RESUMO
Activated B-cell-like diffuse large B-cell lymphomas (ABC-DLBCLs) are characterized by constitutive activation of nuclear factor κB driven by the B-cell receptor (BCR) and Toll-like receptor (TLR) pathways. However, BCR-pathway-targeted therapies have limited impact on DLBCLs. Here we used >1,100 DLBCL patient samples to determine immune and extracellular matrix cues in the lymphoid tumour microenvironment (Ly-TME) and built representative synthetic-hydrogel-based B-cell-lymphoma organoids accordingly. We demonstrate that Ly-TME cellular and biophysical factors amplify the BCR-MYD88-TLR9 multiprotein supercomplex and induce cooperative signalling pathways in ABC-DLBCL cells, which reduce the efficacy of compounds targeting the BCR pathway members Bruton tyrosine kinase and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1). Combinatorial inhibition of multiple aberrant signalling pathways induced higher antitumour efficacy in lymphoid organoids and implanted ABC-DLBCL patient tumours in vivo. Our studies define the complex crosstalk between malignant ABC-DLBCL cells and Ly-TME, and provide rational combinatorial therapies that rescue Ly-TME-mediated attenuation of treatment response to MALT1 inhibitors.
Assuntos
Linfoma Difuso de Grandes Células B , Microambiente Tumoral , Humanos , Linhagem Celular Tumoral , Transdução de Sinais , NF-kappa B/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismoRESUMO
Lymphocyte-rich classic Hodgkin lymphoma (LR-CHL) is a rare subtype of Hodgkin lymphoma. Recent technical advances have allowed for the characterization of specific cross-talk mechanisms between malignant Hodgkin Reed-Sternberg (HRS) cells and different normal immune cells in the tumor microenvironment (TME) of CHL. However, the TME of LR-CHL has not yet been characterized at single-cell resolution. Here, using single-cell RNA sequencing (scRNA-seq), we examined the immune cell profile of 8 cell suspension samples of LR-CHL in comparison to 20 samples of the mixed cellularity (MC, 9 cases) and nodular sclerosis (NS, 11 cases) subtypes of CHL, as well as 5 reactive lymph node controls. We also performed multicolor immunofluorescence (MC-IF) on tissue microarrays from the same patients and an independent validation cohort of 31 pretreatment LR-CHL samples. ScRNA-seq analysis identified a unique CD4+ helper T cell subset in LR-CHL characterized by high expression of Chemokine C-X-C motif ligand 13 (CXCL13) and PD-1. PD-1+CXCL13+ T cells were significantly enriched in LR-CHL compared to other CHL subtypes, and spatial analyses revealed that in 46% of the LR-CHL cases these cells formed rosettes surrounding HRS cells. MC-IF analysis revealed CXCR5+ normal B cells in close proximity to CXCL13+ T cells at significantly higher levels in LR-CHL. Moreover, the abundance of PD-1+CXCL13+ T cells in the TME was significantly associated with shorter progression-free survival in LR-CHL (P = 0.032). Taken together, our findings strongly suggest the pathogenic importance of the CXCL13/CXCR5 axis and PD-1+CXCL13+ T cells as a treatment target in LR-CHL.
Assuntos
Linfócitos B/metabolismo , Quimiocina CXCL13/metabolismo , Doença de Hodgkin/patologia , Receptores CXCR5/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Antígeno B7-H1/metabolismo , Imunofluorescência , Humanos , Linfonodos/citologia , Receptor de Morte Celular Programada 1/metabolismo , RNA-Seq , Células de Reed-Sternberg/patologia , Análise de Célula Única , Microambiente Tumoral/imunologiaRESUMO
Primary mediastinal large B-cell lymphoma (PMBL) is a type of aggressive B-cell lymphoma that typically affects young adults, characterized by presence of a bulky anterior mediastinal mass. Lymphomas with gene expression features of PMBL have been described in nonmediastinal sites, raising questions about how these tumors should be classified. Here, we investigated whether these nonmediastinal lymphomas are indeed PMBLs or instead represent a distinct group within diffuse large B-cell lymphoma (DLBCL). From a cohort of 325 de novo DLBCL cases, we identified tumors from patients without evidence of anterior mediastinal involvement that expressed a PMBL expression signature (nm-PMBLsig+; n = 16; 5%). A majority of these tumors expressed MAL and CD23, proteins typically observed in bona fide PMBL (bf-PMBL). Evaluation of clinical features of nm-PMBLsig+ cases revealed close associations with DLBCL, and a majority displayed a germinal center B cell-like cell of origin (GCB). In contrast to patients with bf-PMBL, patients with nm-PMBLsig+ presented at an older age and did not show pleural disease, and bone/bone marrow involvement was observed in 3 cases. However, although clinically distinct from bf-PMBL, nm-PMBLsig+ tumors resembled bf-PMBL at the molecular level, with upregulation of immune response, JAK-STAT, and NF-κB signatures. Mutational analysis revealed frequent somatic gene mutations in SOCS1, IL4R, ITPKB, and STAT6, as well as CD83 and BIRC3, with the latter genes significantly more frequently affected than in GCB DLBCL or bf-PMBL. Our data establish nm-PMBLsig+ lymphomas as a group within DLBCL with distinct phenotypic and genetic features. These findings may have implications for gene expression- and mutation-based subtyping of aggressive B-cell lymphomas and related targeted therapies.
Assuntos
Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Neoplasias do Mediastino/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/imunologia , Variações do Número de Cópias de DNA/genética , Análise Mutacional de DNA , Feminino , Células HEK293 , Humanos , Evasão da Resposta Imune , Imunofenotipagem , Janus Quinases/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Masculino , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Mutação/genética , Receptores de Interleucina-4/genética , Fatores de Transcrição STAT/metabolismo , Hipermutação Somática de Imunoglobulina/genética , Adulto JovemRESUMO
The mutational landscape of gray zone lymphoma (GZL) has not yet been established, and differences from related entities are largely unknown. Here, we studied coding sequence mutations of 50 Epstein-Barr virus (EBV)-negative GZLs and 20 polymorphic EBV+ diffuse large B-cell lymphoma (DLBCL) not otherwise specified (poly-EBV-L) in comparison with classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), and DLBCL. Exomes of 21 GZL and 7 poly-EBV-L cases, along with paired constitutional DNA, were analyzed as a discovery cohort, followed by targeted sequencing of 217 genes in an extension cohort of 29 GZL and 13 poly-EBV-L cases. GZL cases with thymic niche involvement (anterior mediastinal mass) exhibited a mutation profile closely resembling cHL and PMBCL, with SOCS1 (45%), B2M (45%), TNFAIP3 (35%), GNA13 (35%), LRRN3 (32%), and NFKBIA (29%) being the most recurrently mutated genes. In contrast, GZL cases without thymic niche involvement (n = 18) had a significantly distinct pattern that was enriched in mutations related to apoptosis defects (TP53 [39%], BCL2 [28%], BIRC6 [22%]) and depleted in GNA13, XPO1, or NF-κB signaling pathway mutations (TNFAIP3, NFKBIE, IKBKB, NFKBIA). They also exhibited more BCL2/BCL6 rearrangements compared with thymic GZL. Poly-EBV-L cases presented a distinct mutational profile, including STAT3 mutations and a significantly lower coding mutation load in comparison with EBV- GZL. Our study highlights characteristic mutational patterns in GZL associated with presentation in the thymic niche, suggesting a common cell of origin and disease evolution overlapping with related anterior mediastinal lymphomas.
Assuntos
Doença de Hodgkin/genética , Linfoma Difuso de Grandes Células B/genética , Neoplasias do Mediastino/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Feminino , Doença de Hodgkin/complicações , Humanos , Linfoma Difuso de Grandes Células B/complicações , Masculino , Neoplasias do Mediastino/complicações , Pessoa de Meia-Idade , Timo/metabolismo , Adulto JovemRESUMO
Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct subtype of diffuse large B-cell lymphoma thought to arise from thymic medullary B cells. Gene mutations underlying the molecular pathogenesis of the disease are incompletely characterized. Here, we describe novel somatic IL4R mutations in 15 of 62 primary cases of PMBCL (24.2%) and in all PMBCL-derived cell lines tested. The majority of mutations (11/21; 52%) were hotspot single nucleotide variants in exon 8, leading to an I242N amino acid change in the transmembrane domain. Functional analyses establish this mutation as gain of function leading to constitutive activation of the JAK-STAT pathway and upregulation of downstream cytokine expression profiles and B cell-specific antigens. Moreover, expression of I242N mutant IL4R in a mouse xenotransplantation model conferred growth advantage in vivo. The pattern of concurrent mutations within the JAK-STAT signaling pathway suggests additive/synergistic effects of these gene mutations contributing to lymphomagenesis. Our data establish IL4R mutations as novel driver alterations and provide a strong preclinical rationale for therapeutic targeting of JAK-STAT signaling in PMBCL.
Assuntos
Subunidade alfa de Receptor de Interleucina-4/genética , Janus Quinases/metabolismo , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/metabolismo , Mutação , Fatores de Transcrição STAT/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Camundongos , Fosforilação , Transdução de SinaisRESUMO
Despite receiving rituximab-combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence and understand that the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. In the present study, we show that TRA-1-60-expressing cells are a unique population in FL, converge to the conventional stem cell marker Oct3/4 and ALDH1-positive population, and resist current B-lymphoma agents. TRA-1-60 expression was observed in scattered lymphoma cells in FL tissues only as well as in resting B-lymphocytes inside germinal centers. Retrospective comparison between recurrent and cognate primary tissues showed that the number of TRA-1-60-positive cells from rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP)-treated FL had increased relative to primary tissue, a finding corroborated by assays on different rituximab-treated FL cell lines, FL-18 and DOHH2, wherein TRA-positive cell numbers increased over 10-fold compared to the untreated sample. Concordantly, scanty TRA-1-60-positive FL-18 cells implanted s.c. into mice evinced potent tumor-initiating capacity in vivo, where tumors were 12-fold larger in volume (P = 0.0021 < 0.005) and 13-fold heavier in weight (P = 0.0015 < 0.005) compared to those xenografted from TRA-negative cells. To explain these results, gene expression profiling and qPCR analysis indicated that TRA-1-60-positive cells defined a distinct population from that of TRA-negative cells, with upregulation of multiple drug transporters and therapeutic resistance genes. Hence, TRA-1-60-expressing cells in FL are considered to be vigorously intractable against conventional therapeutic agents, which may explain its refractory recurrence.
Assuntos
Antígenos de Superfície/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma Folicular/tratamento farmacológico , Proteoglicanas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Heterólogo , Carga TumoralRESUMO
Nodal cytotoxic molecule (CM)-positive peripheral T-cell lymphoma (CTL) has recently been recognized as a clinicopathologically distinct disease. To further characterize this disease, here we compared 58 patients with Epstein-Barr virus (EBV)-negative CTL to 48 patients with EBV-positive CTL. The two groups did not differ in histopathology, T-cell receptor (TCR) expression or rearrangement incidences, or survival curves. However, patients with EBV-negative CTL less frequently showed hepatic involvement (P = .007), B symptoms (P = .020), hemophagocytosis (P = .024), and detectable CD4 (P = .002) and CD5 (P = .009). Univariate and multivariate analyses identified three factors that independently predicted favorable survival, onset age <60 years (P = .002), CD5 expression (P = .002), and mixed morphology (P = .013), TCRαß was not an independent predictor (P = .30), but was strongly linked with long survivorship among patients younger than 60 years old. A prognostic model incorporating these factors worked well for prognostic delineation, independently of the International Prognostic Index (P = .007 vs P = .082) and Prognostic Index for PTCL (P = .020 vs P = .15). Moreover, this constellation of findings indicated two nodal indolent diseases: CD5+ TCRαß (n = 13), and CD5+ NK-cell type lacking TCR expression or clonal TCRγ rearrangement (n = 4). The survival curves for these two groups were significantly superior to others (n = 29, P < .001). These diseases appear to be unique in their indolent clinical behavior, and should be managed differently from other diseases.
Assuntos
Antígenos CD5/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Linfoma de Células T Periférico/imunologia , Linfócitos T Citotóxicos/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Células Matadoras Naturais/imunologia , Linfoma Extranodal de Células T-NK/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Adulto JovemRESUMO
Most high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are aggressive B-cell lymphomas. Occasional double-hit follicular lymphomas have been described but the clinicopathological features of these tumors are not well known. To clarify the characteristics of double-hit follicular lymphomas, we analyzed 10 cases of double-hit follicular lymphomas and 15 cases of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements for clinicopathological and genome-wide copy-number alterations and copy-neutral loss-of-heterozygosity profiles. For double-hit follicular lymphomas, the median age was 67.5 years (range: 48-82 years). The female/male ratio was 2.3. Eight patients presented with advanced clinical stage. The median follow-up time was 20 months (range: 1-132 months). At the end of the follow-up, 8 patients were alive, 2 patients were dead including 1 patient with diffuse large B-cell lymphoma transformation. Rearrangements of MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6 were seen in 8, 1, and 1 cases, respectively. The partner of MYC was IGH in 6 cases. There were no cases of histological grade 1, 4 cases of grade 2, 5 cases of grade 3a, and 1 case of grade 3b. Two cases of grade 3a exhibited immunoblast-like morphology. Immunohistochemistry demonstrated 9 cases with ≥50% MYC-positive cells. There was significant difference in MYC intensity (P=0.00004) and MIB-1 positivity (P=0.001) between double-hit follicular lymphomas and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements. The genome profile of double-hit follicular lymphomas was comparable with conventional follicular lymphomas (GSE67385, n=198) with characteristic gains of 2p25.3-p11.1, 7p22.3-q36.3, 12q11-q24.33, and loss of 18q21.32-q23 (P<0.05). In comparison with high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements, double-hit follicular lymphomas had fewer copy-number alterations and minimal common region of gain at 2p16.1 (70%), locus also significant against conventional follicular lymphomas (P=0.0001). In summary, double-hit follicular lymphomas tended to be high-grade histology, high MYC protein expression, high MYC/IGH fusion, and minimal common region of gain at 2p16.1. Double-hit follicular lymphomas seemed to be a different disease from high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements and have an indolent clinical behavior similar to follicular lymphomas without MYC rearrangement.
Assuntos
Rearranjo Gênico , Linfoma de Células B/patologia , Linfoma Folicular/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Linfoma de Células B/genética , Linfoma Folicular/genética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , FenótipoRESUMO
AIMS: Although the neoplastic cells of extranodal natural killer (NK)/T-cell lymphoma (ENKTL) usually do not express T-cell antigens, the T-cell receptor (TCR) gene might be rearranged and TCR protein expressed. The aim is to elucidate the expression of the downstream TCR pathway components and their importance in ENKTL. METHODS AND RESULTS: We used formalin-fixed paraffin-embedded tissues from 91 ENKTL samples to immunohistochemically characterise the expression of TCR pathway components. The following proteins were variably expressed: ZAP70 (94%; 83/88), GRAP2/GADS (68%; 60/88), DOK2 (42%; 38/90), LCK (35%; 31/88), and ITK (10%; 9/90). When these tumours were classified as being of T lineage (16%), NK lineage (45%), or indeterminate lineage (38%), the GRAP2/GADS expression rate was higher in T lineage tumours (versus NK, P = 0.0073; versus indeterminate, P = 0.00082). GRAP2/GADS-positive NK lineage tumours more frequently expressed DOK2 (P = 0.0073), and were more often confined to the nasal areas (P = 0.014). Furthermore, when these tumours were immunophenotypically classified into a T signature (42%) or NK signature (58%), the expression rates of GRAP2/GADS and ITK were higher in T signature tumours (P = 0.00074 and P = 0.067, respectively), whereas that of LCK was higher in NK-signature tumours (P = 0.10). CONCLUSIONS: Although some ENTKL cases were polyclonal for TCR rearrangement and others lacked TCR expression, we speculate that the TCR pathway might be functioning in ENKTLs. A T signature versus a NK signature might be better for delineating the physiology of ENKTL than cellular lineage. Furthermore, ITK may represent a potential therapeutic target for patients with ITK-expressing tumours.
Assuntos
Linfoma Extranodal de Células T-NK/metabolismo , Células T Matadoras Naturais/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Linfoma Extranodal de Células T-NK/patologia , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/patologia , Adulto JovemRESUMO
BACKGROUND AND AIM: Few reports have demonstrated the effectiveness of treatments for intestinal follicular lymphoma (FL) because of the limited number of patients who undergo comprehensive small intestinal examinations. This study compared the efficacy of rituximab-combined chemotherapy in patients with asymptomatic and low tumor burden (LTB) intestinal FL, according to the criteria of the Groupe d'Etude des Lymphomes Folliculaires, with that of a "watch and wait" (W&W) approach. METHODS: The endoscopic examination for entire gastrointestinal tracts was performed in 29 Japanese patients with intestinal FL. These patients had CD21-positive follicular dendritic cells arranged in a duodenal pattern. In a prospective, two-center, open-label trial, this study evaluated the efficacy of rituximab-combined chemotherapy ([cyclophosphamide, doxorubicin, vincristine, and prednisone] or [cyclophosphamide, vincristine, and prednisone]) and prolonged treatment with rituximab (R-Chemo+prolongedR) in 14 patients and compared their outcomes with those of 15 patients managed with a W&W approach. RESULTS: Four patients managed with the W&W plan showed worsening macroscopic findings, lesion area enlargement, or clinical stage progression but stayed on this plan because they had LTB and experienced no changes in bowel function. In the R-Chemo+prolongedR group, all patients achieved complete remission; recurrence occurred in one patient, who was subsequently managed with the W&W plan because of LTB. There were no significant differences in progression-free survival between the two groups (P = 0.1045). Overall survival was 100% in both groups. CONCLUSIONS: The prognoses of patients with asymptomatic intestinal FL and LTB who were managed with a W&W strategy were comparable with those of patients receiving R-Chemo+prolongedR.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Intestinais/terapia , Linfoma Folicular/terapia , Rituximab/administração & dosagem , Conduta Expectante , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Humanos , Neoplasias Intestinais/patologia , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Estudos Prospectivos , Resultado do Tratamento , Carga Tumoral , Vincristina/administração & dosagemRESUMO
The incidence of lymphoma has rapidly increased over the last 40 years in Japan, following a trend that is very similar to that of breast cancer. In particular, the relative frequency of follicular lymphoma (FL) has reached that in Western countries. Given its indolence, a "watch-and-wait" approach is often applied to FL patients. We have shown that FL is often detected in the second portion of the duodenum and has a distinct follicular dendritic cell distribution and heavy chain variable usage similar to mucosa-associated lymphoid tissue (MALT) lymphoma. Although the t(14;18)(q32;q21) frequency is the same as in the nodal subtype of FL, there are also ongoing mutations, immunopositivity for cluster of differentiation 10 and B-cell lymphoma (BCL)6, and overexpression of BCL2. Gene expression profiling has shown that it is more similar to gastric MALT lymphoma than to nodal FL. Duodenal-type FL lacks the activation-induced cytidine deaminase (AID) expression observed in nodal ones, although this may be compensated for by BTB domain and CNC homolog 2. Based on these findings, duodenal-type FL has been included in the Revised 4th edition of the World Health Organization classification published in late 2017.
Assuntos
Neoplasias Duodenais/patologia , Linfoma Folicular/patologia , Neoplasias Duodenais/classificação , Neoplasias Duodenais/genética , Humanos , Japão , Linfoma Folicular/classificação , Linfoma Folicular/genéticaRESUMO
The gastrointestinal (GI) tract is the most commonly involved site of extranodal follicular lymphoma (FL). GI-FL shows very indolent clinical behavior and localized at GI tract without any progression or transformation compared to nodal FL. The most frequently involved site of the GI tract was the duodenum followed by the jejunum and ileum, and only 15% of FL arising in the second part of the duodenum were localized there without scattered very small daughter lesions in other GI tract examined by double-balloon endoscopy. The typical macroscopic appearance of GI-FL was multiple white nodules. Microscopically, neoplastic cells were small- to medium-sized lymphoid cells and formed neoplastic follicles. Most of the cases (>95%) were histologically Grade 1 to 2 (low grade). Several pathological and molecular characteristics were seen in GI-FL (especially duodenal FL) compared with nodal FL: immunoglobulin heavy chain deviation to VH4 and VH5; memory B-cell immunophenotype; and molecular features shared by mucosa-associated lymphoid tissue lymphoma. Considering the pathological and molecular uniqueness of this disease, GI-FL should be separately managed from nodal FL.
Assuntos
Neoplasias Gastrointestinais/patologia , Linfoma Folicular/patologia , HumanosRESUMO
The gastrointestinal (GI) tract is the most frequently involved site of extranodal non-Hodgkin lymphomas, and diffuse large B-cell lymphoma (DLBCL) is the most common subtype occurring in the GI tract. TNFAIP3 (A20) genetic alterations were reported to be involved in DLBCL's pathogenesis and a portion of GI-DLBCL cases harbor this alteration. However, the frequency and clinicopathological relations focusing on small and large intestinal DLBCL are unclear. Here, we examined A20 deletion and protein expression and analyzed the clinicopathological features of 52 cases of primary intestinal DLBCL. The most frequently involved site was the ileocecal region (75%), followed by small bowel (13.5%) and large intestine. Immunohistochemically, the ileocecal cases expressed BCL6 (p=0.027) and MUM1 (p=0.0001) significantly more frequently than the small intestinal cases. Six of 47 cases (13%) had A20 heterozygous deletion, whereas all 6 heterozygously deleted cases had detectable A20 protein expression. In summary, A20 abnormality was less prevalent among intestinal DLBCLs with some discordancy between gene deletion and protein expression. Although the A20 alteration status did not affect any clinicopathological characteristics in this series, further studies exploring alterations of A20 and other NF-κB components in primary intestinal DLBCL are needed.
Assuntos
Neoplasias Gastrointestinais/genética , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Humanos , Linfoma Difuso de Grandes Células B , Masculino , Pessoa de Meia-Idade , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Adulto JovemRESUMO
Pancreatic cancer has a poor prognosis; hence, novel prognostic markers and effective therapeutic targets should be identified. We aimed to evaluate folate receptor alpha (FR-α) expression in pancreatic cancer and examine its association with clinicopathological features. We utilized tissue samples from 100 primary pancreatic cancer patients who underwent surgery. FR-α was expressed in 37 of 100 cases (37%). The FR-α-positive group (median, 18.8 months) had a significantly poorer prognosis than the FR-α-negative group [median 21.3 months; HR 1.89 (1.12-3.12); P = 0.017]. These groups were not significantly different regarding progression-free survival (P = 0.196). Furthermore, other serum tumor markers including CA19-9 (mean, 186 vs. 822 U/ml; P = 0.001), Dupan-2 (286 vs. 1133 U/ml; P = 0.000), and Span-1 (69.7 vs. 171.9 U/ml; P = 0.006) were significantly downregulated in the FR-α-positive group. CA19-9 was another prognostic factor, in addition to FR-α, and patient prognosis showed clear stratification curves with the expression of these two molecules. Along with CA19-9, FR-α expression was an independent prognostic factor for the overall survival. FR-α and CA19-9 helped predict patient prognosis based on stratification curves.
Assuntos
Biomarcadores Tumorais/genética , Receptor 1 de Folato/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/terapia , Idoso , Biomarcadores Tumorais/análise , Antígeno CA-19-9 , Feminino , Receptor 1 de Folato/análise , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Prognóstico , Regulação para CimaRESUMO
Patients with rheumatoid arthritis often develop methotrexate-associated lymphoproliferative disorders (MTX-LPD) during MTX treatment. MTX-LPD occasionally regresses spontaneously after simply discontinuing MTX treatment. In patients without spontaneous regression, additional chemotherapy is required to avoid disease progression. However, the differences between spontaneous and non-spontaneous regression have yet to be elucidated. To clarify the factors important for spontaneous regression, we analyzed the clinicopathological features of 51 patients with rheumatoid arthritis who developed MTX-LPD (diffuse large B-cell lymphoma [DLBCL]-type [n = 34] and classical Hodgkin lymphoma [CHL]-type [n = 17]). We examined the interval from MTX discontinuation to the administration of additional chemotherapy. The majority of DLBCL-type MTX-LPD patients (81%) exhibited remission with MTX discontinuation alone. In contrast, the majority of CHL-type MTX-LPD patients (76%) required additional chemotherapy. This difference was statistically significant (P = 0.001). However, overall survival was not significantly different between DLBCL-type and CHL-type (91% vs 94%, respectively; P > 0.05). Thus, the morphological differences in the pathological findings of MTX-LPD may be a factor for spontaneous or non-spontaneous regression after discontinuation of MTX.
Assuntos
Doença de Hodgkin/induzido quimicamente , Doença de Hodgkin/patologia , Linfoma Difuso de Grandes Células B/induzido quimicamente , Linfoma Difuso de Grandes Células B/patologia , Transtornos Linfoproliferativos/induzido quimicamente , Transtornos Linfoproliferativos/patologia , Metotrexato/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/tratamento farmacológico , Progressão da Doença , Feminino , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-IdadeRESUMO
Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell lymphoma subtype, and the Epstein-Barr virus (EBV)-positive subtype of DLBCL is known to show a more aggressive clinical behavior than the EBV-negative one. BTB and CNC homology 2 (BACH2) has been highlighted as a tumor suppressor in hematopoietic malignancies; however, the role of BACH2 in EBV-positive DLBCL is unclear. In the present study, BACH2 expression and its significance were studied in 23 EBV-positive and 43 EBV-negative patient samples. Immunohistochemistry revealed BACH2 downregulation in EBV-positive cases (P < 0.0001), although biallelic deletion of BACH2 was not detected by FISH. Next, we analyzed the contribution of BACH2 negativity to aggressiveness in EBV-positive B-cell lymphomas using FL-18 (EBV-negative) and FL-18-EB cells (FL-18 sister cell line, EBV-positive). In BACH2-transfected FL-18-EB cells, downregulation of phosphorylated transforming growth factor-ß-activated kinase 1 (pTAK1) and suppression in p65 nuclear fractions were observed by Western blot analysis contrary to non-transfected FL-18-EB cells. In patient samples, pTAK1 expression and significant nuclear p65, p50, and p52 localization were detected immunohistochemically in BACH2-negative DLBCL (P < 0.0001, P = 0.006, and P = 0.001, respectively), suggesting that BACH2 downregulation contributes to constitutive activation of the nuclear factor-κB pathway through TAK1 phosphorylation in BACH2-negative DLBCL (most EBV-positive cases). Although further molecular and pathological studies are warranted to clarify the detailed mechanisms, downregulation of BACH2 may contribute to constitutive activation of the nuclear factor-κB pathway through TAK1 activation.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Regulação para Baixo/fisiologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/patogenicidade , Humanos , Imuno-Histoquímica/métodos , MAP Quinase Quinase Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Fator de Transcrição RelA/metabolismo , Adulto JovemRESUMO
AIMS: The central nervous system (CNS) is a rare primary site of non-Hodgkin lymphoma. Although direct invasion of nasal natural killer (NK)/T cell tumours into CNS is reported occasionally, primary CNS NK/T cell lymphoma is extremely rare, and the clinicopathological features of primary CNS NK/T cell lymphoma remain largely unknown. METHODS AND RESULTS: We identified four cases from our consultation files and analysed the clinicopathological features. Three were immunocompetent and one was immunosuppressed. There were three males and one female and their ages ranged from 21 to 77 years (median: 46 years). Radiotherapy was rendered for all patients, and methotrexate was administered to two patients. The overall survival was 4-29 months (median, 19 months) for the three immunocompetent patients. Neoplastic cells exhibited medium to large atypical nuclei. Angiocentric growth and necrosis were observed. The immunophenotype was typical of NK cell tumours: CD3ε, 100%; CD56, 67%; CD5, 50%; cytotoxic molecules, 100%; Epstein-Barr virus encoded small RNA (EBER), 100% and T cell receptor (TCR)-ß or γ, 0%. No TCR-gene rearrangements were detected. Reviewing 10 additional cases from the literature and comparing with extranasal NK/T cell lymphoma of the more frequent origins (skin or gastrointestinal tract), primary CNS NK/T cell lymphoma was diagnosed at an earlier stage without B symptoms but exhibited aggressive clinical behaviours. CONCLUSIONS: Although extremely rare, primary CNS NK/T cell lymphoma does occur and should always be included in the differential diagnosis and we should apply relevant markers routinely in conjunction with exploring the patient background. The accumulation of cases is indispensable to establish an effective treatment strategy for this rare and aggressive malignancy.
Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Linfoma Extranodal de Células T-NK/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
AIMS: Epstein-Barr virus-positive (EBV+ ) intestinal T/natural killer (NK) cell lymphoma (ITNKL) is an uncommon tumour with an extremely aggressive clinical behaviour. However, the clinicopathological characteristics of this tumour, including T cell receptor (TCR) phenotype and the patient's background, remain unknown. The aim of this study was to elucidate the detailed clinicopathological profile of EBV+ ITNKL. METHODS AND RESULTS: We enrolled 12 patients with EBV+ ITNKL without nasal involvement into the study. All patients were characterized by involvement of the small intestine with concurrent lesions of the large intestine in two patients. Seven patients (58%) had Lugano stages IIE/IV disease and eight (67%) were categorized as high-intermediate/high-risk according to the Prognostic Index for PTCL (PIT). Three patients (25%) with an age of onset of less than 50 years had chronic active EBV infection (CAEBV). Five CD56-positive patients (42%) had a poorer prognosis than those without CD56 expression (P = 0.008). NK cell-type lymphoma defined by the absence of any TCR expression or clonal TCR-γ rearrangement was found in six patients (50%). Interestingly, EBV+ intra-epithelial lymphocytosis was observed in one case with a background of CAEBV. CONCLUSIONS: This study is the first to shed light on the significant heterogeneity of EBV+ ITNKL and its relationship with CAEBV, especially in patients younger than 50 years of age. These observations will provide a guide for diagnostic and therapeutic approaches in routine practice.
Assuntos
Linfoma de Células T Associado a Enteropatia/patologia , Linfoma de Células T Associado a Enteropatia/virologia , Infecções por Vírus Epstein-Barr/complicações , Células T Matadoras Naturais/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfoma de Células T Associado a Enteropatia/mortalidade , Infecções por Vírus Epstein-Barr/epidemiologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-IdadeRESUMO
To evaluate the usefulness of colonoscopy for the detection of ileal involvement in patients with intestinal follicular lymphoma, seventeen patients with intestinal follicular lymphoma who underwent colonoscopy and biopsy sampling from the terminal ileum were enrolled. The patients were divided into 2 groups: cases with ileal involvement (n=6) and cases without ileal involvement (n=11). Patients' clinical backgrounds were compared between the two groups. Subsequently, 10 board-certified endoscopists independently evaluated the endoscopic pictures and determined whether the ileum was involved with follicular lymphoma. Infiltration of follicular lymphoma cells were identified in 6 patients (35.3%). Cases with positive ileal involvement were diagnosed with follicular lymphoma at a younger age than were cases without ileal involvement (55.4±7.4 vs. 68.1±10.3 years, p=0.011). Macroscopically, in patients with ileal involvement, there were multiple polypoid elevations smaller than 5 mm in 4 cases, single polypoid elevation smaller than 5 mm in 1 case, and single polypoid elevation larger than 5 mm in 1 case. In patients without ileal involvement, there were no lesions in the terminal ileum in 7 cases, and multiple polypoid elevations smaller than 5 mm were seen in 4 cases. The accuracy of the macroscopic evaluation by 10 board-certified endoscopists was 68.8%. Colonoscopy is particularly recommended during the initial workup of patients with follicular lymphoma diagnosed at age ≤ 60 years. The diagnosis of ileal involvement based on morphology alone is difficult; thus, biopsy and pathologic diagnosis are required for accurate diagnosis.
Assuntos
Colonoscopia/normas , Íleo/patologia , Neoplasias Intestinais/patologia , Linfoma Folicular/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Follicular lymphoma (FL) shows co-expression of B-cell lymphoma 2 (BCL2) and CD10, whereas downexpression of CD10 is occasionally experienced in gastrointestinal (GI) FL with unknown significance. Gastrointestinal FL is a rare variant of FL, and its similarity with mucosa-associated lymphoid tissue lymphoma was reported. We investigated the clinicopathological and genetic features of CD10 downexpressed (CD10down ) GI-FL. The diagnosis of CD10down FL was carried out with a combination of pathological and molecular analyses. The incidence of CD10down GI-FL was shown in 35/172 (20.3%) cases, which was more frequent than nodal FL (3.5%, P < 0.001). The difference was additionally significant between GI-FL and nodal FL when the analysis was confined to primary GI-FL (55.2% vs 3.5%, P < 0.001). Compared to CD10+ GI-FL, CD10down GI-FL significantly involved the stomach or large intestine (P = 0.015), and additionally showed the downexpression of BCL6 (P < 0.001). The follicular dendritic cell meshwork often showed a duodenal pattern in the CD10down group (P = 0.12). Furthermore, a lymphoepithelial lesion was observed in 5/12 (40%) gastric FL cases, which indicated caution in the differentiation of mucosa-associated lymphoid tissue lymphoma. Molecular analyses were undertaken in seven cases of CD10down GI-FL, and an identical clone was found between CD10down follicles and CD10+ BCL2+ neoplastic follicles. In the diagnosis of cases with CD10down BCL2+ follicles, careful examination with molecular studies should be carried out.