RESUMEN
INTRODUCTION: The incidence of myelodysplastic syndrome and acute myeloid leukemia is significantly increased in children with Down syndrome (DS). Within the revised 2016 WHO edition, these entities are jointly classified as myeloid leukemia associated with DS (ML-DS). Additionally, infants with DS may develop transient abnormal myelopoiesis (TAM) which is histomorphologically similar to ML-DS. While TAM is self-limiting, it is associated with an increased risk of subsequently developing ML-DS. Differentiating TAM and ML-DS is challenging but clinically critical. METHODS: We performed a retrospective review of ML-DS and TAM cases collected from five large academic institutions in the USA. We assessed clinical, pathological, immunophenotypical, and molecular features to identify differentiating criteria. RESULTS: Forty cases were identified: 28 ML-DS and 12 TAM. Several features were diagnostically distinct, including younger age in TAM (p < 0.05), as well as presentation with clinically significant anemia and thrombocytopenia in ML-DS (p < 0.001). Dyserythropoiesis was unique to ML-DS, as well as structural cytogenetic abnormalities aside from the constitutional trisomy 21. Immunophenotypic characteristics of TAM and ML-DS were indistinguishable, including the aberrant expression of CD7 and CD56 by the myeloid blasts. DISCUSSION: The findings of the study confirm marked biological similarities between TAM and ML-DS. At the same time, several significant clinical, morphological, and genetic differences were observed between TAM and ML-DS. The clinical approach and the differential diagnosis between these entities are discussed in detail.
Asunto(s)
Síndrome de Down , Leucemia Mieloide Aguda , Reacción Leucemoide , Lactante , Niño , Humanos , Síndrome de Down/complicaciones , Síndrome de Down/genética , Síndrome de Down/patología , Mutación , Reacción Leucemoide/diagnóstico , Reacción Leucemoide/genética , Reacción Leucemoide/complicacionesRESUMEN
This case report describes an 18-year-old woman with an unusual epithelioid tumor of the omentum with a novel PRRC2B-ALK fusion. Although the atypical pathologic features raised significant diagnostic challenges, expression of CD30 on tumor cells and detection of an ALK rearrangement provided critical information for selecting targeted therapy in a patient not suitable for surgical resection. Despite an initially promising therapeutic response, the patient died. The efficacy of treatment was confirmed by the lack of viable tumor cells at autopsy. This case highlights the role of timely targeted therapy in patients with rare tumors and novel actionable molecular targets.
Asunto(s)
Sarcoma , Adolescente , Quinasa de Linfoma Anaplásico/genética , Femenino , Humanos , Sarcoma/diagnóstico , Adulto JovenRESUMEN
We report comprehensive characterization of an unusual collision tumor comprising extramedullary plasmacytomas and nasopharyngeal angiofibroma in a pediatric patient, which has yet to be reported. Histologically, the nasopharyngeal angiofibroma showed typical morphology with a diffuse, dense plasmacytic infiltrate in the stroma. The neoplastic plasma cells showed a spectrum of well-differentiated, plasmablastic, and anaplastic morphology, Epstein-Barr virus encoded RNA (EBER) positivity, and aberrant immunophenotype. Fluorescence in situ hybridization using a plasma cell myeloma targeted panel detected gains of 1q21.3 (CKS1B, x3), 3q27 (BCL6, x4), and 11q22.3 (ATM, x3), but no rearrangement of ALK and MYC. A 50-gene next generation sequencing lymphoma panel failed to detect any pathogenic mutation. Plasmacytoma with EBER positivity and plasmablastic morphology must be distinguished from plasmablastic lymphoma due to different clinical management and prognosis. This case highlights the importance of a thorough pathological evaluation of a mass lesion with synchronous neoplastic processes.
Asunto(s)
Angiofibroma/patología , Neoplasias Nasofaríngeas/patología , Neoplasias Primarias Múltiples/patología , Plasmacitoma/patología , Adolescente , Infecciones por Virus de Epstein-Barr/complicaciones , Humanos , Masculino , Neoplasias Nasofaríngeas/virología , Plasmacitoma/virologíaRESUMEN
We describe a rare pediatric case of a phalangeal giant cell tumor of bone with extensive bilateral lung metastases following curettage, wide resection, and amputation. Concurrent peripheral blood eosinophilia and pleural effusion with marked eosinophilia (47%) were present. To discover genetic changes driving tumor metastasis, genomic and transcriptome profiling of the metastatic lung mass as well as germline analysis were performed. Whole exome sequencing detected a histone H3F3A p.G35V missense mutation in tumor cells. RNA sequencing revealed overexpression of receptor activator of nuclear factor kappa-B ligand (RANKL). The patient is alive with no residual disease and uncompromised respiratory function 29 months after amputation of primary tumor and 19 months after surgical resection of his metastatic lung disease.
Asunto(s)
Neoplasias Óseas/patología , Falanges de los Dedos de la Mano/patología , Tumor Óseo de Células Gigantes/secundario , Neoplasias Pulmonares/secundario , Adolescente , Amputación Quirúrgica , Neoplasias Óseas/cirugía , Legrado , Falanges de los Dedos de la Mano/cirugía , Tumor Óseo de Células Gigantes/cirugía , Humanos , Neoplasias Pulmonares/cirugía , Masculino , Metastasectomía , Neumonectomía , Resultado del TratamientoAsunto(s)
Crisis Blástica/patología , Médula Ósea/patología , Células Precursoras de Granulocitos/ultraestructura , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Adolescente , Colorantes Azulados , Crisis Blástica/diagnóstico , Gránulos Citoplasmáticos/química , Diabetes Mellitus Tipo 1/complicaciones , Diagnóstico Diferencial , Proteínas de Fusión bcr-abl/análisis , Células Precursoras de Granulocitos/química , Antígenos HLA-DR/análisis , Humanos , Subunidad alfa del Receptor de Interleucina-3/análisis , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucocitosis/etiología , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Coloración y Etiquetado , Trombocitopenia/etiologíaRESUMEN
Chromosome translocation t(16;21)(q24;q22)/RUNX1-RUNX1T3 is an infrequent but recurrent chromosomal abnormality identified in myeloid neoplasms, with only 25 cases have been reported to date. Here, we report eight cases (six women and two men) of myeloid neoplasms associated with t(16;21)(q24;q22): five with therapy-related myeloid neoplasms, two with relapsed acute myeloid leukemia (AML), and one with blast phase of chronic myeloid leukemia. Morphologic and immunophenotypic features include granulocytic dysplasia, blasts with prominent perinuclear hof, large orange-pink granules, long and slim Auer rods, and aberrant expression of CD19. Six patients received AML-based regimens, and five achieved complete remission after initial induction therapy. Our study suggests that myeloid neoplasm with t(16;21)/RUNX1-RUNX1T1 resembles AML with t(8;21)(q22;q22)/RUNX1-RUNX1T1, in regard to morphology, immunophenotype, and response to therapy. Therefore, the clinical management of AML with t(8;21) may provide the best model for patients with myeloid neoplasms with t(16;21).
Asunto(s)
Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 21/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia Mieloide Aguda/genética , Trastornos Mieloproliferativos/genética , Proteínas de Fusión Oncogénica/genética , Proteína 1 Compañera de Translocación de RUNX1/genética , Proteínas Represoras/genética , Translocación Genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Imitación Molecular , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/patologíaRESUMEN
Conditional knock-out (KO) of Polycomb Group (PcG) protein YY1 results in pro-B cell arrest and reduced immunoglobulin locus contraction needed for distal variable gene rearrangement. The mechanisms that control these crucial functions are unknown. We deleted the 25 amino-acid YY1 REPO domain necessary for YY1 PcG function, and used this mutant (YY1ΔREPO), to transduce bone marrow from YY1 conditional KO mice. While wild-type YY1 rescued B-cell development, YY1ΔREPO failed to rescue the B-cell lineage yielding reduced numbers of B lineage cells. Although the IgH rearrangement pattern was normal, there was a selective impact at the Igκ locus that showed a dramatic skewing of the expressed Igκ repertoire. We found that the REPO domain interacts with proteins from the condensin and cohesin complexes, and that YY1, EZH2 and condensin proteins co-localize at numerous sites across the Ig kappa locus. Knock-down of a condensin subunit protein or YY1 reduced rearrangement of Igκ Vκ genes suggesting a direct role for YY1-condensin complexes in Igκ locus structure and rearrangement.
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Adenosina Trifosfatasas/metabolismo , Linfocitos B/fisiología , Proteínas de Unión al ADN/metabolismo , ADN/metabolismo , Cadenas kappa de Inmunoglobulina/metabolismo , Complejos Multiproteicos/metabolismo , Mapeo de Interacción de Proteínas , Factor de Transcripción YY1/metabolismo , Adenosina Trifosfatasas/genética , Animales , Linfocitos B/inmunología , Diferenciación Celular , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Proteína Potenciadora del Homólogo Zeste 2 , Técnicas de Silenciamiento del Gen , Ratones , Ratones Noqueados , Complejos Multiproteicos/genética , Complejo Represivo Polycomb 2/metabolismo , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Eliminación de Secuencia , Transducción Genética , Factor de Transcripción YY1/genéticaAsunto(s)
Diploidia , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Translocación Genética , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Cariotipificación , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Inducción de Remisión , Translocación Genética/genéticaAsunto(s)
Anemia/virología , COVID-19/complicaciones , Pancitopenia/virología , Síndrome de Respuesta Inflamatoria Sistémica/complicaciones , Antiinflamatorios/uso terapéutico , Femenino , Enfermedades Hematológicas/virología , Humanos , Lactante , Metilprednisolona/uso terapéutico , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Trombopoyesis , Tratamiento Farmacológico de COVID-19Asunto(s)
Enfermedad de Hodgkin , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Adolescente , Diagnóstico Diferencial , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/patología , Humanos , Masculino , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , EsclerosisAsunto(s)
Astrocitoma/sangre , Leucocitos Mononucleares/metabolismo , Síndrome de Li-Fraumeni/sangre , Mitosis , Adolescente , Astrocitoma/diagnóstico , Astrocitoma/patología , Astrocitoma/terapia , Humanos , Leucocitos Mononucleares/patología , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/patología , Síndrome de Li-Fraumeni/terapia , MasculinoAsunto(s)
Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 4/genética , Proteínas de Unión al ADN/genética , Reordenamiento Génico , N-Metiltransferasa de Histona-Lisina/genética , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/patología , Proteína de la Leucemia Mieloide-Linfoide/genética , Factores de Elongación Transcripcional/genética , Niño , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Proteínas de Fusión Oncogénica/genética , Fenotipo , Pronóstico , Translocación GenéticaRESUMEN
Studies of coat color mutants have greatly contributed to the discovery of genes that regulate melanocyte development and function. Here, we generated Yy1 conditional knockout mice in the melanocyte-lineage and observed profound melanocyte deficiency and premature gray hair, similar to the loss of melanocytes in human piebaldism and Waardenburg syndrome. Although YY1 is a ubiquitous transcription factor, YY1 interacts with M-MITF, the Waardenburg Syndrome IIA gene and a master transcriptional regulator of melanocytes. YY1 cooperates with M-MITF in regulating the expression of piebaldism gene KIT and multiple additional pigmentation genes. Moreover, ChIP-seq identified genome-wide YY1 targets in the melanocyte lineage. These studies mechanistically link genes implicated in human conditions of melanocyte deficiency and reveal how a ubiquitous factor (YY1) gains lineage-specific functions by co-regulating gene expression with a lineage-restricted factor (M-MITF)-a general mechanism which may confer tissue-specific gene expression in multiple lineages.
Asunto(s)
Color del Cabello , Melanocitos , Factor de Transcripción Asociado a Microftalmía/metabolismo , Pigmentación , Síndrome de Waardenburg , Factor de Transcripción YY1/genética , Animales , Linaje de la Célula , Supervivencia Celular , Modelos Animales de Enfermedad , Regulación del Desarrollo de la Expresión Génica , Color del Cabello/genética , Humanos , Melanocitos/citología , Melanocitos/metabolismo , Ratones , Ratones Noqueados , Factor de Transcripción Asociado a Microftalmía/genética , Pigmentación/genética , Síndrome de Waardenburg/genética , Síndrome de Waardenburg/metabolismo , Factor de Transcripción YY1/metabolismoAsunto(s)
Neoplasias Óseas/diagnóstico , Neoplasias Óseas/secundario , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Mieloma Múltiple/diagnóstico , Anciano de 80 o más Años , Biomarcadores de Tumor , Biopsia , Médula Ósea/metabolismo , Médula Ósea/patología , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , MasculinoAsunto(s)
Antígenos CD/metabolismo , Leucemia de Células Plasmáticas , Proteínas de Neoplasias/metabolismo , Células Plasmáticas , Anciano , Femenino , Humanos , Leucemia de Células Plasmáticas/metabolismo , Leucemia de Células Plasmáticas/patología , Células Plasmáticas/metabolismo , Células Plasmáticas/patologíaRESUMEN
The progression of progenitors to oligodendrocytes requires proliferative arrest and the activation of a transcriptional program of differentiation. While regulation of cell cycle exit has been extensively characterized, the molecular mechanisms responsible for the initiation of differentiation remain ill-defined. Here, we identify the transcription factor Yin Yang 1 (YY1) as a critical regulator of oligodendrocyte progenitor differentiation. Conditional ablation of yy1 in the oligodendrocyte lineage in vivo induces a phenotype characterized by defective myelination, ataxia, and tremor. At the cellular level, lack of yy1 arrests differentiation of oligodendrocyte progenitors after they exit from the cell cycle. At the molecular level, YY1 acts as a lineage-specific repressor of transcriptional inhibitors of myelin gene expression (Tcf4 and Id4), by recruiting histone deacetylase-1 to their promoters during oligodendrocyte differentiation. Thus, we identify YY1 as an essential component of the transcriptional network regulating the transition of oligodendrocyte progenitors from cell cycle exit to differentiation.