RESUMO
Peripheral T-cell lymphomas (PTCL) are morphologically and biologically heterogeneous and a subset expresses CD30, including anaplastic large cell lymphomas (ALCL) and a minority of PTCL, not otherwise specified (PTCL, NOS). ALCL with ALK translocations (ALCL, ALK+) are readily identified by routine diagnostic methods, but differentiating ALCL without ALK translocation (ALCL, ALK-) and PTCL, NOS expressing CD30 (PTCL CD30+) can be challenging. Furthermore, rare PTCL co-express CD30 and CD15 (PTCL CD30+CD15+); some resemble ALCL, ALK- while others resemble classic Hodgkin lymphoma. To explore the relationship between PTCL CD30+CD15+ and ALCL, ALK-, we analysed 19 cases of PTCL with CD30 expression, previously diagnosed as ALCL, ALK- (nine cases) and PTCL CD30+CD15+ (10 cases) for DUSP22/IRF4 rearrangements, coding RNA expression and selected transcriptome analysis using the NanoString nCounter gene expression analysis platform. Unsupervised clustering showed no clear segregation between ALCL, ALK- and PTCL CD30+CD15+. Three cases previously classified as PTCL CD30+CD15+ showed DUSP22/IRF4 rearrangements, favouring a diagnosis of ALCL, ALK-. Our results suggest that cases previously designated PTCL CD30+CD15+, likely fall within the spectrum of ALCL, ALK-; additionally, a subset of ALCL, ALK- with DUSP22/IRF4 rearrangement expresses CD15, consistent with previous reports and expands the immunophenotypic spectrum of this lymphoma subgroup.
Assuntos
Quinase do Linfoma Anaplásico , Antígeno Ki-1 , Antígenos CD15 , Linfoma Anaplásico de Células Grandes , Linfoma de Células T Periférico , Feminino , Humanos , Masculino , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Fosfatases de Especificidade Dupla/genética , Rearranjo Gênico , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Antígeno Ki-1/metabolismo , Antígeno Ki-1/genética , Antígeno Ki-1/análise , Antígenos CD15/análise , Antígenos CD15/metabolismo , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/patologia , Linfoma de Células T Periférico/diagnóstico , Fosfatases da Proteína Quinase Ativada por Mitógeno/genéticaRESUMO
Germ-line GATA2 gene mutations, leading to haploinsufficiency, have been identified in patients with familial myelodysplastic syndrome/acute myeloid leukemia, monocytopenia and mycobacterial infections, Emberger syndrome, and dendritic cell, monocyte, B-, and NK-cell deficiency. GATA2 mutations have also been reported in a minority of patients with congenital neutropenia and aplastic anemia (AA). The bone marrow (BM) from patients with GATA2 deficiency is typically hypocellular, with varying degrees of dysplasia. Distinguishing GATA2 patients from those with AA is critical for selecting appropriate therapy. We compared the BM flow cytometric, morphologic, and cytogenetic features of 28 GATA2 patients with those of 32 patients being evaluated for idiopathic AA. The marrow of GATA2 patients had severely reduced monocytes, B cells, and NK cells; absent hematogones; and inverted CD4:CD8 ratios. Atypical megakaryocytes and abnormal cytogenetics were more common in GATA2 marrows. CD34(+) cells were comparably reduced in GATA2 and AA. Using these criteria, we prospectively identified 4 of 32 patients with suspected AA who had features suspicious for GATA2 mutations, later confirmed by DNA sequencing. Our results show that routine BM flow cytometry, morphology, and cytogenetics in patients who present with cytopenia(s) can identify patients for whom GATA2 sequencing is indicated.
Assuntos
Anemia Aplástica/diagnóstico , Doenças da Medula Óssea/diagnóstico , Fator de Transcrição GATA2/deficiência , Adulto , Anemia Aplástica/genética , Anemia Aplástica/metabolismo , Antígenos CD34/metabolismo , Medula Óssea/patologia , Doenças da Medula Óssea/genética , Estudos de Coortes , Citogenética , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sequência de DNA , Adulto JovemRESUMO
Primary gastrointestinal (GI) T- and NK-cell lymphomas are usually aggressive neoplasms associated with high morbidity and mortality. Over the past two decades, however, cases of primary GI lymphoproliferative disorders (LPDs) or lymphomas of T- or NK-cell derivation with indolent behavior have been reported. These LPDs are rare and they can be challenging to diagnose as they share clinical and pathological features with both, inflammatory disorders and aggressive T- and NK-cell lymphomas. Primary, indolent clonal T-cell proliferations of the GI tract, which can be CD4+, CD8+ or CD4- CD8-, have been included as a provisional entity in the newly revised World Health Organization (WHO) classification of lymphoid neoplasms and designated 'indolent T-cell LPD of the GI tract'. It is currently unclear whether the indolent NK-cell LPDs represent reactive or neoplastic proliferations. In this review, we describe the clinical, morphologic, immunophenotypic and genetic features of indolent GI T- and NK-cell LPDs and provide guidance in differentiating them from other inflammatory and neoplastic diseases. We believe that greater awareness of these LPDs amongst physicians and the research community will lead to timely and accurate diagnoses, stimulate investigations into the pathogenetic mechanisms underlying different entities thereby enhancing our understanding of disease biology and enable the development of effective therapeutic regimens. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Gastroenteropatias/diagnóstico , Trato Gastrointestinal/fisiopatologia , Linfoma de Células T/diagnóstico , Linfoma/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular , Proliferação de Células , Endoscopia , Gastroenteropatias/terapia , Humanos , Imunofenotipagem , Inflamação , Células Matadoras Naturais/citologia , Linfoma/terapia , Linfoma de Células T/terapia , Transtornos Linfoproliferativos/terapiaRESUMO
There are no "benign lymphomas", a fact due to the nature of lymphoid cells to circulate and home as part of their normal function. Thus, benign clonal expansions of lymphocytes are only rarely recognized when localized. Recent studies have identified a number of lymphoid proliferations that lie at the interface between benign and malignant. Some of these are clonal proliferations that carry many of the molecular hallmarks of their malignant counterparts, such as BCL2/IGH and CCND1/IGH translocations associated with the in situ forms of follicular lymphoma and mantle cell lymphoma, respectively. There are other clonal B-cell proliferations with low risk of progression; these include the pediatric variants of follicular lymphoma and marginal zone lymphoma. Historically, early or incipient forms of T/NK-cell neoplasia also have been identified, such as lymphomatoid papulosis and refractory celiac disease. More recently an indolent form of T-cell lymphoproliferative disease affecting the gastrointestinal tract has been described. Usually, CD8(+), the clonal cells are confined to the mucosa. The clinical course is chronic, but non-progressive. NK-cell enteropathy is a clinically similar condition, composed of cytologically atypical NK-cells that may involve the stomach, small bowel or colon. Breast implant-associated anaplastic large cell lymphoma is a cytologically alarming lesion that is self-limited if confined to the seroma cavity. Atypical lymphoid proliferations that lie at the border of benign and malignant can serve as instructive models of lymphomagenesis. It is also critical that they be correctly diagnosed to avoid unnecessary and potentially harmful therapy.
Assuntos
Linfócitos B/patologia , Linfoma/diagnóstico , Linfócitos T/patologia , Antígenos CD/metabolismo , Antineoplásicos/uso terapêutico , Linfócitos B/metabolismo , Biomarcadores/metabolismo , Proliferação de Células , Células Clonais , Diagnóstico Precoce , Expressão Gênica , Humanos , Imunofenotipagem , Linfoma/classificação , Linfoma/patologia , Linfoma/terapia , Linfócitos T/metabolismo , Translocação GenéticaAssuntos
Leishmaniose Visceral/complicações , Leishmaniose Visceral/patologia , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/patologia , Adolescente , Anfotericina B/uso terapêutico , Antiparasitários/uso terapêutico , Medula Óssea/efeitos dos fármacos , Medula Óssea/parasitologia , Medula Óssea/patologia , Dexametasona/uso terapêutico , Glucocorticoides/uso terapêutico , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/isolamento & purificação , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , MasculinoRESUMO
The revised fourth edition of the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues (2017) reflects significant advances in understanding the biology, genetic basis and behaviour of haematopoietic neoplasms. This review focuses on some of the major changes in B-cell and T-cell non-Hodgkin lymphomas in the 2017 WHO and includes more recent updates. The 2017 WHO saw a shift towards conservatism in the classification of precursor lesions of small B-cell lymphomas such as monoclonal B-cell lymphocytosis, in situ follicular and in situ mantle cell neoplasms. With more widespread use of next generation sequencing (NGS), special entities within follicular lymphoma and mantle cell lymphoma were recognised with recurrent genetic aberrations and unique clinicopathological features. The diagnostic workup of lymphoplasmacytic lymphoma and hairy cell leukaemia has been refined with the discovery of MYD88 L265P and BRAF V600E mutations, respectively, in these entities. Recommendations in the immunohistochemical evaluation of diffuse large B-cell lymphoma include determining cell of origin and expression of MYC and BCL2, so called 'double-expressor' phenotype. EBV-positive large B-cell lymphoma of the elderly has been renamed to recognise its occurrence amongst a wider age group. EBV-positive mucocutaneous ulcer is a newly recognised entity with indolent clinical behaviour that occurs in the setting of immunosuppression. Two lymphomas with recurrent genetic aberrations are newly included provisional entities: Burkitt-like lymphoma with 11q aberration and large B-cell lymphoma with IRF4 rearrangement. Aggressive B-cell lymphomas with MYC, BCL2 and/or BCL6 rearrangements, so called 'double-hit/triple-hit' lymphomas are now a distinct entity. Much progress has been made in understanding intestinal T-cell lymphomas. Enteropathy-associated T-cell lymphoma, type II, is now known to not be associated with coeliac disease and is hence renamed monomorphic epitheliotropic T-cell lymphoma. An indolent clonal T-cell lymphoproliferative disorder of the GI tract is a newly included provisional entity. Angioimmunoblastic T-cell lymphoma and nodal T-cell lymphomas with T-follicular helper phenotype are included in a single broad category, emphasising their shared genetic and phenotypic features. Anaplastic large cell lymphoma, ALK- is upgraded to a definitive entity with subsets carrying recurrent rearrangements in DUSP22 or TP63. Breast implant-associated anaplastic large cell lymphoma is a new provisional entity with indolent behaviour. Finally, cutaneous T-cell proliferations include a new provisional entity, primary cutaneous acral CD8-positive T-cell lymphoma, and reclassification of primary small/medium CD4-positive T-cell lymphoma as lymphoproliferative disorder.
Assuntos
Herpesvirus Humano 4/isolamento & purificação , Linfoma de Células B/classificação , Linfoma não Hodgkin/classificação , Linfoma de Células T/classificação , Transtornos Linfoproliferativos/classificação , Fosfatases de Especificidade Dupla/genética , Rearranjo Gênico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fatores Reguladores de Interferon/genética , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Linfoma de Células T/genética , Linfoma de Células T/patologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/patologia , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Mutação , Fator 88 de Diferenciação Mieloide/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Análise de Sequência de DNA , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Organização Mundial da SaúdeRESUMO
Choriocarcinoma is frequently preceded by a complete mole, ectopic pregnancy, nonmolar intrauterine abortion, and uncommonly by a partial mole. Choriocarcinoma coexisting with or after an otherwise "normal" pregnancy is extremely rare, with an estimated occurrence of 1 per 160,000 pregnancies. We here report a case of a placental choriocarcinoma with no metastases in a full-term intrauterine pregnancy. The patient is a 29-year-old gravida 2 para 1 female, who had an uncomplicated full-term vaginal delivery of a healthy 3030 g female infant. Her current pregnancy was uneventful, and past medical history was significant for an elective termination of pregnancy 2 years ago at 8 weeks of gestation. Routine examination of the placenta showed a gray-tan nodule, measuring 2 cm in the largest dimension, with a papillary cut surface. Microscopically, this nodule was composed of highly atypical cytotrophoblastic cells and multinucleated atypical syncytiotrophoblastic cells, which were positive for beta-human chorionic gonadotrophin by immunostaining. Extensive necrosis and multiple foci of hemorrhage were present. The overall morphologic and immunohistochemical features were diagnostic for choriocarcinoma. Further investigations, including a full body computed tomography scan, showed no lesions suspicious for metastases. The patient is currently asymptomatic and being followed-up with monthly beta-human chorionic gonadotrophin levels, the most recent one being negative. By reporting this case and reviewing the literature, we support the opinion of a recent similar case report that the incidence of placental choriocarcinoma may actually be higher than expected, as placental examination after a normal spontaneous delivery is not routinely performed at most of the institutions.
Assuntos
Coriocarcinoma/patologia , Neoplasias Uterinas/patologia , Adulto , Coriocarcinoma/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Achados Incidentais , Gravidez , Nascimento a Termo , Neoplasias Uterinas/metabolismoRESUMO
CONTEXT.: Undifferentiated pleomorphic sarcoma (UPS) of soft tissue is defined as a sarcoma with no recognizable line of differentiation. During the past few decades, advances in ancillary studies and review of prior UPS diagnoses have narrowed the category of UPS by excluding more-specific malignancies. However, few of those studies have specifically targeted pleomorphic hematolymphoid neoplasms. OBJECTIVE.: To determine what fraction of UPS cases are misclassified pleomorphic hematolymphoid neoplasms, such as anaplastic large cell lymphoma, diffuse large B-cell lymphoma, histiocytic sarcoma (HS), myeloid sarcoma, and follicular dendritic cell sarcoma. DESIGN.: Sixty-one UPS cases were screened by tissue microarray and an immunostain panel with subsequent analysis on whole block sections for suspicious cases. RESULTS.: Five of 61 tumors (8%) were suggestive of HS based on the screening panel and were further evaluated with additional immunostains (PU.1, CD45, CD163) using whole sections. The 5 candidate HS cases were only focally positive for at most one stain with most staining in smaller, less-pleomorphic cells. Ultimately, no UPS met criteria for anaplastic large cell lymphoma, diffuse large B-cell lymphoma, myeloid sarcoma, follicular dendritic cell sarcoma, or HS. CONCLUSIONS.: Our results suggest that a UPS of somatic soft tissue is unlikely to represent a misclassified hematopoietic malignancy. Exclusion of HS is most challenging, but immunostaining for PU.1, a nuclear transcription factor, may be easier to interpret in this context.
Assuntos
Sarcoma de Células Dendríticas Foliculares/classificação , Neoplasias Hematológicas/classificação , Linfoma Difuso de Grandes Células B/classificação , Linfoma Anaplásico de Células Grandes/classificação , Proteínas Proto-Oncogênicas/metabolismo , Sarcoma/classificação , Neoplasias de Tecidos Moles/classificação , Transativadores/metabolismo , Sarcoma de Células Dendríticas Foliculares/patologia , Neoplasias Hematológicas/patologia , Sarcoma Histiocítico/classificação , Sarcoma Histiocítico/patologia , Humanos , Linfoma Difuso de Grandes Células B/patologia , Linfoma Anaplásico de Células Grandes/patologia , Sarcoma/patologia , Sarcoma Mieloide/classificação , Sarcoma Mieloide/patologia , Neoplasias de Tecidos Moles/patologiaRESUMO
Outcomes in multiple myeloma (MM) have improved dramatically in the last two decades with the advent of novel therapies including immunomodulatory agents (IMiDs), proteasome inhibitors and monoclonal antibodies. In recent years, immunotherapy for the treatment of MM has advanced rapidly, with the approval of new targeted agents and monoclonal antibodies directed against myeloma cell-surface antigens, as well as maturing data from late stage trials of chimeric antigen receptor CAR T cells. Therapies that engage the immune system to treat myeloma offer significant clinical benefits with durable responses and manageable toxicity profiles, however, the appropriate use of these immunotherapy agents can present unique challenges for practicing physicians. Therefore, the Society for Immunotherapy of Cancer convened an expert panel, which met to consider the current role of approved and emerging immunotherapy agents in MM and provide guidance to the oncology community by developing consensus recommendations. As immunotherapy evolves as a therapeutic option for the treatment of MM, these guidelines will be updated.
Assuntos
Imunoterapia/métodos , Mieloma Múltiplo/tratamento farmacológico , Consenso , HumanosRESUMO
Impairment of ribosome biogenesis or function characterizes several of the inherited bone marrow failure syndromes: Diamond-Blackfan anaemia, dyskeratosis congenita (DC), Shwachman-Diamond syndrome and cartilage-hair hypoplasia. These syndromes exhibit overlapping but distinct clinical phenotypes and each disorder involves different aspects of ribosomal biogenesis. The clinical characteristics of each syndrome are briefly reviewed. Molecular studies of ribosome biogenesis and function in each of these syndromes are discussed. Models of how impairment of ribosomal pathways might affect haematopoiesis and tumorigenesis are explored.
Assuntos
Doenças da Medula Óssea/fisiopatologia , Doenças Genéticas Inatas/fisiopatologia , Ribossomos/fisiologia , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/fisiopatologia , Doenças da Medula Óssea/genética , Transformação Celular Neoplásica , Disceratose Congênita/genética , Disceratose Congênita/fisiopatologia , Doenças Genéticas Inatas/genética , Hematopoese , Humanos , SíndromeRESUMO
Traditionally low-grade B-cell lymphomas have been excluded from the category of monomorphic posttransplant lymphoproliferative disorders. However, recent reports identified Epstein-Barr virus-positive (EBV) extranodal marginal zone lymphomas (MZL), almost exclusively seen in the posttransplant setting. Some reported cases responded to reduced immunosuppression, suggesting that they should be considered as a form of posttransplant lymphoproliferative disorders. We identified 10 cases of EBV MZL, 9 in extranodal sites and 1 presenting in lymph node. Two cases arose following solid organ transplantation, but other settings included iatrogenic immunosuppression for rheumatoid arthritis (2); prior chemotherapy (2); congenital immune deficiency (1); and increased age (3), as the only potential cause of immune dysfunction. There were 4 males and 6 females; age range 18 to 86. The atypical plasmacytoid and/or monocytoid B cells were positive for EBV in all cases, with either latency I or II in all cases tested. Monotypic light chain expression was shown in all with 6 cases positive for IgG, and 2 for IgM, undetermined in 2. Clonal immunoglobulin gene rearrangement was positive in all cases with successful amplification. MYD88 L265P was wild type in the 6 cases tested. We show that EBV MZLs can arise in a variety of clinical settings, and are most often extranodal. Treatment varied, but most patients had clinically indolent disease with response to reduction of immune suppression, or immunochemotherapy.
Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/imunologia , Hospedeiro Imunocomprometido , Linfoma de Zona Marginal Tipo Células B/imunologia , Linfoma de Zona Marginal Tipo Células B/virologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antivirais/uso terapêutico , Biomarcadores Tumorais/genética , Transformação Celular Viral , DNA Viral/genética , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Feminino , Rearranjo Gênico , Genes de Cadeia Leve de Imunoglobulina , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/genética , Humanos , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Imunoglobulina M/genética , Imunoglobulina M/imunologia , Síndromes de Imunodeficiência/imunologia , Imunossupressores/efeitos adversos , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/genética , Masculino , Maryland , Pessoa de Meia-Idade , Mutação , Fator 88 de Diferenciação Mieloide/genética , Prognóstico , Fatores de RiscoRESUMO
Aggressive natural killer cell leukemia (ANKL) is a systemic NK-cell neoplasm, almost always associated with Epstein-Barr virus (EBV). Rare cases of EBV-negative ANKL have been described, and some reports suggested more indolent behavior. We report the clinicopathologic, immunophenotypic, and molecular characteristics of 7 EBV-negative ANKL. All patients were adults, with a median age of 63 years (range 22 to 83 y) and an M:F ratio of 2.5:1. Five patients were White, 1 Black, and 1 Asian. All patients presented acutely, with fever (6/7), cytopenias (6/7), and splenomegaly (4/7). Four patients had lymphadenopathy, 4 had extranodal disease. Bone marrow involvement was present in 5, with hemophagocytosis in 3. Peripheral blood was involved in 5 with the neoplastic cells containing prominent azurophilic granules. By immunohistochemistry and/or flow cytometry, the tumor cells lacked surface CD3 and were positive for CD56 (7/7), CD2 (5/5), CD8 (3/7), CD30 (4/5), and granzyme-B (6/6). They were negative for CD4, CD5, ßF1, TCRγ, LMP1, and EBV-encoded RNA. Polymerase chain reaction for TCRG clonality was polyclonal. Mutational analysis revealed missense mutations in the STAT3 gene in both cases studied. Median survival was 8 weeks from the onset of disease. One patient received allogeneic bone marrow transplant and is alive with no disease (follow-up 15 mo). EBV-negative ANKL exists but is rare. It tends to occur in older patients and is indistinguishable clinically and pathologically from EBV-positive ANKL, with a similar fulminant clinical course. The high prevalence of Asian patients seen with EBV-positive disease seems less evident with EBV-negative cases.
Assuntos
Leucemia Linfocítica Granular Grande/genética , Leucemia Linfocítica Granular Grande/patologia , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Infecções por Vírus Epstein-Barr , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Imunofenotipagem , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Adulto JovemRESUMO
Post-transplant lymphoproliferative disorders of T- or NK-cell origin (T/NK-PTLD) are rare entities and their genetic basis is unclear. We performed targeted sequencing of 465 cancer-related genes and high-resolution copy number analysis in 17 T-PTLD and 2 NK-PTLD cases. Overall, 377 variants were detected, with an average of 20 variants per case. Mutations of epigenetic modifier genes (TET2, KMT2C, KMT2D, DNMT3A, ARID1B, ARID2, KDM6B, n=11). and inactivation of TP53 by mutation and/or deletion(n=6) were the most frequent alterations, seen across disease subtypes, followed by mutations of JAK/STAT pathway genes (n=5). Novel variants, including mutations in TBX3 (n=3), MED12 (n=3) and MTOR (n=1), were observed as well. High-level microsatellite instability was seen in 1 of 14 (7%) cases, which had a heterozygous PMS2 mutation. Complex copy number changes were detected in 8 of 16 (50%) cases and disease subtype-specific aberrations were also identified. In contrast to B-cell PTLDs, the molecular and genomic alterations observed in T/NK-PTLD appear similar to those reported for peripheral T-cell lymphomas occurring in immunocompetent hosts, which may suggest common genetic mechanisms of lymphoma development.
Assuntos
Células Matadoras Naturais/fisiologia , Transtornos Linfoproliferativos/genética , Linfócitos T/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Transtornos Linfoproliferativos/metabolismo , Masculino , Pessoa de Meia-Idade , Linfócitos T/metabolismo , Linfócitos T/patologiaRESUMO
The dura is a rare site of involvement by marginal zone lymphoma (MZL) and the biology of dural MZL is not well understood. We performed genome-wide DNA copy number and targeted mutational analysis of 14 dural MZL to determine the genetic landscape of this entity. Monoallelic and biallelic inactivation of TNFAIP3 by mutation (n=5) or loss (n=1) was observed in 6/9 (67%) dural MZL exhibiting plasmacytic differentiation, including 3 IgG4+ cases. In contrast, activating NOTCH2 mutations were detected in 4/5 (80%) dural MZL displaying variable monocytoid morphology. Inactivating TBL1XR1 mutations were identified in all NOTCH2 mutated cases. Recurrent mutations in KLHL6 (n=2) and MLL2 (n=2) were also detected. Gains at 6p25.3 (n=2) and losses at 1p36.32 (n=3) were common chromosomal imbalances, with loss of heterozygosity (LOH) of these loci observed in a subset of cases. Translocations involving the IGH or MALT1 genes were not identified. Our results indicate genetic similarities between dural MZL and other MZL subtypes. However, recurrent and mutually exclusive genetic alterations of TNFAIP3 and NOTCH2 appear to be associated with distinct disease phenotypes in dural MZL.
Assuntos
Dura-Máter/metabolismo , Variação Genética , Linfoma de Zona Marginal Tipo Células B/genética , Neoplasias Meníngeas/genética , Adulto , Aberrações Cromossômicas , Análise Mutacional de DNA , Dura-Máter/patologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Hibridização in Situ Fluorescente , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma de Zona Marginal Tipo Células B/terapia , Masculino , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/terapia , Pessoa de Meia-Idade , MutaçãoRESUMO
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNAi screening, we identified the E-box transcription factor TCF4 as a master regulator of the BPDCN oncogenic program. TCF4 served as a faithful diagnostic marker of BPDCN, and its downregulation caused the loss of the BPDCN-specific gene expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETis) induced BPDCN apoptosis, which was attributable to disruption of a BPDCN-specific transcriptional network controlled by TCF4-dependent super-enhancers. BETis retarded the growth of BPDCN xenografts, supporting their clinical evaluation in this recalcitrant malignancy.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Células Dendríticas/patologia , Neoplasias Hematológicas/tratamento farmacológico , Proteínas Nucleares/genética , RNA Interferente Pequeno/administração & dosagem , Bibliotecas de Moléculas Pequenas/administração & dosagem , Fatores de Transcrição/genética , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/antagonistas & inibidores , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Células Dendríticas/metabolismo , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Células HL-60 , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Células Jurkat , Camundongos , RNA Interferente Pequeno/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Fator de Transcrição 4 , Fatores de Transcrição/antagonistas & inibidores , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Despite enormous advances in our understanding of aggressive lymphomas, it is clear that progress in the peripheral T-cell lymphomas (PTCL) has lagged well behind other B-cell malignancies. Although there are many reasons for this, the one commonly cited notes that the paradigms for diffuse large B-cell lymphoma (DLBCL) were merely applied to all patients with PTCL, the classic "one-size-fits-all" approach. Despite these challenges, progress is being made. Recently, the FDA has approved four drugs for patients with relapsed/refractory PTCL over the past 5 years, and if one counts the recent Japanese approval of the anti-CCR4 monoclonal antibody for patients with adult T-cell leukemia/lymphoma, five drugs have been approved worldwide. These efforts have led to the initiation of no fewer than four randomized clinical studies exploring the integration of these new agents into standard CHOP (cyclophosphamide-Adriamycin-vincristine-prednisone)-based chemotherapy regimens for patients with newly diagnosed PTCL. In addition, a new wave of studies are exploring the merits of novel drug combinations in the disease, an effort to build on the obvious single-agent successes. What has emerged most recently is the recognition that the PTCL may be a disease-characterized by epigenetic dysregulation, which may help explain its sensitivity to histone deacetylase (HDAC) inhibitors, and open the door for even more creative combination approaches. Nonetheless, advances made over a relatively short period of time are changing how we now view these diseases and, hopefully, have poised us to finally improve its prognosis. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma."
Assuntos
Linfoma de Células T Periférico/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Predisposição Genética para Doença , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfoma de Células T Periférico/etiologia , Linfoma de Células T Periférico/patologia , Recidiva Local de NeoplasiaAssuntos
Neoplasias Gengivais/diagnóstico , Linfoma não Hodgkin/diagnóstico , Idoso , Biópsia , Diagnóstico Diferencial , Evolução Fatal , Feminino , Neoplasias Gengivais/patologia , Neoplasias Gengivais/terapia , Humanos , Imuno-Histoquímica , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/terapia , MaxilaRESUMO
Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic dysfunction, and leukemia predisposition. Mutations in the SBDS gene are identified in most patients with SDS. SBDS encodes a highly conserved protein of unknown function. Data from SBDS orthologs suggest that SBDS may play a role in ribosome biogenesis or RNA processing. Human SBDS is enriched in the nucleolus, the major cellular site of ribosome biogenesis. Here we report that SBDS nucleolar localization is dependent on active rRNA transcription. Cells from patients with SDS or Diamond-Blackfan anemia are hypersensitive to low doses of actinomycin D, an inhibitor of rRNA transcription. The addition of wild-type SBDS complements the actinomycin D hypersensitivity of SDS patient cells. SBDS migrates together with the 60S large ribosomal subunit in sucrose gradients and coprecipitates with 28S ribosomal RNA (rRNA). Loss of SBDS is not associated with a discrete block in rRNA maturation or with decreased levels of the 60S ribosomal subunit. SBDS forms a protein complex with nucleophosmin, a multifunctional protein implicated in ribosome biogenesis and leukemogenesis. Our studies support the addition of SDS to the growing list of human bone marrow failure syndromes involving the ribosome.