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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
3.
Am J Surg Pathol ; 42(7): 936-950, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29738359

RESUMO

Rheumatoid arthritis patients often develop the diffuse large B-cell lymphoma subtype of methotrexate-associated lymphoproliferative disorder (DLBCL). We characterized the genomic profile and pathologic characteristics of 20 biopsies using an integrative approach. DLBCL was associated with extranodal involvement, a high/high-intermediate international prognostic index in 53% of cases, and responded to MTX withdrawal. The phenotype was nongerminal center B-cell in 85% of samples and Epstein-Barr encoding region positive (EBER) in 65%, with a high proliferation index and intermediate MYC expression levels. The immune microenvironment showed high numbers of CD8 cytotoxic T lymphocytes and CD163 M2 macrophages with an (CD163/CD68) M2 ratio of 3.6. Its genomic profile was characterized by 3p12.1-q25.31, 6p25.3, 8q23.1-q24.3, and 12p13.33-q24.33 gains, 6q22.31-q24.1 and 13q21.33-q34 losses, and 1p36.11-p35.3 copy neutral loss-of-heterozygosity. This profile was closer to nongerminal center B-cell DLBCL not-otherwise-specified, but with characteristic 3q, 12q, and 20p gains and lower 9p losses (P<0.05). We successfully verified array results using fluorescent DNA in situ hybridization on PLOD2, MYC, WNT1, and BCL2. Protein immunohistochemistry revealed that DLBCL expressed high IRF4 (6p25.3) and SELPLG (12q24.11) levels, intermediate TNFRSF14 (1p36.32; the exons 1 to 3 were unmutated), BTLA (3q13.2), PLOD2 (3q24), KLHL6 (3q27.1), and MYC (8q24.21) levels, and low AICDA (12p13.31) and EFNB2 (13q33.3) levels. The correlation between the DNA copy number and protein immunohistochemistry was confirmed for BTLA, PLOD2, and EFNB2. The characteristics of EBER versus EBER cases were similar, with the exception of specific changes: EBER cases had higher numbers of CD163 M2 macrophages and FOXP3 regulatory T lymphocytes, high programmed cell death 1 ligand 1 expression levels, slightly fewer genomic changes, and 3q and 4p focal gains. In conclusion, DLBCL has a characteristic genomic profile with 3q and 12 gains, 13q loss, different expression levels of relevant pathogenic biomarkers, and a microenvironment with high numbers of cytotoxic T lymphocytes and M2 macrophages.


Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Biomarcadores Tumorais/genética , Linfoma Difuso de Grandes Células B/genética , Metotrexato/efeitos adversos , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Feminino , Perfilação da Expressão Gênica/métodos , Predisposição Genética para Doença , Humanos , Hibridização in Situ Fluorescente , Linfócitos do Interstício Tumoral/imunologia , Linfoma Difuso de Grandes Células B/induzido quimicamente , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Microambiente Tumoral
4.
Histopathology ; 70(4): 595-621, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27775850

RESUMO

AIMS: We aimed to define the clinicopathological characteristics of 29 primary sinonasal diffuse large B cell lymphoma (DLBCLsn ) in a series of 240 cases of DLBCL not otherwise specified [DLBCLall (NOS) ], including DLBCLsn training set (n = 11) and validation set (n = 18), and DLBCLnon-sn (n = 211). METHODS AND RESULTS: In the training set, 82% had a non-germinal center B-cell-like (Hans' Classifier) (non-GCB) phenotype and 18% were Epstein-Barr virus-encoded small RNAs (EBER)+ . The genomic profile showed gains(+) of 1q21.3q31.2 (55%), 10q24.1 (46%), 11q14.1 (46%) and 18q12.1q23 (46%); losses(-) of 6q26q27 (55%) and 9p21.3 (64%); and copy number neutral loss of heterozygosity (LOH) (acquired uniparental disomy, UPD) at 6p25.3p21.31 (36%). This profile is comparable to DLBCLNOS (GSE11318, n = 203.) and closer to non-GCB/activated B-cell-like subtype (ABC). Nevertheless, +1q31, -9p21.3 and -10q11.1q26.2 were more characteristic of DLBCLsn (P < 0.001). Array results were verified successfully by fluorescence in situ hybridization (FISH) on +1q21.3 (CKS1B), -6q26 (PARK2), +8q24.21 (MYC), -9p21.3 (MTAP, CDKN2A/B), -17p13.1 (TP53) and +18q21.33 (BCL2) with 82-91% agreement. Minimal common regions included biologically relevant genes of MNDA (+1q23.1), RGS1 and RGS13 (+1q31.2), FOXP1 (+3p13), PRDM1 (BLIMP1) and PARK2 (-6q21q26), MYC (+8q24.21), CDKN2A (-9p21.3), PTEN (-10q23.31), MDM2 (+12q15), TP53 (-17p13.1) and BCL2 (+18q21.33). Correlation between DNA copy number and protein immunohistochemistry was confirmed for RGS1, RGS13, FOXP1, PARK2 and BCL2. The microenvironment had high infiltration of M2-like tumour associated macrophages (TAMs) and CD8+ T lymphocytes that associated with higher genomic instability. The DLBCLsn validation set confirmed the clinicopathological characteristics, all FISH loci and immunohistochemistry (IHC) for RGS1. RGS1, one of the most frequently altered genes, was analysed by IHC in DLBCLall and high RGS1 expression associated with non-GCB, EBER+ and unfavourable overall survival (hazard ratio = 1.794; P = 0.016). CONCLUSIONS: DLBCLsn has a characteristic genomic profile. High RGS1 IHC expression associates with poor overall survival in DLBCLall (NOS) .


Assuntos
Cromossomos Humanos Par 1/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas RGS/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Feminino , Dosagem de Genes , Perfilação da Expressão Gênica , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Perda de Heterozigosidade , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Transcriptoma
5.
Clin J Gastroenterol ; 9(5): 289-92, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27590624

RESUMO

A 55-year-old woman experienced gastrointestinal dysfunction caused by scleroderma. An initial endoscopy revealed an erosive lesion in a long segment of Barrett's esophagus, and a biopsy led to a diagnosis of ectopic gastric mucosa. Two years later, an irregular, elevated tumor developed at the same site. This tumor was suspected of having invaded the submucosal layer. A second biopsy led to a diagnosis of adenocarcinoma. The patient subsequently underwent a thoracoscopic esophagectomy. The resected specimen revealed an invasive tumor front that had invaded the deep layer of a duplicated muscularis mucosae. Intraepithelial neoplasia partially surrounded the tumor. This lesion was thought to have developed into an adenocarcinoma according to the orderly sequence of metaplasia, intraepithelial neoplasia and finally adenocarcinoma over a 2-year period. The present case suggests that erosive lesions in Barrett's esophagus should be strictly followed up by endoscopy, even if a biopsy does not reveal any neoplastic findings.


Assuntos
Adenocarcinoma/patologia , Esôfago de Barrett/patologia , Neoplasias Esofágicas/patologia , Lesões Pré-Cancerosas/patologia , Adenocarcinoma/diagnóstico , Biópsia , Progressão da Doença , Neoplasias Esofágicas/diagnóstico , Esofagoscopia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade
6.
Tokai J Exp Clin Med ; 40(3): 104-9, 2015 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-26369263

RESUMO

A 29-year-old female with ulcerative colitis was found to have advanced sigmoid colon cancer on colonoscopy. Computed tomography (CT) was performed after colonoscopy for the evaluation of metastasis. CT colonography (CTC) could be understood adding carbon dioxide because of soon after colonoscopic examination. Images of CTC were evaluated by two- and three-dimensional images including virtual endoscopic, virtual colon dissection and air images, and then compared with conventional endoscopic images. Virtual endoscopic images of flat elevated cancer with shallow ulcer were similar to those findings by conventional endoscopy. This lesion could be depicted by computer-aided detection.


Assuntos
Adenocarcinoma/diagnóstico , Adenocarcinoma/etiologia , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/etiologia , Colonografia Tomográfica Computadorizada/métodos , Neoplasias do Colo Sigmoide/diagnóstico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Colite Ulcerativa/patologia , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Bolsas Cólicas , Colonoscopia , Feminino , Humanos , Invasividade Neoplásica , Proctocolectomia Restauradora/métodos , Neoplasias do Colo Sigmoide/etiologia , Neoplasias do Colo Sigmoide/patologia , Neoplasias do Colo Sigmoide/cirurgia , Interface Usuário-Computador
7.
Mod Pathol ; 28(10): 1286-96, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26226842

RESUMO

Enteropathy-associated T-cell lymphoma (EATL) is a rare primary T-cell lymphoma of the digestive tract. EATL is classified as either Type I, which is frequently associated with and thought to arise from celiac disease and is primarily observed in Northern Europe, and Type II, which occurs de novo and is distributed all over the world with predominance in Asia. The pathogenesis of EATL in Asia is unknown. We aimed to clarify the histological and genomic profiles of EATL in Japan in a homogeneous series of 20 cases. The cases were characterized by immunohistochemistry, high-resolution oligonucleotide microarray, and fluorescence in situ hybridization (FISH) at five different loci: 1q21.3 (CKS1B), 6q16.3 (HACE1), 7p22.3 (MAFK), 9q33.3 (PPP6C), and 9q34.3 (ASS1, CARD9) using formalin-fixed paraffin-embedded sections. The histological appearance of EATL ranged from medium- to large-sized cells in 13 cases (65%), small- to medium-sized cells in five cases (25%), and medium-sized in two cases (10%). The immunophenotype was CD2(+) (60%), CD3ɛ(+) (100%), CD4(+) (10%), CD7(+) (95%), CD8(+) (80%), CD56(+) (85%), TIA-1(+) (100%), Granzyme B(+) (25%), T-cell receptor (TCR)ß(+) (10%), TCRγ(+) (35%), TCRγδ(+) (50%), and double negative for TCR (six cases, 30%). All cases were EBER(-). The genomic profile showed recurrent copy number gains of 1q32.3, 4p15.1, 5q34, 7q34, 8p11.23, 9q22.31, 9q33.2, 9q34.13, and 12p13.31, and losses of 7p14.1. FISH showed 15 patients (75%) with a gain of 9q34.3 with good correlation with array comparative genomic hybridization. EATL in Japan is characterized by non-monomorphic cells with a cytotoxic CD8(+) CD56(+) phenotype similar to EATL Type II. The genomic profile is comparable to EATL of Western countries, with more similarity to Type I (gain of 1q and 5q) rather than Type II (gain of 8q24, including MYC). The 9q34.3 gain was the most frequent change confirmed by FISH irrespective of the cell origin of αß-T-cells and γδ-T-cells.


Assuntos
Linfoma de Células T Associado a Enteropatia/genética , Linfoma de Células T Associado a Enteropatia/patologia , Adulto , Idoso , Hibridização Genômica Comparativa , Linfoma de Células T Associado a Enteropatia/imunologia , Feminino , Genoma Humano , Humanos , Imuno-Histoquímica , Imunofenotipagem , Hibridização in Situ Fluorescente , Japão , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos
8.
J Clin Exp Hematop ; 55(1): 45-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26106007

RESUMO

We report a 16-year-old male with histiocytic sarcoma (HS) originating in the lung. Partial resection of the lung was performed for a 3-cm mass with a clear boundary detected in the right inferior pulmonary lobe on a health checkup. Histologically, the tumor infiltrated into the surrounding tissue, and was comprised of spindle cells, mainly, and foam cells accompanied by mild nuclear atypia. The tumor cells were immunohistochemically positive for CD68 and CD163, indicating histiocytic lineage and the MIB-1-positive rate was low. Spindle cell morphology of HS is quite rare and only 3 cases of pulmonary HS have previously been reported.


Assuntos
Sarcoma Histiocítico/diagnóstico , Neoplasias Pulmonares/diagnóstico , Adolescente , Biomarcadores , Sarcoma Histiocítico/cirurgia , Humanos , Imuno-Histoquímica , Pulmão/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Tomografia Computadorizada por Raios X
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