RESUMEN
In recent years, undifferentiated small round cell sarcomas (USRCSs) have been divided into a variety of new, rare, sarcoma subtypes, including the group of Ewing-like sarcomas, which have the morphological appearance of Ewing sarcomas, but carry CIC-DUX4, BCOR-CCNB3 and other gene fusions different from the classic EWSR1-ETS gene fusion. Using high-throughput RNA-sequencing (RNA-seq) analyses, we identified a novel recurrent gene fusion, CRTC1-SS18, in two cases of USRCS that lacked any known translocation. RNA-seq results were confirmed by reverse transcription polymerase chain reaction, long-range polymerase chain reaction, and fluorescence in situ hybridization. In vitro, we showed that the cells expressing the gene fusion were morphologically distinct and had enhanced oncogenic potential as compared with control cells. Expression profile comparisons with tumours of other sarcoma subtypes demonstrated that both cases clustered close to EWSR1-CREB1-positive tumours. Moreover, these analyses indicated enhanced NTRK1 expression in CRTC1-SS18-positive tumours. We conclude that the novel gene fusion identified in this study adds a new subtype to the USRCSs with unique gene signatures, and may be of therapeutic relevance. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Biomarcadores de Tumor/genética , Diferenciación Celular , Fusión Génica , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Sarcoma de Células Pequeñas/genética , Neoplasias de los Tejidos Blandos/genética , Factores de Transcripción/genética , Adulto , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Movimiento Celular , Proliferación Celular , Femenino , Predisposición Genética a la Enfermedad , Células HEK293 , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Invasividad Neoplásica , Fenotipo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Sarcoma de Células Pequeñas/metabolismo , Sarcoma de Células Pequeñas/patología , Sarcoma de Células Pequeñas/terapia , Neoplasias de los Tejidos Blandos/metabolismo , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/terapia , Factores de Transcripción/metabolismoAsunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Fibrosarcoma/diagnóstico por imagen , Proteína EWS de Unión a ARN/genética , Neoplasias de los Tejidos Blandos/diagnóstico por imagen , Adulto , Diafragma/patología , Células Epitelioides/patología , Femenino , Fibrosarcoma/clasificación , Fibrosarcoma/genética , Fibrosarcoma/patología , Humanos , Imagen por Resonancia Magnética , Proteínas Mutantes Quiméricas/genética , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patologíaRESUMEN
Epithelioid hemangioendothelioma is a rare vascular tumor of borderline malignancy characterized by recurrent WWTR1-CAMTA1 gene fusions in approximately 90 % of cases. In addition, a recurrent YAP1-TFE3 gene fusion has been identified in WWTR1-CAMTA1 negative epithelioid hemangioendotheliomas. This subset has been reported as having a distinct morphology with more obvious vasoformation, voluminous eosinophilic cytoplasm, and TFE3 positivity on immunohistochemistry. We report a case of a YAP1-TFE3 translocated epithelioid hemangioendothelioma arising in a groin lymph node in a 29-year-old male. Plump spindle cell morphology and absence of vasoformation made correct diagnosis particularly difficult. Immunohistochemistry showed nuclear positivity for both ERG and TFE3, fluorescence in situ hybridization showed break apart for TFE3 and RT-PCR identified a YAP1 exon1 to TFE3 exon 6 transcript, a previously unreported fusion variant. Awareness of this solid morphology and variant fusion will aid in identification of future cases of this rare vascular tumor.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patología , Proteínas de Fusión Oncogénica/genética , Fosfoproteínas/genética , Adulto , Secuencia de Bases , Fibrosis Quística/complicaciones , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Trasplante de Pulmón , Ganglios Linfáticos/patología , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción , Translocación Genética , Proteínas Señalizadoras YAPRESUMEN
BCOR-CCNB3 fusion transcripts resulting from an X-chromosomal paracentric inversion were recently identified in a series of unclassifiable soft tissue and bone sarcomas with Ewing sarcoma-like morphology. The morphologic and clinical features of these sarcomas are, as yet, not well characterized. Here we describe the clinicopathologic features of 10 cases of BCOR-CCNB3 sarcoma and compare their clinical course with typical Ewing sarcoma. Nine of 10 patients were male, and all were 11 to 18 years of age. Seven tumors were located in the bone and 3 in the deep soft tissues. The histomorphologic spectrum was quite wide, with 7 tumors predominately showing small primitive cell morphology with angulated nuclei simulating so-called atypical Ewing sarcoma and 3 predominately showing spindle cell morphology. Recurrent and metastatic lesions showed increased cellularity and marked pleomorphism. Immunohistochemistry showed expression of CCNB3 (100%), bcl2 (90%), CD99 (60%), and CD117 (60%). Reverse transcription polymerase chain reaction for BCOR-CCNB3 fusion transcripts was positive in all 9 cases, which yielded sufficient extracted RNA. Five- and 10-year survival rates were 75% and 56%, respectively. BCOR-CCNB3 sarcomas located in axial skeleton and soft tissues showed a significantly shorter survival. The Ewing sarcoma overall survival was not statistically different, although there was a trend for longer survival of patients with BCOR-CCNB3 sarcomas in the extremities. In conclusion, this study provides a detailed description of the histologic spectrum, immunohistochemical features, and clinical characteristic of BCOR-CCNB3 sarcoma justifying distinction from Ewing sarcoma with its typical EWS/FUS-ETS translocations. Ideally immunohistochemistry is used in combination with reverse transcription polymerase chain reaction for definitive diagnosis.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias Óseas/diagnóstico , Ciclina B/análisis , Proteínas Proto-Oncogénicas/análisis , Proteínas Represoras/análisis , Sarcoma de Ewing/diagnóstico , Adolescente , Biomarcadores de Tumor/genética , Biopsia , Neoplasias Óseas/química , Neoplasias Óseas/genética , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Niño , Ciclina B/genética , Fusión Génica , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sarcoma de Ewing/química , Sarcoma de Ewing/genética , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/secundario , Factores de Tiempo , Translocación GenéticaRESUMEN
Alongside histomorphology and immunohistochemistry, molecular pathology is now established as one of the cornerstones in the tissue diagnosis of bone tumours. We describe the principal molecular pathological techniques employed, and each of the bone tumour entities where their identified characteristic molecular pathological changes can be detected to support and confirm the suspected histological diagnosis. Tumours discussed include fibrous dysplasia, classical and subtype osteosarcomas, central and surface cartilaginous tumours, Ewing's sarcoma, vascular tumours, aneurysmal bone cyst, chordoma, myoepithelioma, and angiomatoid fibrous histiocytoma. This is a rapidly evolving field with discoveries occurring every few months, and some of the newer entities (the Ewing's-like sarcomas), which are principally identified by their molecular pathology characteristics, are discussed.
