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1.
J Clin Exp Hematop ; 59(1): 1-16, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30918139

RESUMO

The microenvironment influences the behavior of follicular lymphoma (FL) but the specific roles of the immunomodulatory BTLA and TNFRSF14 (HVEM) are unknown. Therefore, we examined their immunohistochemical expression in the intrafollicular, interfollicular and total histological compartments in 106 FL cases (57M/49F; median age 57-years), and in nine relapsed-FL with transformation to DLBCL (tFL). BTLA expression pattern was of follicular T-helper cells (TFH) in the intrafollicular and of T-cells in the interfollicular compartments. The mantle zones were BTLA+ in 35.6% of the cases with similar distribution of IgD. TNFRSF14 expression pattern was of neoplastic B lymphocytes (centroblasts) and "tingible body macrophages". At diagnosis, the averages of total BTLA and TNFRSF14-positive cells were 19.2%±12.4STD (range, 0.6%-58.2%) and 46.7 cells/HPF (1-286.5), respectively. No differences were seen between low-grade vs. high-grade FL but tFL was characterized by low BTLA and high TNFRSF14 expression. High BTLA correlated with good overall survival (OS) (total-BTLA, Hazard Risk=0.479, P=0.022) and with high PD-1 and FOXP3+Tregs. High TNFRSF14 correlated with poor OS and progression-free survival (PFS) (total-TNFRSF14, HR=3.9 and 3.2, respectively, P<0.0001), with unfavorable clinical variables and higher risk of transformation (OR=5.3). Multivariate analysis including BTLA, TNFRSF14 and FLIPI showed that TNFRSF14 and FLIPI maintained prognostic value for OS and TNFRSF14 for PFS. In the GSE16131 FL series, high TNFRSF14 gene expression correlated with worse prognosis and GSEA showed that NFkB pathway was associated with the "High-TNFRSF14/dead-phenotype".In conclusion, the BTLA-TNFRSF14 immune modulation pathway seems to play a role in the pathobiology and prognosis of FL.


Assuntos
Linfoma Folicular/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Receptores Imunológicos/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/química , Linfócitos B/patologia , Transformação Celular Neoplásica , Feminino , Humanos , Fatores Imunológicos , Linfoma Folicular/mortalidade , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Linfócitos T/química
2.
J Cutan Pathol ; 46(3): 182-189, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30511443

RESUMO

BACKGROUND: Primary cutaneous follicular center-cell lymphoma (PCFCL) is one of the most common types of cutaneous B-cell lymphoma. Differences in immunohistochemical expression of BCL2 and CD10 antigens along with the presence of t(14:18) translocation in neoplastic cells have been postulated as relevant clues in differentiating PCFCL from cutaneous lesions secondary to a systemic follicular lymphoma (SCFL). The aim of this study is to evaluate the significance and usefulness of these parameters in a large series of patients. METHODS: Patients with PCFCL and SCFL diagnosed at three university hospitals in Barcelona, from 2000 to 2015 were reviewed. Clinical, histopathological, immunophenotypical, genetic, and outcome parameters were analyzed. RESULTS: Eighty-one cases (59 PCFCL and 22 SCFL) were included. There were no significant differences between PCFCL and SCFL cases regarding clinical presentation, site of involvement, or predominant type of skin lesions. Most patients in both groups showed positivity for BCL2 and CD10, but strong expression of BCL2 and CD10 was associated with SCFL cases. Although more frequent in SCFL, a small proportion of PCFCL cases also showed the t(14:18) on FISH analysis. CONCLUSION: The intensity of BCL2 expression was found to be the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds.


Assuntos
Biomarcadores Tumorais/análise , Linfoma Folicular/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 18/genética , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina/análise , Neprilisina/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Translocação Genética/genética , Adulto Jovem
3.
Cancer Genomics Proteomics ; 14(1): 75-82, 2017 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-28031239

RESUMO

BACKGROUND: Over the last years, our knowledge on pathogenesis of gastric MALT lymphoma has greatly improved, but its morphological diagnosis is still hampered by overlapping histological features with advanced chronic gastritis. MicroRNAs are deregulated in lymphomas, but their role and usefulness in gastric MALT lymphoma has not been extensively investigated. MATERIALS AND METHODS: We analyzed the expression of 384 miRNAs using TaqMan microRNA assay in a training series of 10 gastric MALT lymphomas, 3 chronic gastritis and 2 reactive lymph nodes. Then, significantly deregulated miRNAs were individually assessed by real-time PCR in a validation series of 16 gastric MALT lymphomas and 12 chronic gastritis. RESULTS: Gastric MALT lymphoma is characterized by a specific miRNA expression profile. Among the differentially expressed miRNAs, a significant overexpression of miR-142-3p and miR-155 and down-regulation of miR-203 was observed in gastric MALT lymphoma when compared to chronic gastritis. CONCLUSION: miR-142-3p, miR-155 and miR-203 expression levels might be helpful biomarkers for the differential diagnosis between gastric MALT lymphomas and chronic gastritis.


Assuntos
Gastrite/genética , Regulação da Expressão Gênica , Linfoma de Zona Marginal Tipo Células B/genética , MicroRNAs/genética , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Doença Crônica , Análise por Conglomerados , Feminino , Gastrite/diagnóstico , Gastrite/microbiologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Gástricas/diagnóstico , Transcriptoma
5.
Pediatr. catalan ; 76(2): 71-73, abr.-jun. 2016. ilus
Artigo em Catalão | IBECS | ID: ibc-156637

RESUMO

Introducció: la malaltia de Kikuchi-Fujimoto, o limfadenitis necrosant histiocítica, és una patologia benigna poc freqüent que es caracteritza per clínica de febre i limfadenopatia cer-vical. Predomina en noies joves i habitualment sautolimita entre els 2 i els 4 mesos sense complicacions. Cas clínic: es presenta el cas duna pacient de 14 anys que presenta febre de tres dies devolució i adenopaties cervicals dretes. Les setmanes prèvies va presentar un quadre febril que es va autolimitar sense poder filiar-ne letiologia. Samplia lestudi amb proves complementàries, i es descarten amb lanalítica sanguínia i les proves dimatge les causes infeccioses o tumorals. Es fa exèresi quirúrgica duna adenopatia cervical amb intenció diagnosticotera-pèutica. Lestudi immunohistoquímic presenta característiques típiques de la limfadenitis necrosant histiocítica. La pacient presenta remissió de la simptomatologia i desaparició de les adenopaties. Comentaris: la limfadenitis necrosant histiocítica és una malaltia poc freqüent, però és important tenir-la en compte en pacients joves amb quadre febril i adenopaties de llarga evolució. La biòpsia del gangli per al diagnòstic definitiu és important per evitar altres proves o tractaments més agressius i innecessaris


Introducción. La enfermedad de Kikuchi-Fujimoto, o linfadenitis necrotizante histiocítica, es una patología benigna poco frecuente que se caracteriza por clínica de fiebre y linfadenopatía. Predomina en mujeres jóvenes y habitualmente se autolimita a los 2-4 meses sin presentar complicaciones. Caso clínico. Se presenta el caso de una paciente de 14 años que presenta fiebre de tres días de evolución y adenopatías cervicales derechas. Las semanas previas presentó cuadro febril que se autolimitó sin poder filiar su etiología. Se amplía el estudio con pruebas complementarias, descartando con la analítica sanguínea y las pruebas de imagen causas infecciosas o tumorales. Se realiza extirpación quirúrgica de una adenopatía cervical con intención diagnóstico-terapéutica. El estudio immunohistoquímico presenta características típicas de la linfadenitis necrotizante histiocítica. La paciente presenta remisión de la sintomatología y desaparición de las adenopatías. Comentarios. La linfadenitis necrotizante histiocítica es una enfermedad poco frecuente, pero es importante tenerla en cuenta en pacientes jóvenes con cuadro febril y adenopatías de larga evolución. La biopsia del ganglio para el diagnóstico definitivo es importante para evitar otras pruebas o tratamientos más agresivos e innecesarios (AU)


Introduction. Kikuchi-Fujimoto disease, or histiocytic necrotizing lymphadenitis, is a rare benign disease characterized by fever and lymphadenopathy. It mostly affects young women and it resolves spontaneously in 2-4 months without complications. Case report. A 14-year old female presented with a three-day history of fever and cervical lymphadenopathies. During the weeks prior to presentation, the patient had a self-limited febrile episode of unknown etiology. The laboratory and imaging evaluation ruled out a known infectious or neoplastic etiology. An excisional biopsy of a cervical node showed a pattern consistent with histiocytic necrotizing lymphadenitis. The symptoms and lymphadenopathies resolved in subsequent weeks. Comments. Although histiocytic necrotizing lymphadenitis is a rare disease, it should be considered in the diagnosis of young patients with longstanding fever and lymphadenopaties. Lymph node biopsy may provide definitive diagnosis while preventing other tests and more aggressive and unnecessary treatments (AU)


Assuntos
Humanos , Feminino , Adolescente , Linfadenite Histiocítica Necrosante/sangue , Linfadenite Histiocítica Necrosante/complicações , Linfadenite Histiocítica Necrosante/diagnóstico , Imuno-Histoquímica/métodos , Doenças Linfáticas/sangue , Doenças Linfáticas/complicações , Linfadenite Histiocítica Necrosante/patologia , Radiografia Torácica/métodos , Diagnóstico Diferencial
6.
Mod Pathol ; 29(8): 844-53, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27125356

RESUMO

MYC rearrangement can be detected in a subgroup of diffuse large B-cell lymphoma characterized by unfavorable prognosis. In contrast to Burkitt lymphoma, the correlation between MYC rearrangement and MYC protein expression in diffuse large B-cell lymphoma is less clear, as approximately one-third of rearranged cases show negative or low expression by immunohistochemistry. To better understand whether specific characteristics of the MYC rearrangement may influence its protein expression, we investigated 43 de novo diffuse large B-cell lymphoma positive for 8q24 rearrangement by FISH, using 14 Burkitt lymphoma for comparison. Different cell populations (clones), breakpoints (classical vs non-classical FISH patterns), partner genes (IGH vs non-IGH) and immunostaining were detected and analyzed using computerized image systems. In a subgroup of diffuse large B-cell lymphoma, we observed different clones within the same tumor distinguishing the founder clone with MYC rearrangement alone from other subclones, carrying MYC rearrangement coupled with loss/extra copies of derivatives/normal alleles. This picture, which we defined MYC genetic heteroclonality, was found in 42% of cases and correlated to negative MYC expression (P=0.026). Non-classical FISH breakpoints were detected in 16% of diffuse large B-cell lymphoma without affecting expression (P=0.040). Non-IGH gene was the preferential partner of rearrangement in those diffuse large B-cell lymphoma showing MYC heteroclonality (P=0.016) and/or non-classical FISH breakpoints (P=0.058). MYC heteroclonality was not observed in Burkitt lymphoma and all cases had positive MYC expression. Non-classical FISH MYC breakpoint and non-IGH partner were found in 29 and 20% of Burkitt lymphoma, respectively. In conclusion, MYC genetic heteroclonality is a frequent event in diffuse large B-cell lymphoma and may have a relevant role in modulating MYC expression.


Assuntos
Biomarcadores Tumorais/genética , Cromossomos Humanos Par 8 , Rearranjo Gênico , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Feminino , Regulação Neoplásica da Expressão Gênica , Genes de Cadeia Pesada de Imunoglobulina , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/química , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas c-myc/análise , Espanha , Suíça
7.
Pathol Res Pract ; 212(2): 148-50, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26725534

RESUMO

Follicular lymphomas are characterized by overexpression of BCL2 which, in the large majority of cases, is due to a t(14;18) translocation which juxtaposes the BCL2 locus to the immunoglobulin heavy chain locus (IGH). Here, we report partial absence of BCL2 immunohistochemical staining in a case of FL, due to a mutation in the part of BCL2 that encodes the epitope for the most frequently used antibody against BCL2. This finding shows that mutations in BCL2 occur in an ongoing process in follicular which can give rise to unusual immunohistochemical staining patterns.


Assuntos
Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Imuno-Histoquímica , Linfoma Folicular/química , Linfoma Folicular/genética , Mutação , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/genética , Análise Mutacional de DNA , Regulação para Baixo , Humanos , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes
8.
Clin Cancer Res ; 22(11): 2755-64, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-26792260

RESUMO

PURPOSE: Mutations in MYD88 are found in different lymphoproliferative disorders associated with particular biologic characteristics and clinical impact. The aim of this study was to analyze the incidence of MYD88 mutations and its clinical impact in diffuse large B-cell lymphoma (DLBCL). EXPERIMENTAL DESIGN: The incidence, clinicobiological features, and outcome of 213 patients (115 M/98 F; median age, 65 years) with DLBCL treated with immunochemotherapy in a single institution according to MYD88 mutational status as assessed by an allele-specific PCR assay were analyzed. The cell of origin (COO) was determined in 129 cases by gene expression. RESULTS: MYD88 mutations were found in 47 cases (22%), including L265P in 39 and S219C and M232F in 4 cases, respectively. Patients with MYD88 L265P were older, presenting frequent extranodal involvement, and mostly corresponded to activated B-cell like (ABC) subtype, whereas no preference in COO was observed in patients with other MYD88 mutations. Five-year overall survival (OS) for MYD88 wild-type, MYD88 L265P, and other variants was 62%, 52%, and 75%, respectively (P = 0.05). International Prognostic Index (IPI) (HR, 2.71; P < 0.001) and MYD88 L265P (HR, 1.786; P = 0.023) were independent variables predicting OS in the multivariate analysis. However, MYD88 L265P lost its independent value when COO was included in the model. CONCLUSIONS: Our findings indicate that MYD88 L265P mutations, but no other variants, identify a subgroup of DLBCL mainly of ABC origin, with extranodal involvement and poor outcome. Clin Cancer Res; 22(11); 2755-64. ©2016 AACR.


Assuntos
Linfoma Difuso de Grandes Células B/genética , Fator 88 de Diferenciação Mieloide/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Ativação Linfocitária , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Resultado do Tratamento , Adulto Jovem
9.
Ann Hematol ; 94(5): 803-12, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25501975

RESUMO

A retrospective study was performed to assess the outcome of patients with diffuse large B cell lymphoma (DLBCL) who did not achieve complete response or who relapsed before and after the use of rituximab. Clinical features and outcome of 816 (425 M/391 F; median age 63 years) patients diagnosed from 1991 to 2001 (pre-rituximab era, N = 348) and from 2002 to 2012 (rituximab era, N = 468) in a single institution were evaluated. Five hundred fifty-three patients achieved complete remission (CR), 57 partial response (PR), and 206 were refractory with a median overall survival of 15, 1.5, and 0.4 years, respectively. Patients receiving rituximab had lower risk of refractoriness or relapse. In primarily refractory and PR patients, there was not a difference in survival depending on whether patients received or not rituximab-containing frontline treatment. Early death rate was 11%, including 3.6% due to infectious complications. Rituximab did not modify these figures. In the relapse setting, 5-year survival from relapse was 25% for patients who never received rituximab, 54% for those who received rituximab only at relapse, and 48% for those treated with immunochemotherapy both as frontline and at relapse. In conclusion, relapsed/refractory patients with DLBCL show poor prognosis despite the use of frontline immunochemotherapy. New therapeutic approaches are needed in this group of patients.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Rituximab , Adulto Jovem
10.
J Cutan Pathol ; 42(1): 66-72, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25354337

RESUMO

A case of a 78-year-old woman with a CD8-positive peripheral T-cell lymphoma with aberrant expression of CD20 associated with follicular lymphoma in situ (FLIS) is reported. The neoplasm presented initially as cutaneous macules, papules, plaques and nodules. A skin biopsy was performed and the diagnosis of peripheral T-cell lymphoma (PTCl) with aberrant expression of CD20 was made. The staging procedures included an excisional inguinal lymph node biopsy that showed findings similar to those of the previous diagnosis. In addition, FLIS was identified. The clinicopathologic features of PTCLs with aberrant CD20 expression involving the skin as well as this uncommon association are reviewed.


Assuntos
Antígenos CD20/biossíntese , Linfócitos T CD8-Positivos/metabolismo , Linfoma Folicular/patologia , Linfoma de Células T Periférico/patologia , Neoplasias Primárias Múltiplas/patologia , Idoso , Linfócitos T CD8-Positivos/patologia , Feminino , Humanos , Linfoma Folicular/metabolismo , Linfoma de Células T Periférico/metabolismo , Neoplasias Primárias Múltiplas/metabolismo
11.
Medicine (Baltimore) ; 93(16): e95, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25310744

RESUMO

Although rapid diagnostic testing is essential in suspicious peripheral lymphadenopathy, delays in accessing them can be considerable. We investigated the usefulness of an internist-led outpatient quick diagnosis unit (QDU) in assessing patients with unexplained peripheral lymphadenopathy, focusing on the characteristics, diagnostic, and treatment waiting times of those with malignancy. Patients aged ≥ 18 years, consecutively referred from 12 primary health care centers (PHCs) or the emergency department (ED) for unexplained peripheral lymphadenopathy, were prospectively evaluated during 7 years. Diagnostic investigations were done using a predefined study protocol. Three experienced cytopathologists performed a fine-needle aspiration cytology (FNAC) systematic approach of clinically suspicious lymphadenopathy with cytomorphology and immunophenotyping analyses. We evaluated 372 patients with a mean age (SD) of 45.3 (13.8) years; 56% were women. Malignancy was diagnosed in 120 (32%) patients, including 81 lymphomas and 39 metastatic tumors. Metastatic lymphadenopathy was diagnosed by FNAC in all 39 patients and the primary tumor site was identified in 82% of them when cytomorphology and immunocytochemistry were combined. A correct diagnosis of lymphoma was reached by FNAC in 73% of patients. When accepting "suspicious of" as correct diagnosis, the FNAC diagnosis rate of lymphoma increased to 94%. Among patients with malignancy, FNAC yielded 1.3% of false negatives and no false positives. All patients with an FNAC report of correct or suspicious lymphoma underwent a surgical biopsy, as it is a mandatory requirement of the hematology department. Mean times from first QDU visit to FNAC diagnosis of malignancy were 5.4 days in metastatic lymphadenopathy and 7.5 days in lymphoma. Mean times from receiving the initial referral report to first treatment were 29.2 days in metastatic lymphadenopathy and 40 days in lymphoma. In conclusion, a distinct internal medicine QDU allows an expeditious, agile, and prearranged system to diagnose malignant peripheral lymphadenopathy. Because of the close collaboration with the cytopathology unit and the FNAC methodical approach, diagnostic and treatment waiting times of patients with malignancy fulfilled national and international time frame standards. This particular diagnostic delivery unit could help overcome the difficulties facing PHC, ED, and other physicians when trying to provide rapid access to investigations to patients with troublesome lymphadenopathy.


Assuntos
Assistência Ambulatorial/métodos , Linfonodos/patologia , Linfoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial/organização & administração , Biópsia por Agulha Fina , Diagnóstico Diferencial , Feminino , Hospitais Universitários , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Espanha , Centros de Atenção Terciária , Fatores de Tempo , Listas de Espera , Adulto Jovem
13.
Leuk Res ; 38(4): 509-15, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24480549

RESUMO

The analysis of immunoglobulin heavy chain variable (IGHV) region may disclose the influence of antigens in Burkitt's lymphomas (BL). IGHV sequences from 38 patients and 35 cell lines were analyzed. IGHV3 subset genes were the most used and IGHV4-34 gene was overrepresented. IGHV genes were mutated in 98.6% of the cases, 36% acquired potential glycosylation sites, and in 52% somatic-hypermutation-process was ongoing. Binding motifs for superantigens like Staphylococcal protein A and carbohydrate I/i were preserved in 89% of the cases. IGHV analysis of BL cells supports a germinal center origin and points toward a role for superantigens in lymphomagenesis.


Assuntos
Linfoma de Burkitt/genética , Transformação Celular Neoplásica , Análise Mutacional de DNA , Centro Germinativo/patologia , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Superantígenos/fisiologia , Adolescente , Adulto , Idoso , Linfoma de Burkitt/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Criança , Pré-Escolar , Feminino , Centro Germinativo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade
14.
Am J Surg Pathol ; 38(1): 86-93, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24145648

RESUMO

The diagnosis of mantle cell lymphoma (MCL) can be difficult, especially when no t(11;14) translocation and cyclin D1 overexpression can be detected. In such cases, the transcription factor SOX11 represents an important diagnostic marker, as it is expressed in most MCLs and, in particular, in all cyclin D1-negative MCLs reported so far. A reliable anti-SOX11 antibody is therefore a very useful tool for routine diagnosis. Here, we characterize the new monoclonal anti-SOX11 antibodies, suitable for Western blot assay and immunohistochemistry (IHC) on formalin-fixed paraffin-embedded tissue; we tested them on a large series of primary lymphoid tumors and compared these results with those of other routinely used antibodies. Moreover, we show that IHC results depend on transcription levels of SOX11, which suggests that posttranscriptional and posttranslational modifications do not significantly affect cutoff levels for IHC detection of SOX11.


Assuntos
Anticorpos Monoclonais , Biomarcadores Tumorais/análise , Imuno-Histoquímica , Linfoma de Célula do Manto/química , Fatores de Transcrição SOXC/análise , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Western Blotting , Ciclina D1/análise , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/imunologia , Linfoma de Célula do Manto/patologia , Valor Preditivo dos Testes , Prognóstico , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/imunologia , Transcrição Genética
15.
Proc Natl Acad Sci U S A ; 110(45): 18250-5, 2013 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-24145436

RESUMO

Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.


Assuntos
Evolução Clonal/genética , Variação Genética , Genoma Humano/genética , Linfoma de Célula do Manto/genética , Mutação/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Sequência de Bases , Ciclina D1/genética , Estudo de Associação Genômica Ampla , Genômica/métodos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma de Célula do Manto/fisiopatologia , Análise em Microsséries , Dados de Sequência Molecular , Receptor Notch2/genética , Receptor 2 Toll-Like/genética
16.
Mod Pathol ; 26(10): 1329-37, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23599149

RESUMO

ALK-positive large B-cell lymphoma is an aggressive lymphoid neoplasm characterized by a monomorphic proliferation of immunoblast-like cells expressing a plasmablastic phenotype and carrying ALK rearrangements. MYC rearrangements are frequent in plasmablastic lymphomas, advanced plasma cell myelomas and a subgroup of diffuse large B-cell lymphomas, but their presence in ALK-positive large B-cell lymphomas is unknown. MYC expression is downregulated by BLIMP1, a master modulator of plasma cell differentiation. BLIMP1 and MYC are upregulated by STAT3, a signal transducer activated by ALK. To determine the role of BLIMP1, MYC and STAT3 in the pathogenesis of ALK-positive large B-cell lymphomas, we investigated MYC rearrangement and the expression of MYC, phosphorylated STAT3, BLIMP1, PAX5 and XBP1 in 12 ALK-positive large B-cell lymphomas. All cases expressed ALK with a granular cytoplasmic pattern. Nine cases had a split signal consistent with an ALK rearrangement. Three additional cases showed a deletion of the 5' or 3' end of the ALK probe consistent with cryptic translocation. PAX5 was virtually negative in all cases tested, whereas BLIMP1 was expressed in all tumors and XBP1 in 11 of 12. Phosphorylated STAT3 was observed in all cases with a strong and diffuse nuclear pattern. MYC rearrangements were not identified in any tumor, but MYC gains and amplification were detected in six cases and one case, respectively. MYC protein was expressed in all tumors independently of MYC gene alterations. These results indicate that ALK-positive large B-cell lymphomas express a complete plasmablastic differentiation program but, contrary to plasmablastic lymphomas, do not have MYC rearrangements. STAT3 is constantly activated and may be an alternative mechanism to promote MYC expression in these tumors. The relevance of the ALK/STAT3 pathway in the pathogenesis of ALK-positive large B-cell lymphomas may offer an attractive target for new therapies.


Assuntos
Linfócitos B/metabolismo , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-myc/genética , Receptores Proteína Tirosina Quinases/genética , Fator de Transcrição STAT3/genética , Adulto , Quinase do Linfoma Anaplásico , Linfócitos B/patologia , Diferenciação Celular/genética , Feminino , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Fosforilação , Fator 1 de Ligação ao Domínio I Regulador Positivo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética
17.
Am J Surg Pathol ; 37(2): 272-81, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23282972

RESUMO

Histologic transformation of low-grade B-cell lymphoma to diffuse large B-cell lymphoma is associated with poor prognosis. Although plasma cell differentiation is common in these lymphomas, an overt plasmablastic transformation (PBL-T) has been only rarely reported. We report 6 cases of PBL-T occurring in 3 chronic lymphocytic leukemias (CLL) and 3 follicular lymphomas. Five patients were men, and the mean age was 65 years (range, 52 to 72 y). None of them had history of immunodeficiency. In 3 cases the PBL-T occurred 34 to 85 months after the initial diagnosis, and in 3 it was detected simultaneously with the small cell component at diagnosis. All patients received chemotherapy after transformation, and 4 died 4 to 24 months after this diagnosis. In 3 cases, PBL-T occurred in an extranodal site. All PBL-Ts had immunoblastic morphology with admixed plasma cells, were CD20 and PAX5 negative, expressed λ light chain, and 5 were CD138 positive. All cases were negative for HHV8, and only 1 PBL-T was Epstein-Barr virus positive. Evidence of a clonal relationship between the small cell and PBL-T components was found in 5 cases. In 2 CLL cases, both components had 13q deletions, and in all follicular lymphoma cases both components harbored the t(14;18) translocation. MYC translocations were observed in 2 cases transformed from a CLL. In conclusion, PBL-T expands the clinicopathologic spectrum of the transformation of low-grade B-cell lymphomas. These transformed tumors are clinically, histologically, and phenotypically similar to primary plasmablastic lymphomas, but they are not associated with immunodeficiency and rarely have Epstein-Barr virus infection or MYC alterations.


Assuntos
Transformação Celular Neoplásica/patologia , Linfoma de Células B/patologia , Plasmocitoma/patologia , Idoso , Aberrações Cromossômicas , Células Clonais , DNA de Neoplasias/análise , Evolução Fatal , Feminino , Humanos , Hibridização in Situ Fluorescente , Linfoma de Células B/genética , Linfoma de Células B/mortalidade , Masculino , Pessoa de Meia-Idade
18.
Am J Med Sci ; 344(3): 241-4, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22739563

RESUMO

In this study, the case of a 58-year-old man with a 2-month history of left chin paresthesia with difficulty swallowing and chewing, and dysphonia is reported. He had an absence of the gag reflex, unilateral palatal palsy and deviation of the tongue upon attempted protrusion with unilateral atrophy. Magnetic resonance imaging of the skull base revealed a tumoral infiltration of the left side of Meckel's cave, involvement of the clivus with extension into the cavernous sinus and signs of focal leptomeningeal infiltration. The patient was eventually diagnosed with generalized Burkitt's lymphoma. In this study, the authors suggest an initial diagnostic workup that includes a computed tomography scan of the mandible and a magnetic resonance imaging of the skull base searching for malignancy in patients with isolated numb chin syndrome, a rare disorder often associated with cancer, especially breast cancer and lymphoma, with mandibular metastases, leptomeningeal seeding and metastases of the base of the skull explaining the origin of the syndrome in most cases.


Assuntos
Linfoma de Burkitt/complicações , Linfoma de Burkitt/diagnóstico , Queixo/inervação , Doenças dos Nervos Cranianos/etiologia , Hipestesia/etiologia , Linfoma de Burkitt/tratamento farmacológico , Humanos , Nervo Hipoglosso/fisiopatologia , Masculino , Pessoa de Meia-Idade , Paralisia/etiologia , Paralisia/fisiopatologia , Radiografia , Crânio/diagnóstico por imagem , Crânio/patologia , Resultado do Tratamento , Nervo Vago/fisiopatologia
19.
Histol Histopathol ; 26(2): 213-21, 2011 02.
Artigo em Inglês | MEDLINE | ID: mdl-21154235

RESUMO

FOXP1 protein is expressed in normal activated B cells and overexpressed in a subset of diffuse large B-cell lymphomas, including primary cutaneous large B-cell lymphomas (PCLBCL), leg type. High expression of FOXP1 has been associated to an unfavourable prognosis with independent survival significance. However, little is known regarding the mechanisms underlying the overexpression of FOXP1 in PCLBCL, leg type. Our aims were to analyze FOXP1 cytogenetic status and protein expression in a series of PCLBCL, leg type. Finally, we compared the observed results with those obtained in a group of patients with primary cutaneous follicle centre lymphoma (PCFCL). Fifteen patients with PCLBCL, leg type and nine patients with primary cutaneous follicle centre lymphoma (PCFCL) were included in the study. For each biopsy specimen, FOXP1 translocation and copy number changes were evaluated by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry (IHC). Immunohistochemistry showed FOXP1 staining in 13 PCLBCL, leg type, whereas all PCFCL were negative. FISH analysis disclosed no translocations involving FOXP1 gene in any of the cases. However, FOXP1 gene gains (3 to 4 copies) were observed in 82% of samples of PCLBCL, leg type and in 37% of PCFCL. FOXP1 expression was independent from FOXP1 translocation. Our results confirm that overexpression of FOXP1 is present in a considerable proportion of PCLBCL, leg type and might indicate an unfavourable prognosis. Mechanisms not related to translocation seem to be responsible for this overexpression.


Assuntos
Fatores de Transcrição Forkhead/genética , Linfoma Difuso de Grandes Células B/genética , Proteínas Repressoras/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Aberrações Cromossômicas , Feminino , Fatores de Transcrição Forkhead/metabolismo , Dosagem de Genes , Duplicação Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Perna (Membro)/patologia , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Repressoras/metabolismo , Estudos Retrospectivos , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
20.
Dig Liver Dis ; 42(12): 877-81, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20810331

RESUMO

BACKGROUND: The diagnosis of pancreatic cystic lesions is still a challenge. AIM: To prospectively investigate the usefulness and safety of EUS-guided cytology brushing (EUS BR) in the cellular diagnosis of pancreatic cysts. METHODS: Cysts >15mm were sampled with a 19G needle. The fluid was aspirated and processed for cytology. The brush was introduced to scrub the cystic wall and processed as standard brushings. Antibiotic prophylaxis was administered. Complications were assessed in the first 24h and 7 days after the procedure. RESULTS: 30 patients were included. In 8 patients the technique failed for technical reasons. EUS BR provided with a cellular diagnosis in 20/22 cases (91%). The EUS BR was superior to the aspirated fluid for detecting diagnostic cells (73% vs. 36%, p=0.08) and mucinous cells (50% vs. 18%, p=0.016). In the 8 patients operated on, the specimen was consistent with EUS BR diagnosis. Three patients (10%) had complications, one of them a subacute retroperitoneal haemorrhage in a patient on anticoagulation therapy who died for complications 1 month later. CONCLUSIONS: EUS BR increases cellular diagnosis of pancreatic cystic lesions as compared with fluid analysis, mainly in mucinous lesions. Its use is not recommended in patients under anticoagulation therapy.


Assuntos
Cisto Pancreático/diagnóstico por imagem , Cisto Pancreático/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Biópsia por Agulha , Citodiagnóstico , Técnicas Citológicas , Endossonografia , Feminino , Humanos , Masculino , Estudos Prospectivos
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