MALT lymphoma and extranodal diffuse large B-cell lymphoma are targeted by aberrant somatic hypermutation

Recently, a novel mechanism introducing genetic instability, termed aberrant somatic hypermutation (ASHM), has been described in diffuse large B-cell lymphoma. To further investigate whether ASHM also occurs in mucosa-associated lymphoid tissue type (MALT) lymphoma, we studied the mutation profile of PIM1, PAX5, RhoH/TTF, and c-MYC in 17 MALT lymphomas and 17 extranodal diffuse large B-cell lymphomas (DLBCLs) still exhibiting a low-grade MALT lymphoma component (transformed MALT lymphoma). Mutations in one or more genes were detected in 13 (76.5%) of 17 cases of MALT lymphomas and in all of 17 (100%) cases of extranodal DLBCL. A total of 100 sequence variants were found in 30 of 34 cases, 28 in the MALT lymphomas and 72 in extranodal DLBCL. Further, in PIM1 and c-MYC some of the mutations were found to affect coding exons, leading to amino acid exchanges, thus potentially altering gene function. Expression levels of activation-induced cytidine deaminase (AID), an enzyme essential for somatic hypermutation (SHM), was associated with the mutational load. These data indicate that aberrant SHM is associated with extranodal DLBCL and MALT lymphoma, likewise. By mutating regulatory and coding sequences of the targeted genes, ASHM may represent a major contributor to their pathogenesis.     

Hyperfibrinogenemia is a poor prognostic factor in diffuse large B cell lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphomas worldwide. Previous studies indicated that hyperfibrinogenemia was a poor predictor in various tumors. The purpose of our study was to evaluate the prognostic effect of hyperfibrinogenemia in DLBCL. Data of 228 patients, who were diagnosed with DLBCL in our hospital between May 2009 and February 2016, were analyzed retrospectively. The Kaplan-Meier method and Cox regression were performed to find prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Receiver operator characteristic (ROC) curve and the areas under the curve were used to evaluate the predictive accuracy of predictors. Comparison of characters between groups indicated that patients with high National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score (4–8) and advanced stage (III–IV) were more likely to suffer from hyperfibrinogenemia. The Kaplan-Meier method revealed that patients with hyperfibrinogenemia showed inferior PFS (P?<?0.001) and OS (P?<?0.001) than those without hyperfibrinogenemia. Multivariate analysis showed that hyperfibrinogenemia was an independent prognostic factor associated with poor outcomes (HR?=?1.90, 95% CI: 1.15–3.16 for PFS, P?=?0.013; HR?=?2.65, 95% CI: 1.46–4.79 for OS, P?=?0.001). We combined hyperfibrinogenemia and NCCN-IPI to build a new prognostic index (NPI). The NPI was demonstrated to have a superior predictive effect on prognosis (P?=?0.0194 for PFS, P?=?0.0034 for OS). Hyperfibrinogenemia was demonstrated to be able to predict poor outcome in DLBCL, especially for patients with advanced stage and high NCCN-IPI score. Adding hyperfibrinogenemia to NCCN-IPI could significantly improve the predictive effect of NCCN-IPI.     

Immunologic heterogeneity of diffuse large cell lymphoma

The cellular lineage of 57 diffuse large-cell lymphomas (DLCLs) was determined using a panel of monoclonal antibodies directed against lineage-restricted and -associated T, B, and monocyte antigens. The majority (82%) were of B cell lineage as determined by the expression of sig and/or B1, with the remaining 16% being of T cell lineage and 2%, of monocyte-myeloid lineage. By the expression of other B cell- restricted and -associated antigens, two major and two minor subgroups could be identified. These subgroups expressed the following phenotypes: (1) B1+B4+sIG+B2- (51%); (2) B1+B4+sIg+B2+ (29%); (3) B1+B4+sIg-B2+ (10%); and (4) B1+B4-sIg+B2- (10)%. The morphology of transformed lymphocytes, the weak to absent expression of the early B cell antigens B2 and sIgD, and the absence of the late B cell differentiation antigens PCA-1 and PC-1 suggested that these tumors were the neoplastic counterparts of normal B cells at the mid-stages of differentiation. Further support for the notion that B-DLCLs correspond to transformed B lymphocytes was concluded from the observation that B cells could be identified in normal spleen that expressed the cell surface phenotype and morphological appearance of the majority of B- DLCLs.     

Pathogenesis of diffuse large B cell lymphoma

Substantial additional insight has been obtained in the past decade regarding the pathogenesis of diffuse large B cell lymphoma (DLBCL). Distinct subtypes of DLBCL have been defined by gene expression profiling (GEP) and they differ not only in GE profiles but also in the pattern of genetic abnormalities. The ability to correlate corresponding genetic and GEP data markedly facilitates the identification of target genes in regions with copy number abnormalities. Oncogenic pathways are often differentially activated in these different subtypes of DLBCL, suggesting that therapy should be targeted according to these differences. The tumor microenvironment plays a significant role in determining outcome and may be a novel target for therapy. The role of microRNA in lymphomagenesis is increasingly being recognized and mutation of key genes has been demonstrated to drive the activation of the NF-κB pathway and B cell receptor signaling. The pace of discovery will be even more rapid in the near future with the convergence of data from multiple complementary genome-wide studies and technological innovations including the rapid advance in the technology of high-throughput sequencing.     

Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma

Global hypomethylation has been linked to disease progression in several cancers, but has not been reported for Diffuse Large B Cell Lymphoma (DLBCL). This study aimed to assess global methylation in DLBCL and describe its prognostic value. Mean LINE1 methylation, a validated surrogate measure for global methylation, was measured in DNA from 67 tumor biopsies. Additionally, cell‐free circulating DNA (cfDNA) in plasma samples from 74 patients was tested to assess the feasibility of global hypomethylation as a biomarker in liquid biopsies. LINE1 methylation was assessed using a commercially available kit, based on pyrosequencing of PCR amplified bisulfite‐treated DNA. Global hypomethylation was detected in a subset of cases and was associated with poor overall survival in both tumor biopsies (P = .001) and cfDNA (P = .009). It was the strongest risk factor in multivariate analysis in both biopsies (HR: 10.65, CI: 2.03‐55.81, P = .005) and cfDNA (HR: 11.87, CI: 2.80‐50.20, P = .001), outperforming conventional clinical risk factors. Finally, hierarchical cluster analyses were performed for the cfDNA samples using previously published gene‐specific methylation data. This analysis shows that global hypomethylation co‐occurs with other epigenetic abnormalities, including DAPK1 promoter hypermethylation. In conclusion, we have shown that global hypomethylation is strongly associated with poor survival in DLBCL both when present in tumor biopsy DNA and when detected in plasma cfDNA, and has potential for clinical application as a prognostic biomarker.     

Mast cell infiltration is a favourable prognostic factor in diffuse large B-cell lymphoma

Previous studies indicate that the inflammatory response in diffuse large B-cell lymphomas (DLBCL) is important for the clinical outcome. Mast cells are key regulators in this response; we investigated whether the number of tryptase-positive mast cells is correlated with clinical outcome. Patients with many mast cells had a significantly better event-free survival (EFS) compared to those with few mast cells (P < 0.03 in both germinal centre (GC) and non-GC DLBCL. This supports the idea that the infiltration of mast cells is a reflection of the host inflammatory response and is related to a favourable outcome.     

Primary hepatic diffuse large B cell lymphoma: A case report: Primary hepatic diffuse large B cell lymphoma

In this report we describe a rare case of primary hepatic diffuse large B cell lymphoma in a 67-year-old man who presented with abdominal pain, deteriorated liver function, elevated lactate dehydrogenase. He was found to have diffuse nodular intrahepatic space-occupying lesion with normal α-fetoprotein and carcino-embryogenic antigen. The final diagnosis was made by percutaneous biopsy of the liver as the clinical manifestation not consistent with common liver diseases. The patient was treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) without surgical resection with a favorable response. However, serious complication was occurred after 4 cycles of chemotherapy, and the patient finally died of concurrent acute respiratory distress syndrome.     

FOXP1 expression and its clinicopathologic significance in nodal and extranodal diffuse large B-cell lymphoma

The aims of this study were to investigate FOXP1 expression in nodal and extranodal diffuse large B-cell lymphoma (DLBCL) and its association with the subclassification and other clinicopathologic parameters of DLBCL. Expression of FOXP1, CD10, Bcl6, MUM1, and Bcl2 was detected by immunohistochemistry on tissue microarray sections. The Kaplan–Meier method was used to estimate the overall survival of patients, and the log-rank test was used to compare survival differences between groups with different FOXP1 protein expressions. Expression of FOXP1 was detected in 67.4% (95/141) of DLBCLs. FOXP1 expression in non-GCB (67/90, 74.4%) was significantly higher than that in GCB (28/51, 54.9%) (p < 0.05). FOXP1 expression in MUM1-positive cases (62/81, 76.5%) was significantly higher than that in MUM1-negative cases (33/60, 55%) (p < 0.01). FOXP1 expression was positively correlated with Bcl2 (p < 0.05) in non-GCB among nodal DLBCL cases. Among the extranodal group, patients with FOXP1 expression had a significantly inferior OS compared to those with negative FOXP1 expression (p < 0.05), which was not seen in nodal group. In conclusion, FOXP1 expression might be involved in the tumorigenesis of both nodal and extranodal DLBCL. The most striking finding of this study was that FOXP1 expression had an adverse effect on survival of patients with extranodal DLBCL, which indicated that FOXP1 function might be mediated by different mechanisms in nodal and extranodal DLBCLs. FOXP1 might play a role in the pathogenesis of nodal non-GCB DLBCL through the pathways in which Bcl2 was involved, and it might be a second important biomarker for non-GCB.     

Accelerated therapeutic progress in diffuse large B cell lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in the world. Clinically, biologically, and pathologically, DLBCL is a heterogeneous entity with a range of potential outcomes. Immunochemotherapy regimens, consisting of the chimeric monoclonal anti-CD20 antibody rituximab in combination with chemotherapy, have improved the outcomes. Relapsed DLBCL is generally treated with salvage immunochemotherapy followed by high-dose therapy and autologous stem cell transplantation; however, DLBCL is not yet curable in up to a third of patients. The real promise for cure lies in novel agents and their rational combinations. The improved understanding of DLBCL subtypes and gene expression profiling has led to the identification of targeted drugs that may allow for subtype specific therapy. We have summarized the existing data on the prognostic factors and the treatment of DLBCL, including the use of novel agents such as lenalidomide, carfilzomib, and ibrutinib. We also share our thoughts on the direction of future clinical trials.     

Bad-deficient mice develop diffuse large B cell lymphoma

The proapoptotic activity of the "BH3-only" molecule BAD can be differentially regulated by survival factor signaling. Bad-deficient mice lacking both BAD long and BAD short proteins proved viable, and most cell types appeared to develop normally. BAD did not exclusively account for cell death after withdrawal of survival factors, but it was an intermediate for epidermal growth factor- or insulin-like growth factor I-countered apoptosis, consistent with a "sensitizing" BH3-only molecule. Lymphocytes developed normally with no premalignant hyperplasia, but they displayed subtle abnormalities in proliferation and IgG production. Despite the minimal phenotype, Bad-deficient mice progressed, with aging, to diffuse large B cell lymphoma of germinal center origin. Exposure of Bad-null mice to sublethal gamma-irradiation resulted in an increased incidence of pre-T cell and pro-/pre-B cell lymphoblastic leukemia/lymphoma. Thus, proapoptotic BAD suppresses tumorigenesis in the lymphocyte lineage.     

Clinical impact of bulky mass in the patient with primary extranodal diffuse large B cell lymphoma treated with R-CHOP therapy

Although numerous studies about primary extranodal diffuse large B cell lymphoma (DLBCL) were reported sporadically, the literature of clinical value of immunophenotype and bulky diameter in rituximab era is limited. Ninety-six patients with primary extranodal DLBCL receiving R-CHOP therapy were analyzed to evaluate whether immunophenotype and size of bulky disease are significantly important. The International Prognostic Index was still an important prognostic factor for progression-free survival (PFS) and overall survival (OS; p?=?0.003, p?=?0.027). Difference of survival between germinal center (GC) type and non-GC type was not different (PFS: p?=?0.192; OS: p?=?0.197). In two separated groups according to extranodal maximum tumor diameter (EN-MTD) 7.5 cm as cutoff value for survival, the group of EN-MTD ≥7.5 cm had lower PFS and OS than <7.5 cm (PFS: p?=?0.001; OS: p?=?0.008). In four divided subgroups according to EN-MTD combined with immunophenotype, the subgroup of non-GC type with EN-MTD ≥ 7.5 cm had lower PFS and OS compared with the other subgroups (PFS: p?<?0.001; OS: p?=?0.008). Multivariate analysis revealed that non-GC with EN-MTD ≥ 7.5 cm was an independent prognostic parameter (PFS: HR?=?5.407, 95%CI?=?2.378–12.294, p?<?0.001; OS: HR?=?4.136, 95%CI?=?1.721–9.941, p?=?0.002). Bulky primary extranodal DLBCL would be associated with unfavorable outcome especially in non-GC type.     

Low T3 syndrome is a strong prognostic predictor in diffuse large B cell lymphoma

The aim of this study was to evaluate the prognostic effect of low triiodothyronine (T3) syndrome on patients with diffuse large B cell lymphoma (DLBCL ). A hundred and eighty‐eight patients with detailed thyroid hormone levels at diagnosis of DLBCL were enrolled. Low T3 syndrome was defined as a low serum free T3 (FT 3) level with low or normal serum free tetraiodothyronine (FT 4) and thyroid stimulating hormone levels. Multivariate Cox regression analysis was used to screen prognostic factors associated with progression‐free survival (PFS ) and overall survival (OS ). Receiver‐operator characteristic curves and the corresponding areas under the curve were calculated to assess the predictive accuracy of International Prognostic Index (IPI ) and low T3 syndrome. Twenty‐four patients were diagnosed with low T3 syndrome, which was associated with worse PFS and OS in the rituximab era. It was an independent prognostic factor for PFS and OS , especially for those with IPI 0−2, extranodal sites ≤1 and stage III−IV. Synchronously low FT 3 and FT 4 had poorer survival outcome compared to only low FT 3 and adding criterion of low T3 syndrome improved the prognostic capacity of IPI for predicting PFS and OS in DLBCL . Low T3 syndrome was found to be a strong prognostic predictor in DLBCL .     

New developments in the field of diffuse large cell lymphoma

This update will focus on new developments which can impact the understanding and management of patients with DLCL. The latter disorder is mostly derived from B lymphocytes which can be further subdivided into those that originate from the germinal center versus those that arise from non-germinal center areas in the lymph node. The differences between these two types will be discussed. The management of several new entities that relate to DLCL such as 'double hit lymphoma' and so called borderline entities will also be featured. New entities such as breast implant associated anaplastic large cell lymphoma will be described.