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1.
Virchows Arch ; 476(1): 109-119, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31802230

RESUMO

Ewing sarcoma (ES) and Ewing-like sarcomas are highly aggressive round cell mesenchymal neoplasms, most often occurring in children and young adults. The identification of novel molecular alterations has greatly contributed to a profound reappraisal of classification, to the extent that the category of undifferentiated round cell sarcoma has significantly shrunk. In fact, in addition to Ewing sarcoma, we currently recognize three main categories: round cell sarcomas with EWSR1 gene fusion with non-ETS family members, CIC-rearranged sarcomas, and BCOR-rearranged sarcomas. Interestingly, despite significant morphologic overlap, most of these entities tend to exhibit morphologic features predictive of the underlying molecular alteration. Ewing sarcoma is the prototype of round cell sarcoma whereas in CIC sarcomas, focal pleomorphism and epithelioid morphology can predominate. BCOR sarcomas often exhibit a spindled neoplastic cell population. NFATC2 sarcoma may exhibit remarkable epithelioid features, and PATZ1 sarcomas often feature a sclerotic background. The differential diagnosis for these tumors is rather broad, and among round cell sarcomas includes alveolar rhabdomyosarcoma, desmoplastic small round cell tumor, poorly differentiated round cell synovial sarcoma, small cell osteosarcoma, and mesenchymal chondrosarcoma. A combination of morphologic, immunohistochemical, and molecular findings allows accurate classification in most cases. A granular diagnostic approach to Ewing sarcoma and Ewing-like sarcomas is justified by significant differences in terms of both response to chemotherapy and overall survival. As all these entities are in part defined by specific fusion genes, a molecular diagnostic approach based on NGS technology should be considered. In consideration of the extreme rarity of many of these tumor entities, referral to expert rare cancer centers or to rare cancer networks represents the best strategy in order to minimize diagnostic inaccuracy, and allow proper patient management.


Assuntos
Neoplasias Ósseas/patologia , Sarcoma de Ewing/patologia , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/genética , Diagnóstico Diferencial , Proteínas de Homeodomínio/genética , Humanos , Imuno-Histoquímica , Proteínas Proto-Oncogênicas/genética , Proteína EWS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/genética , Proteínas Repressoras/genética , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/genética
2.
Virchows Arch ; 476(1): 97-108, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31696361

RESUMO

Rhabdomyosarcomas are malignancies associated with a rhabdomyoblastic phenotype which can be demonstrated morphologically or by immunohistochemistry for MYOD1 and myogenin. Rhabdomyosarcomas are currently subdivided into 4 types in the 2013 WHO classification of tumors of soft tissue and bone, including embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, spindle cell/sclerosing rhabdomyosarcoma, and pleomorphic rhabdomyosarcoma. Recent studies have significantly impacted this classification with the emergence of three distinct new subtypes of rhabdomyosarcomas, namely rhabdomyosarcoma with MYOD1 mutations, rhabdomyosarcoma with TFCP2 fusions, and rhabdomyosarcoma with VGLL2/NCOA2 fusions. Although all these tumors share the terminology "rhabdomyosarcoma," their morphology, clinical behavior, and underlying molecular alterations are dramatically different. Finally, the presence of a rhabdomyoblastic phenotype within a tumor is by no means a diagnostic of a rhabdomyosarcoma, as this may be seen in many other mesenchymal malignancies, such as mesenchymal chondrosarcomas, malignant peripheral nerve sheaths tumors, and biphenotypic sinonasal sarcomas. In this review, we present the main clinical, morphological, and molecular features of these tumors and discuss the evolution of the current classification.


Assuntos
Rabdomiossarcoma/patologia , Predisposição Genética para Doença , Humanos , Fatores de Transcrição Kruppel-Like/genética , Proteína EWS de Ligação a RNA/genética , Proteínas Repressoras/genética , Rabdomiossarcoma/classificação , Rabdomiossarcoma/genética
3.
Virchows Arch ; 476(1): 3-15, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31701221

RESUMO

Although traditional morphological evaluation remains the cornerstone for the diagnosis of soft tissue tumors, ancillary diagnostic modalities such as immunohistochemistry and molecular genetic analysis are of ever-increasing importance in this field. New insights into the molecular pathogenesis of soft tissue tumors, often obtained from high-throughput sequencing technologies, has enabled significant progress in the characterization and biologic stratification of mesenchymal neoplasms, expanding the spectrum of immunohistochemical tests (often aimed towards recently discovered genetic events) and molecular genetic assays (most often fluorescence in situ hybridization and reverse transcription-polymerase chain reaction). This review discusses selected novel molecular and immunohistochemical assays with diagnostic applicability in mesenchymal neoplasms, with emphasis on diagnosis, refinement of tumor classification, and treatment stratification.


Assuntos
Neoplasias de Tecidos Moles/diagnóstico , DNA Helicases/análise , Fusão Gênica , Humanos , Imuno-Histoquímica , Proteínas Nucleares/análise , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-fos/genética , Proteína EWS de Ligação a RNA/genética , Receptor trkA/genética , Proteínas Repressoras/genética , Proteína SMARCB1/análise , Neoplasias de Tecidos Moles/química , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição/análise
4.
Virchows Arch ; 476(1): 41-55, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31828431

RESUMO

Over the last 10 years, a number of advances have been made in our understanding of fibroblastic and myofibroblastic tumors. The rapidly evolving field of molecular diagnostics has resulted in the recognition of new entities and better understanding of tumor pathogenesis, while careful clinicopathologic correlative analyses have led to improvements in modeling tumor behavior. This review will discuss new and emerging entities in fibroblastic neoplasia and provide updates on the pathogenesis, diagnosis, and prognostication of these diverse and challenging tumors.


Assuntos
Fibroblastos/patologia , Neoplasias de Tecido Fibroso/patologia , Antígenos CD34/análise , Rearranjo Gênico , Humanos , Neoplasias de Tecido Fibroso/etiologia , Neoplasias de Tecido Fibroso/genética , Prognóstico , Proteína EWS de Ligação a RNA/genética , Sarcoma/patologia , Proteína Smad3/genética , Neoplasias de Tecidos Moles/etiologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia
5.
Nat Commun ; 10(1): 3999, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488818

RESUMO

Clear cell sarcoma (CCS) is a rare soft tissue sarcoma caused by the EWS/ATF1 fusion gene. Here, we established induced pluripotent stem cells (iPSCs) from EWS/ATF1-controllable murine CCS cells harboring sarcoma-associated genetic abnormalities. Sarcoma-iPSC mice develop secondary sarcomas immediately after EWS/ATF1 induction, but only in soft tissue. EWS/ATF1 expression induces oncogene-induced senescence in most cell types in sarcoma-iPSC mice but prevents it in sarcoma cells. We identify Tppp3-expressing cells in peripheral nerves as a cell-of-origin for these sarcomas. We show cell type-specific recruitment of EWS/ATF1 to enhancer regions in CCS cells. Finally, epigenetic silencing at these enhancers induces senescence and inhibits CCS cell growth through altered EWS/ATF1 binding. Together, we propose that distinct responses to premature senescence are the basis for the cell type-specificity of cancer development.


Assuntos
Fator 1 Ativador da Transcrição/genética , Proteínas de Fusão Oncogênica/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma de Células Claras/genética , Animais , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Exoma/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Neoplasias Experimentais , Sistema Nervoso , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Sarcoma de Células Claras/patologia , Transcriptoma
6.
Anticancer Res ; 39(8): 4463-4465, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366545

RESUMO

This case report describes a patient with a rare occurrence of primary spinal intramedullary Ewing's sarcoma (ES) in the cervical and thoracic spine. The older age of disease occurrence, uncommon location in the cervical and thoracic spine, and EWSR1 gene fusion as the basis of diagnosis are unique features of this case. There is no clear protocol for treatment of primary extraskeletal ES of the spine, with controversy between evidence for pursuing surgery versus a combination of radiation and chemotherapy. Our patient was treated with temozolomide chemotherapy for recurrent metastatic disease of primary ES of the spine.


Assuntos
Tumores Neuroectodérmicos Primitivos/tratamento farmacológico , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/tratamento farmacológico , Temozolomida/administração & dosagem , Adulto , Idoso , Humanos , Masculino , Pescoço/patologia , Tumores Neuroectodérmicos Primitivos/genética , Tumores Neuroectodérmicos Primitivos/patologia , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Coluna Vertebral/efeitos dos fármacos , Coluna Vertebral/patologia , Parede Torácica/efeitos dos fármacos , Parede Torácica/patologia
7.
Nucleic Acids Res ; 47(18): 9619-9636, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31392992

RESUMO

Connections between epigenetic reprogramming and transcription or splicing create novel mechanistic networks that can be targeted with tailored therapies. Multiple subunits of the chromatin remodeling BAF complex, including ARID1A, play a role in oncogenesis, either as tumor suppressors or oncogenes. Recent work demonstrated that EWS-FLI1, the oncogenic driver of Ewing sarcoma (ES), plays a role in chromatin regulation through interactions with the BAF complex. However, the specific BAF subunits that interact with EWS-FLI1 and the precise role of the BAF complex in ES oncogenesis remain unknown. In addition to regulating transcription, EWS-FLI1 also alters the splicing of many mRNA isoforms, but the role of splicing modulation in ES oncogenesis is not well understood. We have identified a direct connection between the EWS-FLI1 protein and ARID1A isoform protein variant ARID1A-L. We demonstrate here that ARID1A-L is critical for ES maintenance and supports oncogenic transformation. We further report a novel feed-forward cycle in which EWS-FLI1 leads to preferential splicing of ARID1A-L, promoting ES growth, and ARID1A-L reciprocally promotes EWS-FLI1 protein stability. Dissecting this interaction may lead to improved cancer-specific drug targeting.


Assuntos
Carcinogênese/genética , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/genética , Fatores de Transcrição/genética , Processamento Alternativo/genética , Linhagem Celular Tumoral , Montagem e Desmontagem da Cromatina/genética , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Nucleares/química , Proteínas de Fusão Oncogênica/química , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Estabilidade Proteica , Proteína Proto-Oncogênica c-fli-1/química , Proteína EWS de Ligação a RNA/química , Sarcoma de Ewing/patologia , Fatores de Transcrição/química
8.
Exp Mol Pathol ; 110: 104291, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31376366

RESUMO

We present a case of EWSR1-SMAD3 positive fibroblastic tumor that occurred in a 24-year-old man who presented with a recurrent tumor in the dorsum of his right foot. Magnetic resonance imaging (MRI) demonstrated a subcutaneous nodule located in the third metatarsophalangeal joint region, measuring 10 × 8 × 5 mm in size. Histological examination revealed a monomorphic spindle cell tumor composed of cellular fascicles of bland fibroblasts with hyalinization. Immunohistochemically, the tumor showed diffuse nuclear staining of ERG. Fluorescence in situ hybridization (FISH) assessment demonstrated an unbalanced rearrangement of the EWSR1 gene. Further next-generation sequencing (NGS) analysis identified EWSR1-SMAD3 gene fusion. Molecular detection may be helpful for identifying new entities, in particular to those that lack lineage-specific differentiation by conventional pathological examinations.


Assuntos
Tumor de Células Gigantes de Bainha Tendinosa/patologia , Proteínas de Fusão Oncogênica/genética , Proteína EWS de Ligação a RNA/genética , Proteína Smad3/genética , Adulto , Tumor de Células Gigantes de Bainha Tendinosa/genética , Humanos , Masculino , Prognóstico , Adulto Jovem
9.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370265

RESUMO

Osteosarcoma and Ewing sarcoma are the most common malignant primary bone tumors mainly occurring in children, adolescents and young adults. Current standard therapy includes multidrug chemotherapy and/or radiation specifically for Ewing sarcoma, associated with tumor resection. However, patient survival has not evolved for the past decade and remains closely related to the response of tumor cells to chemotherapy, reaching around 75% at 5 years for patients with localized forms of osteosarcoma or Ewing sarcoma but less than 30% in metastatic diseases and patients resistant to initial chemotherapy. Despite Ewing sarcoma being characterized by specific EWSR1-ETS gene fusions resulting in oncogenic transcription factors, currently, no targeted therapy could be implemented. It seems even more difficult to develop a targeted therapeutic strategy in osteosarcoma which is characterized by high complexity and heterogeneity in genomic alterations. Nevertheless, the common point between these different bone tumors is their ability to deregulate bone homeostasis and remodeling and divert them to their benefit. Therefore, targeting different actors of the bone tumor microenvironment has been hypothesized to develop new therapeutic strategies. In this context, it is well known that the Wnt/ß-catenin signaling pathway plays a key role in cancer development, including osteosarcoma and Ewing sarcoma as well as in bone remodeling. Moreover, recent studies highlight the implication of the Wnt/ß-catenin pathway in angiogenesis and immuno-surveillance, two key mechanisms involved in metastatic dissemination. This review focuses on the role played by this signaling pathway in the development of primary bone tumors and the modulation of their specific microenvironment.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Osteossarcoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Adolescente , Neoplasias Ósseas/genética , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/mortalidade , Osso e Ossos , Criança , Humanos , Metástase Linfática , Terapia de Alvo Molecular/métodos , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/mortalidade , Neovascularização Patológica/prevenção & controle , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/imunologia , Osteossarcoma/genética , Osteossarcoma/imunologia , Osteossarcoma/mortalidade , Proteínas Proto-Oncogênicas c-ets/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/imunologia , Proteína EWS de Ligação a RNA/antagonistas & inibidores , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/imunologia , Sarcoma de Ewing/genética , Sarcoma de Ewing/imunologia , Sarcoma de Ewing/mortalidade , Análise de Sobrevida , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Via de Sinalização Wnt/efeitos dos fármacos , Adulto Jovem , beta Catenina/antagonistas & inibidores , beta Catenina/genética , beta Catenina/imunologia
10.
Medicine (Baltimore) ; 98(25): e16031, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31232935

RESUMO

Accurate diagnoses of sarcoma are sometimes challenging on conventional histomorphology and immunophenotype. Many specific genetic aberrations including chromosomal translocations have been identified in various sarcomas, which can be detected by fluorescence in situ hybridization and polymerase chain reaction analysis. Next-generation sequencing-based RNA sequencing can screen multiple sarcoma-specific chromosome translocations/fusion genes in 1 test, which is especially useful for sarcoma without obvious differentiation. In this report, we utilized RNA sequencing on formalin-fixed paraffin-embedded (FFPE) specimens to investigate the possibility of diagnosing sarcomas by identifying disease-specific fusion genes. Targeted RNA sequencing was performed on 6 sarcoma cases. The expected genetic alterations (clear cell sarcoma/EWSR1-ATF1, Ewing sarcoma/EWSR1-FLI1, myxoid liposarcoma/DDIT3-FUS) in four cases were detected and confirmed by secondary tests. Interestingly, three SS18 fusion genes (SS18-SSX2B, SS18-SSX2, and SS18-SSX4) were identified in a synovial sarcoma case. A rare fusion gene (EWSR1-PATZ1) was identified in a morphologically challenging case; which enabled us to establish the diagnosis of low grade glioneural tumor. In conclusion, RNA sequencing on FFPE specimen is a reliable method in establishing the diagnosis of sarcoma in daily practice.


Assuntos
Biomarcadores Tumorais/genética , Proteínas Proto-Oncogênicas/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inclusão em Parafina , Reação em Cadeia da Polimerase , Sarcoma/genética , Análise de Sequência de RNA , Neoplasias de Tecidos Moles/genética
11.
Nucl Med Commun ; 40(8): 827-834, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31107830

RESUMO

OBJECTIVES: Ewing sarcoma breakpoint region 1 (EWSR1) translocation-negative tumors represent a minor portion of small round cell tumors consistent with Ewing sarcoma morphology. The purpose of this study was to differentiate EWSR1 translocation-positive tumors from EWSR1 translocation-negative tumors using PET-computed tomography features. MATERIALS AND METHODS: In this retrospective study 27, Ewing sarcoma patients (December 2011 to November 2016) were divided into two groups, EWSR1 translocation-positive and EWSR1 translocation-negative based on cytogenetic analysis. Pretreatment standardized uptake value maximum (SUVmax) and Hounsfield Units (HU) were measured in the primary tumor in the axial slice with the largest tumor diameter.The associations between SUVmax, HU and the presence of EWSR1 translocation were evaluated. Receiver operating characteristic curve analysis was used to determine cut-off levels of SUVmax and HU suggestive of EWSR1-negative tumors. RESULTS: Twenty-one patients were classified as EWSR1-positive and six as EWSR1-negative. Eighteen had SUVmax and 21 had HU measurements. EWSR1-negative tumors had significantly higher SUVmax values (P = 0.003) and significantly lower HU values (P = 0.008). Receiver operating characteristic curve analysis showed that SUVmax had diagnostic ability to discriminate between EWSR1-negative and EWSR1-positive tumors (area under the curve = 0.964, P = 0.006). A SUVmax of at least 10 had a sensitivity of 100% and specificity of 85.7% for EWSR1-negative tumors. HU had lower diagnostic ability than SUVmax (area under the curve = 0.881, P = 0.012). A HU up to 57 had a sensitivity of 81.3% and specificity of 80.0% for EWSR1-negative tumors. CONCLUSION: Higher SUVmax and lower HU may differentiate between EWSR1-positive and EWSR1-negative tumors. This may reflect EWSR1-negative tumor aggressiveness.


Assuntos
Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/diagnóstico por imagem , Sarcoma de Ewing/genética , Translocação Genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Adulto Jovem
12.
Diagn Cytopathol ; 47(9): 930-934, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31120625

RESUMO

Primary thyroid teratomas are rare, usually benign, and typically occur in children. We report the unusual occurrence of a malignant thyroid teratoma in a young man. Initial ultrasound and CT studies revealed an 8.5 heterogeneous mass involving the entire right thyroid lobe causing tracheal compression and deviation. Fine-needle aspiration (FNA) revealed malignant cells with possible neuroendocrine features. Similar findings have been previously reported, with an occasional interpretation as possible medullary thyroid carcinoma. In no report, as with our case, has the correct diagnosis been suggested with FNA. The surgical specimen contained abundant primitive neuroepithelium with a very minor component of mature ectodermal tissue in one area. Like this case, an abundance of immature neuroepithelium has been reported in essentially all previous reports of primary malignant thyroid teratoma, sometimes creating a challenge to find another type of germ cell tissue. Array comparative genomic hybridization studies in this case revealed a markedly complex karyotype including gain of chromosome 12 and loss of 17p. Amplification of MYCN, EWSR1 rearrangement and isochromosome 12p were not identified, providing no evidence for neuroblastoma or Ewing sarcoma/peripheral neuroectodermal tumor, both of which have also rarely been reported as primary thyroid tumors. With the use of cisplatinum-based chemotherapy combined with radiation, survival times have increased dramatically. Our patient is now disease free and back to his normal activities after relatively short follow-up. Although rare, it is important to be aware that teratomas may present as a thyroid nodule. Recognition by FNA is challenging, and requires multiple modalities for full identification.


Assuntos
Quimiorradioterapia , Cisplatino/administração & dosagem , Teratoma , Neoplasias da Glândula Tireoide , Adolescente , Biópsia por Agulha Fina , Deleção Cromossômica , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 12/metabolismo , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/metabolismo , Humanos , Masculino , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/metabolismo , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/metabolismo , Síndrome de Smith-Magenis/patologia , Síndrome de Smith-Magenis/terapia , Teratoma/genética , Teratoma/metabolismo , Teratoma/patologia , Teratoma/terapia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia
13.
Histopathology ; 75(3): 431-436, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31050844

RESUMO

AIMS: In thymic carcinomas, focal clear cell change is a frequent finding. In addition to a prominent, diffuse clear cell morphology, some of these carcinomas show an exuberant hyalinised extracellular matrix, and therefore probably represent a separate entity. However, a characteristic genomic alteration remains elusive. We hypothesised that, analogous to hyalinising clear cell carcinomas of the salivary gland, hyalinising clear cell carcinomas of the thymus might also harbour EWSR1 translocations. METHODS AND RESULTS: We identified nine archived cases of thymic carcinoma with focal clear cell features and two cases that showed remarkable hyalinised stroma and prominent, diffuse clear cell morphology. These two cases expressed p40 and were negative for Pax8, CD5, and CD117. Programmed death-ligand 1 was highly positive in one case (70%), and negative in the other one. EWSR1 translocation was identified in both cases of hyalinising clear cell carcinoma, and was absent in all nine carcinomas that showed clear cell features without substantial hyalinisation. In one of the EWSR1-translocated cases, a fusion between exon 13 and exon 6 of EWSR1 and ATF1, respectively was identified by next-generation sequencing. CONCLUSIONS: These findings suggest that the EWSR1 translocation and possibly the EWSR1-ATF1 fusion might be unifying genomic alterations for thymic clear cell carcinomas with prominent hyalinised stroma, for which we propose the term 'hyalinising clear cell carcinoma of the thymus'. Because the immunophenotype is unspecific, testing for the EWSR1 translocation might be helpful in discriminating this entity from other thymic neoplasms or metastases, in particular those with clear cell change.


Assuntos
Adenocarcinoma de Células Claras/genética , Proteína EWS de Ligação a RNA/genética , Neoplasias do Timo/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Translocação Genética
14.
Diagn Pathol ; 14(1): 43, 2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31103034

RESUMO

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare soft tissue tumor that generally involves the retroperitoneum, pelvis, omentum and mesentery in younger patients. However, extra-abdominal DSRCT is very rare. CASE PRESENTATION: A 49-year-old Japanese man noticed a mass in the right parotid gland. Ultrasound examination revealed a solid tumor about 2 cm in diameter. Computed tomography (CT) of the whole body revealed no other tumors or lymph node swelling. Superficial parotidectomy was performed. Histologically, the tumor was composed of various-sized tumor cell nests in an abundant fibromyxoid and collagenous background. The tumor cells were small to medium-sized. Immunohistochemistry showed that the tumor cells were immunoreactive for epithelial markers and desmin. They also showed strong nuclear staining with a Wilms tumor 1 (WT1) antibody detecting the C-terminal region (C-WT1), but not the N-terminal region (N-WT1). We also performed 3'/5' expression imbalance assay based on reverse transcription polymerase chain reaction (RT-PCR) to determine whether aberrant WT1 gene expression was present. This tumor was found to lack 5'-regional expression of the WT1 gene, as well as immunoreactivity with the N-WT1 antibody. Finally, fluorescence in situ hybridization (FISH) and RT-PCR analyses revealed the presence of a gene showing fusion between exon 7 of EWSR1 and exon 8 of WT1. The tumor was diagnosed as a DSRCT of the right parotid gland. The patient has been followed for 3 years without recurrence or metastasis. CONCLUSIONS: Although DSRCT in the salivary gland is extremely rare, it should be included in the differential diagnosis of poorly differentiated salivary gland neoplasms, especially with a fibromyxoid background. Pathologists should bear in mind that DSRCT may occur in major salivary glands and should perform immunohistochemistry with appropriate antibodies, not only those against keratin and desmin, but also one detecting the C-terminal region of WT-1. Furthermore, molecular detection of EWSR1-WT1 fusion gene conclusively confirmed the diagnosis of DSRCT in this uncommon location.


Assuntos
Tumor Desmoplásico de Pequenas Células Redondas/diagnóstico por imagem , Neoplasias Parotídeas/diagnóstico por imagem , Proteína EWS de Ligação a RNA/genética , Proteínas WT1/genética , Tumor Desmoplásico de Pequenas Células Redondas/genética , Tumor Desmoplásico de Pequenas Células Redondas/patologia , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica , Glândula Parótida/diagnóstico por imagem , Glândula Parótida/patologia , Neoplasias Parotídeas/genética , Neoplasias Parotídeas/patologia
15.
Ann Diagn Pathol ; 41: 1-7, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31108450

RESUMO

We present clinicopathological and molecular cytogenetic features of five rare cases of Ewing sarcomas, occurring in the female genital tract. A 40 year-old lady presented with a 5.4 cm-sized vaginal mass of 3 months duration, which was histopathologically diagnosed as ES. She defaulted chemotherapy and 8 months later, presented with a recurrence. She underwent chemotherapy and radiotherapy. A 45 year-old lady presented with recurrent vaginal bleeding, for which she underwent total abdominal hysterectomy (TAH) and unilateral salpingo-oophorectomy (USO), 2 and 1/2 years back. Subsequent vaginal biopsy was reported inconclusively, elsewhere. Thereafter, a 5 cm-sized, residual cervicovaginal mass was reported as ES. She completed induction chemotherapy with a significant response. A 35 year-old-lady was referred with a 4 cm-sized cervical mass, for which she underwent TAH-USO with pelvic and para-aortic lymphadenectomy. A 39 year-old-lady presented with a right labial lesion, which recurred. She underwent initial excision, chemotherapy, wide excision and brachytherapy. A year later, she developed multiple metastases; received palliative radiotherapy and died-of-disease. A 16 year-old girl presented with perineal swelling of 4 months duration. She underwent surgical excision of a recurrent right-sided labial cyst, followed by chemotherapy. On histopathological review, all 5 cases were malignant round cell tumors. Immunohistochemically, tumor cells displayed MIC2/CD99 and Fli1 positivity, along with focal positivity for pan cytokeratin (AE1/AE3) (cases 1 and 2) and p63 (case 2). Furthermore, tumor cells in the 1st, 2nd, 3rd and 5th cases displayed EWSR1 rearrangement. Five uncommon cases of ES involving the female genital tract are presented with diagnostic challenges and therapeutic implications.


Assuntos
Neoplasias dos Genitais Femininos/genética , Neoplasias dos Genitais Femininos/patologia , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Adolescente , Adulto , Feminino , Rearranjo Gênico , Humanos , Pessoa de Meia-Idade , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia
17.
J Cutan Pathol ; 46(6): 421-424, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30834570

RESUMO

Cutaneous syncytial myoepithelioma (CSM) is a recently recognized, histopathological variant of myoepithelial (ME) tumors of the skin. It is characterized by a syncytial arrangement of spindled, ovoid, and/or epithelioid cells forming a well-circumscribed, unencapsulated dermal nodule. There is a paucity of intervening stroma, and absent duct or gland formation. Strong immunohistochemical staining for S100 and epithelial membrane antigen (EMA) has been described, while cytokeratin expression has been uncommon. The majority of CSMs harbor a rearrangement involving the EWSR1 gene. Although various fusion partner genes have been discovered in ME tumors at other anatomic sites, none has yet been described in CSM. We present a case of CSM represented clinically by a papule on the mid-upper back of a healthy 44-year-old female. It exhibited morphological and immunohistochemical features of a CSM with strong, diffuse S100 and alpha-actin expression, and focal positivity for EMA and cytokeratin AE1/AE3. Fluorescence in-situ hybridization showed an EWSR1 gene rearrangement. Massively parallel next-generation RNA sequencing revealed PBX3 as the fusion partner. The EWSR1-PBX3 gene fusion has been previously identified in three cases of ME tumors of bone and soft tissue, and in a case of retroperitoneal leiomyoma. This is the first report of an EWSR1-PBX3 fusion in CSM.


Assuntos
Biomarcadores Tumorais , Proteínas de Homeodomínio , Mioepitelioma , Proteínas de Fusão Oncogênica , Proteínas Proto-Oncogênicas , Proteína EWS de Ligação a RNA , Neoplasias Cutâneas , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Queratinas/genética , Queratinas/metabolismo , Mioepitelioma/genética , Mioepitelioma/metabolismo , Mioepitelioma/patologia , Fusão Oncogênica , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
18.
J Cancer Res Clin Oncol ; 145(5): 1273-1281, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30895378

RESUMO

PURPOSE: Recent studies revealed divergent gene expression patterns in Ewing sarcoma (EwS) with canonical EWSR1-ETS gene fusions and undifferentiated round cell sarcomas (URCS) with EWSR1 rearrangements fused to the non-ETS gene NFATc2. Thus, the question arises whether the latter tumors really belong to EwS. METHODS: We collected five cases matching the group of URCS with EWSR1-NFATc2 fusion and performed DNA methylation and copy number profiling. Results were compared to methylation data of 30 EwS with various EWSR1-ETS fusions and one EwS with FUS-ERG fusion, 16 URCS with CIC rearrangement and 10 URCS with BCOR alteration and a total of 81 EWSR1-associated soft tissue sarcomas including 7 angiomatoid fibrous histiocytomas, 7 clear cell sarcomas of the soft tissue, 28 desmoplastic small round cell tumors, 10 extraskeletal myxoid chondrosarcomas and 29 myxoid liposarcomas. RESULTS: Unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analysis of DNA methylation data revealed a homogeneous methylation cluster for URCS with EWSR1-NFATc2 fusion, which clearly segregated from EwS and the other subtypes. Copy number profiles of EWSR1-NFATc2 cases showed recurrent losses on chromosome 9q and segmental gains on 20q13 and 22q12 involving the EWSR1 and NFATc2 loci, respectively. CONCLUSION: In summary, URCS with EWSR1-NFATc2 fusion share a distinct DNA methylation signature and carry characteristic copy number alterations, which emphasizes that these sarcomas should be considered separately from EwS.


Assuntos
Metilação de DNA , Fatores de Transcrição NFATC/genética , Proteínas de Fusão Oncogênica/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/genética , Sarcoma/diagnóstico , Sarcoma/genética , Adolescente , Adulto , Idoso , Variações do Número de Cópias de DNA , Diagnóstico Diferencial , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Transcriptoma , Adulto Jovem
19.
Jpn J Clin Oncol ; 49(7): 604-613, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30927420

RESUMO

BACKGROUND: Ewing sarcoma is a malignant bone tumor mainly affecting teenagers and young adults. Its main driver mutation, the EWS-FLI1 fusion gene, has been identified more than 20 years ago, whereas its other somatic mutations have been just recently reported. METHODS: In this study, we organized the somatic mutations from 216 Ewing sarcoma cases into 216 individual protein-protein interaction networks by using interactome information. These mutation networks were then classified into five different clusters based on their structural similarities. The prognostic effect of mutation genes was evaluated according to their network features. RESULTS: The cases in cluster two exhibited remarkably high metastasis and mortality rates, and STAG2, TP53 and TTN were the three most significantly mutated genes in this cluster. Microarray data demonstrate that the expression of STAG2, TP53 and TTN are down-regulated in the EWS-FLI1-knockdown Ewing sarcoma cells. However, the mutation effect analysis shows that the somatic mutations in TTN are less damaging than those in STAG2 and TP53. The analyses of functional network modules further revealed that STAG2, TP53 and their interacting gene partners participate in the oncogenic-related biological modules such as cell cycle and regulation of transcription from RNA polymerase II promoter while TTN, TP53 and their interacting gene partners constitute the modules less relevant to oncogenesis. The results of Gene Ontology analyses demonstrated that the uniquely mutated genes associated with poor prognosis in Clusters 1, 4 and 5 were distinctively enriched in epidermal growth factor-related functions and phosphoproteins. CONCLUSIONS: Our study identified the highly lethal mutation combination cases and characterized the possible prognostic genes in Ewing sarcoma from a network perceptive.


Assuntos
Redes Reguladoras de Genes , Mutação/genética , Sarcoma de Ewing/genética , Linhagem Celular Tumoral , Análise por Conglomerados , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Taxa de Mutação , Proteínas de Fusão Oncogênica/genética , Prognóstico , Modelos de Riscos Proporcionais , Proteína Proto-Oncogênica c-fli-1/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/patologia , Análise de Sobrevida
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