Purpose: We have recently reported EBV+ B-cell lymphoproliferative disorders (LPD) occurring predominantly in elderly patients, which shared features of EBV+ B-cell neoplasms arising in the immunologically deteriorated patients despite no predisposing immunodeficiency and were named as senile or age-related EBV+ B-cell LPDs.To further characterize this disease, age-related EBV+ B-cell LPDs were compared with EBV-negative diffuse large B-cell lymphomas (DLBCL). Experimental Design: Among 1,792 large B-cell LPD cases, 96 EBV+ cases with available clinical data set were enrolled for the present study. For the control group, 107 patients aged over 40 years with EBV-negative DLBCL were selected.We compared clinicopathologic data between two groups and determined prognostic factors by univariate and multivariate analysis. Results: Patients with age-related EBV+ B-cell LPDs showed a higher age distribution and aggressive clinical features or parameters than EBV-negative DLBCLs: 44% with performance status >1, 58% with serum lactate dehydrogenase level higher than normal, 49% with B symptoms, and higher involvement of skin and lung. Overall survival was thus significantly inferior in age-related EBV+ group than in DLBCLs. Univariate and multivariate analyses further identified two factors, B symptoms and age older than 70 years, independently predictive for survival. A prognostic model using these two variables well defined three risk groups: low risk (no adverse factors), intermediate risk (one factor), and high risk (two factors). Conclusions: These findings suggest that age-related EBV+ B-cell LPDs constitute a distinct group, and innovative therapeutic strategies such as EBV-targeted T-cell therapy should be developed for this uncommon disease.
De novo CD5 ؉ diffuse large B-cell lymphoma (CD5 ؉ DLBCL) is known to have phenotypically and genotypically different characteristics than CD5 ؊ DLBCL and mantle cell lymphoma (MCL). To further characterize CD5 ؉ DLBCL, 109 patients with CD5 ؉ DLBCL were reviewed, and the results were compared with those of 384 CD5 ؊ DLBCL and 128 cyclin D1 ؉ MCL patients. Patients with CD5 ؉ DLBCL showed a higher age distribution (median, 66 years; P ؍ .0083) and a female predominance (male-female ratio, 49:60, P ؍ .011) compared with those with CD5 ؊ DLBCL. CD5 ؉ DLBCL was more closely associated with many aggressive clinical features or parameters than CD5 ؊ DLBCL: 69% older than 60 years (P ؍ .039), 34% with performance status greater than 1 (P ؍ .0016), 69% with serum lactate dehydrogenase level higher than normal (P < .0001), 62% with stage III/IV disease at diagnosis (P ؍ .0023), 35% with more than one extranodal site (P ؍ .023), and 40% with B symptoms (P ؍ .0031). The overall International Prognostic Index score was thus significantly higher for the patients with CD5 ؉ DLBCL than for those with CD5 ؊ DLBCL (P ؍ .00005). The most frequent site of extranodal involvement was bone marrow (28%), a higher frequency than that for CD5 ؊ DLBCL (P < .0001) but lower than that for cyclin D1 ؉ MCL (P ؍ .0015). Histopathologically, CD5 ؉ DLBCL showed centroblastic morphology except for 3 patients with immunoblastic disease, and interfollicular growth pattern (7%) and intravascular or intrasinusoidal infiltration (19%) were observed. Immunophenotypically, CD5 ؉ DLBCL was characterized by a CD5 ؉ CD10 ؊ CD19 ؉ CD20 ؉ CD21 ؊ CD23 ؊ cyclin D1 ؊ phenotype and a predominance of surface IgM. Of particular interest is that CD5 ؉ DLBCL was characterized by a survival curve significantly inferior to that for patients with CD5 ؊ DLBCL (P ؍ .0026). These findings suggest that CD5 ؉ DLBCL may constitute a unique subgroup of DLBCL.
The current prognostic model successfully stratified patients with NK cell neoplasms with different outcomes.
We performed comprehensive genome-wide gene expression profiling (GEP) of extranodal nasal-type natural killer/T-cell lymphoma (NKTL) using formalin-fixed, paraffin-embedded tissue (n = 9) and NK cell lines (n = 5) in comparison with normal NK cells, with the objective of understanding the oncogenic pathways involved in the pathogenesis of NKTL and to identify potential therapeutic targets. Pathway and network analysis of genes differentially expressed between NKTL and normal NK cells revealed significant enrichment for cell cycle-related genes and pathways, such as PLK1, CDK1, and Aurora-A. Furthermore, our results demonstrated a pro-proliferative and anti-apoptotic phenotype in NKTL characterized by activation of Myc and nuclear factor kappa B (NF-κB), and deregulation of p53. In corroboration with GEP findings, a significant percentage of NKTLs (n = 33) overexpressed c-Myc (45.4%), p53 (87.9%), and NF-κB p50 (67.7%) on immunohistochemistry using a tissue microarray containing 33 NKTL samples. Notably, overexpression of survivin was observed in 97% of cases. Based on our findings, we propose a model of NKTL pathogenesis where deregulation of p53 together with activation of Myc and NF-κB, possibly driven by EBV LMP-1, results in the cumulative up-regulation of survivin. Down-regulation of survivin with Terameprocol (EM-1421, a survivin inhibitor) results in reduced cell viability and increased apoptosis in tumour cells, suggesting that targeting survivin may be a potential novel therapeutic strategy in NKTL.
Genetic alteration is considered a probable cause of malignant lymphoma. Folate and methionine metabolism play essential roles in DNA synthesis and DNA methylation, and their metabolic pathways might thus affect disease susceptibility. In the present study, 2 polymorphisms were evaluated for a folate metabolic enzyme, methylenetetrahydrofolate reductase (MTHFR), and one was evaluated for methionine synthase (MS). The 2 polymorphisms, MTHFR677 C3T and MTHFR1298 A3C, are reported to reduce the enzyme activity, which causes intracellular accumulation of 5,10-methylenetetrahydrofolate and results in a reduced incidence of DNA double-strand breakage. The MS2756 A3G polymorphism also reduces the enzyme activity and results in the hypomethylation of DNA. To evaluate the association between malignant lymphoma susceptibility and these polymorphisms, hospitalbased case-control study was conducted in Aichi Cancer Center. Ninety-eight patients with histologically confirmed lymphoma and 243 control subjects without cancer were evaluated. Unconditional logistic regression analyses revealed a higher susceptibility with the MTHFR677 CC and the MTHFR1298 AA genotypes (odds ratio, 2.26; 95% confidence interval, 1.26-4.02) when those harboring at least one variant allele in either polymorphism of MTHFR were defined as the reference. For the MS polymorphism, the MS2756 GG genotype also showed a higher susceptibility (odds ratio, 3.83; 95% CI, 1.21-12.1) than those with MS2756 AA or AG types. The significance was not altered when these 3 polymorphisms were evaluated in combination, and the results suggest that folate and methionine metabolism play important roles in the occurrence of malignant lymphomas. IntroductionBiologic mechanisms underlying the genesis of lymphoid malignancies remain to be clarified in detail. However, accumulated evidence suggests that certain genetic events during cell differentiation, such as chromosomal translocation, 1,2 play an important role. Methylation status of various oncogenes or tumor suppressor genes may induce the selective growth transformation of cells or its inhibition. 3 Regardless, a single genetic event is insufficient to explain carcinogenesis of lymphoid tissue, as supported by the transgenic mouse experiment. 4 Folic acid is an important nutrient required for DNA synthesis, and the related methionine metabolic pathway is necessary for DNA methylation (Figure 1). An antifolic acid agent, methotrexate, has proven to be an effective chemotherapeutic drug for lymphoid malignancies, giving insight into the association between folate metabolism and the carcinogenesis of these malignancies.Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate (methylene THF) to 5-methyltetrahydrofolate (5-methyl THF), 5 the predominant circulatory form of folate and carbon donor for the remethylation of homocysteine to methionine (Figure 1). The MTHFR gene, which is located on chromosome 1p36, 6 is reported to have 2 polymorphisms involving nucleotides 677 (C3T;...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.