RESUMEN
The DUSP22-IRF4 gene rearrangement results in downregulation of DUSP22, a presumed tumor suppressor in T-cell lymphomagenesis. It has been described in some cases of primary cutaneous and systemic anaplastic large-cell lymphoma, lymphomatoid papulosis, and transformed mycosis fungoides. Here we describe two patients with clinical lesions resembling patch/plaque mycosis fungoides that did not meet WHO criteria for large-cell transformation on histopathology yet showed a DUSP22 translocation. One patient who had a history of systemic anaplastic large-cell lymphoma with DUSP22 translocation presented with cutaneous involvement by his systemic lymphoma along with lymphomatoid papulosis and mycosis-fungoides-like lesions, all showing an identical immunophenotype and T-cell clone. These cases expand the spectrum of DUSP22-rearranged lymphomas to include mycosis-fungoides-like presentations without large-cell transformation.
Asunto(s)
Fosfatasas de Especificidad Dual/genética , Linfoma Cutáneo de Células T/patología , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Neoplasias Cutáneas/patología , Adulto , Anciano , Femenino , Reordenamiento Génico , Humanos , Linfoma Cutáneo de Células T/genética , Masculino , Neoplasias Cutáneas/genética , Translocación GenéticaRESUMEN
Fine needle aspiration (FNA) has become increasingly popular in the evaluation of lymph nodes for lymphoproliferative disorders, but there are limitations to accurate subclassification of lymphoma using morphology alone. This case aims to expand diagnostic considerations of large B-cell populations identified on FNA material. We also address the significance of Epstein-Barr virus (EBV) DNA in the workup of patients with suspected lymphoma by FNA.
Asunto(s)
Linfocitos B/patología , Ganglios Linfáticos/patología , Linfoma de Células B/diagnóstico , Linfoma de Células B/patología , Anciano , Biopsia con Aguja Fina/métodos , Citodiagnóstico/métodos , Humanos , MasculinoRESUMEN
Follicle center lymphomas, including primary cutaneous follicle center lymphoma (PCFCL), may rarely show plasmacytic differentiation. Such cases can pose a diagnostic challenge and can be mistaken for other lymphomas that more commonly include plasma cells. Here, we report four cases of PCFCL and one case of systemic follicular lymphoma involving the skin with associated monotypic plasma cells, including the clinical, morphologic and immunophenotypic features.
Asunto(s)
Cadenas kappa de Inmunoglobulina/metabolismo , Linfoma de Células B/diagnóstico , Linfoma Folicular/diagnóstico , Células Plasmáticas/patología , Neoplasias Cutáneas/patología , Adulto , Anciano , Biopsia , Diferenciación Celular , Femenino , Humanos , Cadenas lambda de Inmunoglobulina/metabolismo , Inmunofenotipificación/métodos , Linfoma de Células B/patología , Linfoma Folicular/cirugía , Linfoma Folicular/ultraestructura , Masculino , Persona de Mediana Edad , Células Plasmáticas/metabolismo , Resultado del TratamientoRESUMEN
Mixed-phenotype acute leukemia (MPAL) is a heterogeneous category in the World Health Organization classification that comprises acute leukemias with discrete admixed populations of myeloid and lymphoid blasts ("bilineal") or with extensive coexpression of lymphoid and myeloid markers in a single blast population ("biphenotypic"). Flow cytometric findings suggestive of MPAL are often met with consternation by pathologists and oncologists alike, owing to unfamiliarity with the disease and uncertainty about how MPAL fits into established paradigms for treatment of acute leukemia. The purpose of this review is to explain the diagnostic criteria for MPAL, summarize its biological and clinical features, and address common diagnostic pitfalls of these unusual leukemias.
Asunto(s)
Leucemia Bifenotípica Aguda/diagnóstico , Guías de Práctica Clínica como Asunto , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/metabolismo , Diagnóstico Diferencial , Proteínas de Fusión bcr-abl/sangre , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , N-Metiltransferasa de Histona-Lisina/sangre , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Inmunohistoquímica/tendencias , Inmunofenotipificación/tendencias , Leucemia Bifenotípica Aguda/genética , Leucemia Bifenotípica Aguda/metabolismo , Leucemia Bifenotípica Aguda/terapia , Proteína de la Leucemia Mieloide-Linfoide/sangre , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Pronóstico , Translocación Genética , Organización Mundial de la SaludAsunto(s)
Síndrome de Down/complicaciones , Leucemia Mieloide Aguda/etiología , Antígenos CD/análisis , Antígenos de Neoplasias/análisis , Preescolar , Codón sin Sentido , Femenino , Factor de Transcripción GATA1/deficiencia , Factor de Transcripción GATA1/genética , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Proteínas de Neoplasias/deficiencia , Proteínas de Neoplasias/genéticaRESUMEN
Incidental cases of localized fibrin-associated Epstein-Barr virus (EBV)+ large B-cell proliferations have been described at unusual anatomic sites and have been included in the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) in the WHO Classification. We describe 12 cases and review the literature to define their clinicopathologic spectrum and compare features with typical cases of DLBCL-CI. Median age was 55.5 years with a M:F ratio of 3. In all 12 cases, the lymphoma was an incidental microscopic finding involving atrial myxomas (n=3), thrombi associated with endovascular grafts (n=3), chronic hematomas (n=2), and pseudocysts (n=4). All cases tested were nongerminal center B-cell origin, type III EBV latency, and were negative for MYC rearrangements and alternative lengthening of telomeres by FISH. Most showed high CD30, Ki67, and PD-L1, and low to moderate MYC and p53 expression. Among 11 patients with detailed follow-up, 6 were treated surgically, 3 with cardiac or vascular lesions had persistent/recurrent disease at intravascular sites, and 4 died of causes not directly attributable to lymphoma. Reports of previously published fibrin-associated cases showed similar features, whereas traditional DLBCL-CI cases with a mass lesion had significantly higher lymphoma-associated mortality. Fibrin-associated EBV+ large B-cell lymphoma is clinicopathologically distinct from DLBCL-CI, warranting separate classification. Most cases, particularly those associated with pseudocysts, behave indolently with the potential for cure by surgery alone and may represent a form of EBV+ lymphoproliferative disease rather than lymphoma. However, primary cardiac or vascular disease may have a higher risk of recurrence despite systemic chemotherapy.
Asunto(s)
Infecciones por Virus de Epstein-Barr/complicaciones , Fibrina/metabolismo , Linfoma de Células B/patología , Linfoma de Células B/virología , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Estudios de Casos y Controles , Enfermedad Crónica , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/patología , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Inflamación/metabolismo , Inflamación/patología , Inflamación/virología , Linfoma de Células B/diagnóstico , Linfoma de Células B/metabolismo , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
Evaluation of peripheral blood and bone marrow for an indication of persistent eosinophilia can be a challenging task because there are many causes of eosinophilia and the morphologic differences between reactive and neoplastic causes are often subtle or lack specificity. The purpose of this review is to provide an overview of the differential diagnosis for eosinophilia, to recommend specific steps for the pathologist evaluating blood and bone marrow, and to emphasize 2 important causes of eosinophilia that require specific ancillary tests for diagnosis: myeloproliferative neoplasm with PDGFRA rearrangement and lymphocyte-variant hypereosinophilic syndrome.
Asunto(s)
Médula Ósea/patología , Eosinofilia/sangre , Eosinofilia/diagnóstico , Diagnóstico Diferencial , Eosinofilia/genética , Reordenamiento Génico , Humanos , Síndrome Hipereosinofílico/sangre , Síndrome Hipereosinofílico/diagnóstico , Síndrome Hipereosinofílico/genética , Trastornos Mieloproliferativos/sangre , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Proteínas de Fusión Oncogénica/genética , Pronóstico , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genéticaRESUMEN
Primary mediastinal large B-cell lymphoma (PMBL) is a distinct subtype of diffuse large B-cell lymphoma (DLBCL) that shows overlap with classical Hodgkin lymphoma (CHL) and a favorable prognosis compared to mediastinal gray-zone lymphoma (MGZL). We performed immunohistochemistry on initial diagnostic specimens of 49 cases of uniformly treated PMBL to determine the frequency and clinical significance of expression of antigens commonly seen in CHL and MGZL, along with markers previously shown to be prognostic in DLBCL, not otherwise specified. The median age was 37 years with a female:male ratio of 2.3. After a median follow-up of 78 months, 24% of patients had relapsed or refractory disease and 22% had died; the 5-year PFS was 70%. Variable CD15 expression was seen in 31% of cases, but was not associated with adverse outcome. Hans cell-of-origin, proliferation index, and MYC/BCL2 coexpression were not associated with outcome, while low PDL1 (P = 0.011) and high MUM1 (P = 0.065) staining were each associated with shorter PFS. A biologic risk score (one point each for low PDL1 and high MUM1) stratified patients into three prognostic risk groups for PFS (P = 0.001) and OS (P = 0.032). On separate multivariate models, low PDL1 was independent of R-IPI risk group for PFS (HR 6.0, P = 0.023), as was a biologic risk score of 2 (HR 5.6, P = 0.011). Incorporation of the biologic risk score sub-stratified patients within R-IPI groups for both PFS (P < 0.001) and OS (P < 0.001). In summary, we characterize the immunophenotypic spectrum of PMBL and identify PDL1 and MUM1 as prognostic biomarkers for high-risk disease. Am. J. Hematol. 91:E436-E441, 2016. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Antígeno B7-H1/análisis , Inmunofenotipificación , Factores Reguladores del Interferón/análisis , Linfoma de Células B Grandes Difuso/patología , Neoplasias del Mediastino/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Supervivencia sin Enfermedad , Femenino , Enfermedad de Hodgkin/patología , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Neoplasias del Mediastino/diagnóstico , Neoplasias del Mediastino/inmunología , Neoplasias del Mediastino/mortalidad , Persona de Mediana Edad , Pronóstico , Medición de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is relatively common, and patients occasionally develop other neoplasms; however, patients who develop other types of lymphomas are rare. We encountered 3 patients with CLL/SLL (one 59-y-old man and 2 women aged 56 and 66 y) who developed T-cell lymphomas. Both women developed ALK anaplastic large cell lymphomas (ALCLs), whereas the man developed CD8 peripheral T-cell lymphoma, not otherwise specified. All 3 T-cell lymphomas expressed granzyme B and perforin, indicating a cytotoxic immunophenotype. In 1 case, the first presentation was a lymph nodal composite lymphoma. In the other 2 cases, the T-cell lymphomas arose <1 year after the diagnosis of CLL/SLL and were identified in a lymph node in one case and in the spleen in the other. The patient with a composite lymphoma (SLL/ALK ALCL) was treated and was free of disease at last follow-up, whereas the other 2 patients succumbed to their disease, 1 month and 7 months after the diagnosis of T-cell lymphoma. Peripheral T-cell lymphomas rarely occur in CLL/SLL patients. On the basis of our small series, those with a cytotoxic phenotype appear to be more common in this setting. The occurrence of ALK ALCL in 2 older patients was especially surprising and suggested that CLL/SLL may have played a role in the development of ALCL.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/inmunología , Linfoma Anaplásico de Células Grandes/inmunología , Linfoma de Células T Periférico/inmunología , Linfocitos T Citotóxicos/inmunología , Anciano , Quinasa de Linfoma Anaplásico , Biomarcadores de Tumor/análisis , Resultado Fatal , Femenino , Granzimas/análisis , Humanos , Inmunohistoquímica , Inmunofenotipificación , Leucemia Linfocítica Crónica de Células B/enzimología , Leucemia Linfocítica Crónica de Células B/terapia , Linfoma Anaplásico de Células Grandes/química , Linfoma Anaplásico de Células Grandes/terapia , Linfoma de Células T Periférico/química , Linfoma de Células T Periférico/terapia , Masculino , Persona de Mediana Edad , Perforina/análisis , Fenotipo , Proteínas Tirosina Quinasas Receptoras/análisis , Linfocitos T Citotóxicos/química , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Linfadenitis Necrotizante Histiocítica/patología , Ganglios Linfáticos/patología , Adulto , Diagnóstico Diferencial , Eosinófilos/patología , Infecciones por Virus de Epstein-Barr/diagnóstico , Fiebre/etiología , Linfadenitis Necrotizante Histiocítica/complicaciones , Humanos , Recuento de Leucocitos , Lupus Eritematoso Sistémico/diagnóstico , Enfermedades Linfáticas/etiología , Masculino , Cuello , Linfocitos T , ViajeRESUMEN
Using single transcription factors to reprogram cells could produce important insights into the epigenetic mechanisms that direct normal differentiation, or counter inappropriate plasticity, or even provide new ways of manipulating normal ontogeny in vitro to control lineage diversification and differentiation. We enforced Pdx1 expression from the Neurogenin-3-expressing endocrine commitment point onward and found during the embryonic period a minor increased ß-cell allocation with accompanying reduced α-cell numbers. More surprisingly, almost all remaining Pdx1-containing glucagon/Arx-producing cells underwent a fairly rapid conversion at postnatal stages, through glucagon-insulin double positivity, to a state indistinguishable from normal ß cells, resulting in complete α-cell absence. This α-to-ß conversion was not caused by activating Pdx1 in the later glucagon-expressing state. Our findings reveal that Pdx1 can work single-handedly as a potent context-dependent autonomous reprogramming agent, and suggest a postnatal differentiation evaluation stage involved in normal endocrine maturation.
Asunto(s)
Células Secretoras de Glucagón/metabolismo , Proteínas de Homeodominio/metabolismo , Células Secretoras de Insulina/metabolismo , Transactivadores/metabolismo , Animales , Animales Recién Nacidos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Glucagón/genética , Glucagón/metabolismo , Células Secretoras de Glucagón/citología , Proteínas de Homeodominio/genética , Inmunohistoquímica , Insulina/genética , Insulina/metabolismo , Células Secretoras de Insulina/citología , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Páncreas/embriología , Páncreas/crecimiento & desarrollo , Páncreas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transactivadores/genéticaRESUMEN
The unique, well-demarcated expression domain of Pdx1 within the posterior foregut suggests that investigating its transcriptional regulation will provide insight into mechanisms that regionally pattern the endoderm. Previous phylogenetic comparison identified conserved noncoding regions that stimulate transcriptional activity selectively in cultured pancreatic beta cells. Characterization of these regulatory elements is helping to dissect the transcription factor networks that operate within beta cells, which is important for understanding the etiology of beta cell dysfunction and diabetes, as well as for developing methods to produce beta cells in vitro for cell-based therapies. We recently reported that deletion of three proximally located conserved areas (Area I-II-III) from the endogenous Pdx1 locus resulted in severely reduced expression of Pdx1 in the pancreas, and a milder decrease in other foregut tissues. Here, we report transgene-based complementation experiments on Pdx1 null mice, which reveal that the proximal promoter/enhancer region, including Area I-II-III, rescues the pancreatic defects caused by Pdx1 deficiency, but only weakly promotes expression of Pdx1 in the postnatal stomach and duodenum. These results reveal a role for distal cis-regulatory elements in achieving the correct level of extra-pancreatic Pdx1 expression, which is necessary for the production of duodenal GIP cells and stomach gastrin cells.
Asunto(s)
Duodeno/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/fisiología , Páncreas/metabolismo , Elementos Reguladores de la Transcripción , Transactivadores/genética , Transactivadores/fisiología , Animales , Diferenciación Celular , Duodeno/citología , Células Enteroendocrinas/metabolismo , Mucosa Gástrica/metabolismo , Dosificación de Gen , Expresión Génica , Prueba de Complementación Genética , Intolerancia a la Glucosa , Proteínas de Homeodominio/metabolismo , Ratones , Ratones Noqueados , Modelos Biológicos , Páncreas/fisiología , Fenotipo , Transactivadores/metabolismoRESUMEN
Ectopic pancreas is a developmental anomaly occasionally found in humans. Hes1, a main effector of Notch signaling, regulates the fate and differentiation of many cell types during development. To gain insights into the role of the Notch pathway in pancreatic fate determination, we combined the use of Hes1-knockout mice and lineage tracing employing the Cre/loxP system to specifically mark pancreatic precursor cells and their progeny in Ptf1a-cre and Rosa26 reporter mice. We show that inactivation of Hes1 induces misexpression of Ptf1a in discrete regions of the primitive stomach and duodenum and throughout the common bile duct. All ectopic Ptf1a-expressing cells were reprogrammed, or transcommitted, to multipotent pancreatic progenitor status and subsequently differentiated into mature pancreatic exocrine, endocrine, and duct cells. This process recapitulated normal pancreatogenesis in terms of morphological and genetic features. Furthermore, analysis of Hes1/Ptf1a double mutants revealed that ectopic Ptf1a-cre lineage-labeled cells adopted the fate of region-appropriate gut epithelium or endocrine cells similarly to Ptf1a-inactivated cells in the native pancreatic buds. Our data demonstrate that the Hes1-mediated Notch pathway is required for region-appropriate specification of pancreas in the developing foregut endoderm through regulation of Ptf1a expression, providing novel insight into the pathogenesis of ectopic pancreas development in a mouse model.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Conductos Biliares , Coristoma/patología , Enfermedades Duodenales/patología , Endodermo , Tracto Gastrointestinal , Proteínas de Homeodominio/metabolismo , Páncreas , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Conductos Biliares/anatomía & histología , Conductos Biliares/embriología , Conductos Biliares/fisiología , Linaje de la Célula , Coristoma/metabolismo , Enfermedades Duodenales/metabolismo , Embrión de Mamíferos/anatomía & histología , Embrión de Mamíferos/patología , Embrión de Mamíferos/fisiología , Tracto Gastrointestinal/anatomía & histología , Tracto Gastrointestinal/embriología , Tracto Gastrointestinal/fisiología , Genes Reporteros , Proteínas de Homeodominio/genética , Humanos , Ratones , Ratones Noqueados , Morfogénesis , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Páncreas/citología , Páncreas/patología , Páncreas/fisiología , Proteínas/genética , Proteínas/metabolismo , ARN no Traducido , Receptores Notch/genética , Receptores Notch/metabolismo , Transducción de Señal/fisiología , Factor de Transcripción HES-1 , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Pdx1 (IPF-1 in humans, which is altered in MODY-4) is essential for pancreas development and mature beta-cell function. Pdx1 is expressed dynamically within the developing foregut, but how its expression characteristics are linked to the various steps of organ specification, differentiation, and function is unknown. Deletion of a conserved enhancer region (Area I-II-III) from Pdx1 produced a hypomorphic allele (Pdx1(DeltaI-II-III)) with altered timing and level of expression, which was studied in combination with wild-type and protein-null alleles. Lineage labeling in homozygous Area I-II-III deletion mutants (Pdx1(DeltaI-II-III/DeltaI-II-III)) revealed lack of ventral pancreatic bud specification and early-onset hypoplasia in the dorsal bud. Acinar tissue formed in the hypoplastic dorsal bud, but endocrine maturation was greatly impaired. While Pdx1(-/-) (protein-null) mice have nonpancreatic abnormalities (e.g., distorted pylorus, absent Brunner's glands), these structures formed normally in Pdx1(DeltaI-II-III/DeltaI-II-III) and Pdx1(DeltaI-II-III/-) mice. Surprisingly, heterozygous (Pdx1(+/DeltaI-II-III)) mice had abnormal islets and a more severe prediabetic condition than Pdx1(+/-) mice. These findings provide in vivo evidence of the differential requirements for the level of Pdx1 gene activity in the specification and differentiation of the various organs of the posterior foregut, as well as in pancreas and gut endocrine cell differentiation.