfície Celular , Rabdomiossarcoma Embrionário/complicações , Transdução de SinaisRESUMO
Rhabdomyosarcoma (RMS) of the lung is a very rare lesion, but the association with cystic adenomatoid malformation (CCAM) is unlikely to be a coincidence. Although the etiologic factors predisposing infants and children to pulmonary neoplasms are unknown, pulmonary developmental abnormalities may play a pathogenetic role. A case of embryonal pulmonary RMS is described, which was discovered within a congenital CCAM in a 22-month-old child. The hypothesis regarding histogenesis of this neoplasm are also briefly discussed. Because of the risk of malignant change, early removal of the congenital cystic lesions of the lung is advisable.
Assuntos
Malformação Adenomatoide Cística Congênita do Pulmão/complicações , Neoplasias Pulmonares/etiologia , Rabdomiossarcoma Embrionário/etiologia , Biópsia , Causalidade , Malformação Adenomatoide Cística Congênita do Pulmão/classificação , Feminino , Humanos , Lactente , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirurgia , Pneumonectomia , Rabdomiossarcoma Embrionário/diagnóstico , Rabdomiossarcoma Embrionário/cirurgia , Tomografia Computadorizada por Raios XRESUMO
Replication errors (RERs) were initially identified in hereditary nonpolyposis colon cancer and other tumors of Lynch syndrome II. Mutations in genes involved in mismatch repair give rise to a mutator phenotype, resulting in RERs. The mutator phenotype is thought to predispose to malignant transformation. Here we show that in the embryonal form of childhood rhabdomyosarcoma, RERs also occur, but in contrast to hereditary nonpolyposis colon cancer, only a subset of the microsatellite loci analyzed show RERs. The occurrence of RERs is strongly correlated with increased fractional allelic loss (P < 0.001), suggesting that the occurrence of RERs is a secondary phenomenon in rhabdomyosarcoma. Coincidental loss of genes involved in mismatch repair, possibly due to their proximity to tumor suppressor genes involved in tumor progression of embryonal form of childhood rhabdomyosarcoma, could explain the observed phenomenon.