Germinal-center type B-cell classification and clinical characteristics of Chinese pediatric diffuse large B-cell lymphoma:a report of 76 cases

Pediatric diffuse large B-cell lymphoma （DLBCL） is a highly aggressive disease with unique clinical characteristics. This study analyzed the germinal-center type B-cell （GCB） classification and clinical characteristics of Chinese pediatric DLBCL. A total of 76 patients with DLBCL newly diagnosed in Sun Yat- sen University Cancer Center between February 2000 and May 2011, with an age younger than 18 years, were included in the analysis. The male/female ratio was 3.47：1. The median age was 12 years （range, 2 to 18 years）, and 47 （61.8%） patients were at least 10 years old. Of the 76 patients, 48 （63.2%） had stage Ill/IV disease, 9 （11.8%） had bone marrow involvement, 1 （1.3%） had central nervous system （CNS） involvement, and 5 （6.6%） had bone involvement. The GCB classification was assessed in 45 patients： 26 （57.8%） were classified as GCB subtype, and 19 （42.2%） were classified as non-GCB subtype. The modified B-NHL-BFM-90/95 regimen was administered to 50 patients, and the 4-year event-free survival （EFS） rate was 85.8%. Among these 50 patients, 31 were assessed for the GCB classification： 17 （54.8%） were classified as GCB subtype, with a 4-year EFS rate of 88.2%; 14 （45.2%） were classified as non-GCB subtype, with a 4-year EFS rate of 92.9%. Our data indicate that bone marrow involvement and stage III/ IV disease are common in Chinese pediatric DLBCL patients, whereas the percentage of patients with the GCB subtype is similar to that of patients with the non-GCB subtype. The modified B-NHL-BFM-90/95 protocol is an active and effective treatment protocol for Chinese pediatric patients with DLBCL.     

Immunophenotype and intermediate‐high international prognostic index score are prognostic factors for therapy in diffuse large B‐cell lymphoma patients

BACKGROUND.

The development of gene expression profiling and tissue microarray techniques have provided more information about the heterogeneity of diffuse large B‐cell lymphoma (DLBCL), enabling categorization of DLBCL patients into 3 prognostic groups according to cell origin (but independently from the International Prognostic Index [IPI] score): germinal center (GCB), activated B‐cell (ABC), and not classified (NC) diffuse large B‐cell lymphoma. This study investigated the role of immunohistochemical discrimination between GCB and ABC&NC‐DLBCL subtypes in identifying those high‐risk patients who may benefit from a more aggressive first‐line therapeutic approach.

METHODS.

From February 2003 to August 2006, 45 newly diagnosed DLBCL patients, with IPI≥2, were considered eligible for this study: 13 had a GCB, 8 an ABC, and 24 a NC‐DLBCL. GCB patients received 6 courses of rituximab, cyclophophosphamide, doxorubicin, vinicristine, and prednisone (R‐CHOP) chemotherapy, with a subsequent, autologous stem cell transplantation in case of partial response. All ABC and NC‐DLBCL patients received 6 R‐CHOP cycles and autologous stem cell transplantation.

RESULTS.

Complete response rate for each treatment arm was 84.6% for GCB and 89.7% for ABC&NC‐DLBCL (P = .50), with a continuous complete response rate of 81.8% and 84.6%, respectively (P = .59). Projected 4‐year overall survival is 100% for GCB and 82% for ABC&NC patients (P = .12). Progression‐free survival is 77% and 79% (P = .7), respectively.

CONCLUSIONS.

The autologous stem cell transplantation consolidation in the ABC&NC‐DLBCL subtypes induced the same rate of complete response (and similar progression‐free survival rate) compared with GCB‐DLBCL. In ABC&NC‐DLBCL patients the authors observed a complete response rate of 89.7% vs. 84.6% in the GCB‐DLBCL subset, without any significant difference in progression‐free survival rate. Cancer 2010. © 2010 American Cancer Society.     

NanoString荧光条形码技术在弥漫大B细胞淋巴瘤分子分型中的临床应用

目的:探讨NanoString荧光条形码技术在弥漫大B细胞淋巴瘤（DLBCL）分子分型中的临床应用,分析细胞起源亚型与患者预后的相关性。方法:收集2014年1月至2019年12月山西省大同市第三人民医院12例及北京大学医学部8例DLBCL患者的肿瘤组织样本,采用Hans模型分为生发中心B细胞（GCB）型1例和非GCB型19例。在mRNA水平利用NanoString技术平台分析样本中15个Lymph2Cx分子分型相关基因的表达水平差异。通过聚类分析对20例DLBCL患者分型,并分析按此分型组间预后的差别。结果:通过NanoString荧光条形码技术对20例DLBCL患者样本进行检测并进行聚类分析后分型显示,11例为类GCB样型,9例为类活化B细胞（ABC）样型;10例类GCB样型按Hans模型为非GCB型。生存分析显示,类GCB样组总生存优于类ABC样型组（ P=0.019）。 结论:NanoString荧光条形码技术可用于DLBCL的细胞起源分型,该分子分型策略可有效预测患者预后。     

bcl-2与NF-κB／p65在弥漫性大B细胞淋巴瘤不同亚型中表达的意义

 目的　探讨bcl-2与NF-κB／p65蛋白在弥漫性大B细胞淋巴瘤（DLBCL）不同亚型中的表达及其意义。方法　用免疫组织化学方法检测DLBCL患者CD10、bcl-6、MUM-1蛋白的表达,以Hans等的分型原则将其划分为GCB和非GCB／ABC亚型,同时标记bcl-2与NF-κB／p65抗体,比较bcl-2与NF-κB／p65蛋白在GCB和ABC亚型中的表达情况并分析二者与DLBCL两种主要亚型生存率的相关性。结果　bcl-2与NF-κB／p65蛋白在DLBCL中的表达率为67.1 %和77.1 %, 二者表达呈正相关;GCB亚型中bcl-2与NF-κB／p65的表达率分别为52.0 %和56.0 %,ABC亚型中bcl-2与NF-κB／p65蛋白的表达率分别为75.6 %和88.9 %,ABC亚型中bcl-2与NF-κB／p65的表达率高于GCB亚型;在GCB亚型中,bcl-2与NF-κB／p65蛋白的表达与总生存率无显著的相关性,而在ABC亚型DLBCL中,bcl-2与NF-κB／p65蛋白的表达与生存率密切相关。结论　仅在ABC亚型DLBCL中,bcl-2与NF-κB／p65蛋白的表达是影响预后的重要不利因素,因此,需在DLBCL亚分型的基础上评估bcl-2与NF-κB／p65蛋白表达的预后意义。     

The GCB subtype of diffuse large B-cell lymphoma is less frequent in Asian countries

Patients with the germinal center B-cell-like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL) have a significantly better survival rate than those with non-GCB DLBCL. Several studies have examined the proportions of GCB and non-GCB subtypes in large series of DLBCL patients, but it remains unclear if these proportions are the same in different countries. We performed an immunohistochemical analysis of the numbers of GCB and non-GCB subtypes in a large number of patients with DLBCL in Japan and compared the results with literature data for other countries. We found that 71 of 248 patients (29%) had the GCB phenotype and 177 patients (71%) had the non-GCB subtype of DLBCL among our patient population. Assessment of data collected from other studies showed that 31% of DLBCL patients (102/330) have the GCB subtype in Asian countries, but 50% (206/416) express GCB phenotypes in Western countries; based on these data, the occurrence of the GCB subtype of DLBCL was significantly less in Asian countries (p<0.001). Since patients with the GCB phenotype of DLBCL have better survival, future studies of DLBCL should recognize the difference in the proportions of GCB and non-GCB subtypes of DLBCL between Asian and Western populations.     

Cerdulatinib,a novel dual SYK/JAK kinase inhibitor,has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma

B-cell receptor (BCR) and JAK/STAT pathways play critical roles in diffuse large B-cell lymphoma (DLBCL). Herein, we investigated the anti-lymphoma activity of cerdulatinib, a novel compound that dually targets SYK and JAK/STAT pathways. On a tissue microarray of 62 primary DLBCL tumors, 58% expressed either phosphorylated SYK or STAT3 or both. SYK and STAT3 are also phosphorylated in a panel of eleven DLBCL cell lines although ABC and GCB subtypes exhibited different JAK/STAT and BCR signaling profiles. In both ABC and GCB cell lines, cerdulatinib induced apoptosis that was associated with caspase-3 and PARP cleavage. The compound also blocked G1/S transition and caused cell cycle arrest, accompanied by inhibition of RB phosphorylation and down-regulation of cyclin E. Phosphorylation of BCR components and STAT3 was sensitive to cerdulatinib in both ABC and GCB cell lines under stimulated conditions. Importantly, JAK/STAT and BCR signaling can be blocked by cerdulatinib in primary GCB and non-GCB DLBCL tumor cells that were accompanied by cell death. Our work provides mechanistic insights into the actions of cerdulatinib, suggesting that the drug has a broad anti-tumor activity in both ABC and GCB DLBCL, at least in part by inhibiting SYK and JAK pathways.     

BCL2 mutations in diffuse large B-cell lymphoma

BCL2 is deregulated in diffuse large B-cell lymphoma (DLBCL) by the t(14;18) translocation, gene amplification and/or nuclear factor-κB signaling. RNA-seq data have recently shown that BCL2 is the most highly mutated gene in germinal center B-cell (GCB) DLBCL. We have sequenced BCL2 in 298 primary DLBCL biopsies, 131 additional non-Hodgkin lymphoma biopsies, 24 DLBCL cell lines and 51 germline DNAs. We found frequent BCL2 mutations in follicular lymphoma (FL) and GCB DLBCL, but low levels of BCL2 mutations in activated B-cell DLBCL, mantle cell lymphoma, small lymphocytic leukemia and peripheral T-cell lymphoma. We found no BCL2 mutations in GC centroblasts. Many mutations were non-synonymous; they were preferentially located in the flexible loop domain, with few in BCL2-homology domains. An elevated transition/transversions ratio supports that the mutations result from somatic hypermutation. BCL2 translocations correlate with, and are likely important in acquisition of, additional BCL2 mutations in GCB DLBCL and FL. DLBCL mutations were not independently associated with survival. Although previous studies of BCL2 mutations in FL have reported mutations to result in pseudo-negative BCL2 protein expression, we find this rare in de-novo DLBCL.     

Hypomagnesemia at the time of autologous stem cell transplantation for patients with diffuse large B-cell lymphoma is associated with an increased risk of failure

Magnesium is an essential element that is involved in critical metabolic pathways. A diet deficient in magnesium is associated with an increased risk of developing cancer. Few studies have reported whether a serum magnesium level below the reference range (RR) is associated with prognosis in patients with diffuse large B cell lymphoma (DLBCL). Using a retrospective approach in DLBCL patients undergoing autologous stem cell transplant (AHSCT), we evaluated the association of hypomagnesemia with survival. Totally, 581 patients eligible for AHSCT with a serum magnesium level during the immediate pre-transplant period were identified and 14.1% (82/581) had hypomagnesemia. Hypomagnesemia was associated with an inferior event-free (EFS) and overall survival (OS) compared to patients with a serum magnesium level within RR; median EFS: 3.9 years (95% CI: 1.63–8.98 years) versus 6.29 years (95% CI: 4.73–8.95 years) with HR 1.63 (95% CI: 1.09–2.43, p = 0.017) for EFS, and median OS: 7.3 years (95% CI: 2.91—upper limit not estimable) versus 9.7 years (95% CI: 6.92–12.3 years) with HR 1.90 (95% CI: 1.22–2.96, p = 0.005) for OS months 0–12, respectively. These findings suggest a potentially actionable prognostic factor for patients with DLBCL undergoing AHSCT.Subject terms: B-cell lymphoma, B-cell lymphoma     

Comparison of the expression and prognostic significance of differentiation markers between diffuse large B-cell lymphoma of central nervous system origin and peripheral nodal origin.

PURPOSE: Whether diffuse large B-cell lymphoma (DLBCL) of primary central nervous system origin (PCNSL) is biologically different from DLBCL of peripheral nodal origin (NL) remains unclear. The purpose of this study was to compare the expression frequencies and prognostic significance of a panel of cell differentiation markers between these two disease entities. EXPERIMENTAL DESIGN: This study included HIV-unrelated patients with PCNSL (n = 51) and NL (n = 72) treated at four hospitals in Taiwan for whom archival tumor tissue was available. Immunohistochemistry for CD10, BCL-6, MUM-1, vs38c, CD138, and BCL-2 was done. CD10, BCL-6, and MUM-1 expression results were used to classify all cases into the germinal center B-cell (GCB) or the non-GCB subgroup. The prognostic significances of clinical and immunophenotypic markers were evaluated. RESULTS: Nuclear MUM-1 expression was significantly higher in PCNSL than in NL (P < 0.001; 84% versus 53%). PCNSL tumors were more frequently classified into the non-GCB subgroup than NL tumors (P = 0.020; 78% versus 62%). For patients with PCNSL, univariate analysis showed that patients with BCL-6 expression had a trend towards longer survival (P = 0.073; median survival, 25.3 versus 7.3 months), and multivariate analysis showed BCL-6 was an independent prognostic factor (P = 0.026). For patients with NL, both of univariate (P = 0.003) and multivariate analyses (P = 0.002) showed that GCB was significantly associated with favorable survival. CONCLUSION: The higher frequency of non-GCB subclassification, which was mainly contributed by nuclear MUM-1 expression in PCNSL implies that it has a more differentiated cellular origin than NL. BCL-6 expression in patients with PCNSL and GCB subgroup in patients with NL were favorable prognostic factors.     

Evaluation of BCL-6, CD10, CD138 and MUM-1 Expression in Diffuse Large B-Cell Lymphoma patients: CD138 is a Marker of Poor Prognosis

The diffuse large B-cell lymphoma (DLBCL) encompasses two major groups of tumors with uneven survivaloutcomes - germinal center B-cell (GCB) and non-germinal center B-cell (non-GCB). In the present study, weinvestigated the expression of GCB markers (BCL-6 and CD10) and non-GCB markers (CD138 and MUM-1) in an effort to evaluate their prognostic value. Paraffin-embedded tumor biopsies of 46 Jordanian DLBCLpatients were analyzed, retrospectively, by immunohistochemistry to investigate the expression of BCL-6, CD10,CD138 and MUM-1. In addition, survival curves were calculated with reference to marker expression, age, sexand nodal involvement. Positive expression of BCL-6, CD10, CD138 and MUM-1 was shown in 78%, 61%,39% and 91% of the cases, respectively, that of BCL-6 being associated with better overall survival (p = 0.02),whereas positive CD138 was linked with poor overall survival (p = 0.01). The expression of CD10 and MUM-1 had no impact on the overall survival. Among the clinical characteristics studied, diagnosis at an early age,nodal involvement and maleness were associated with a higher overall survival for DLBCL patients. Our resultsunderline the importance of BCL-6 as a marker of better prognosis and CD138 as a marker of poor prognosisfor DLBCL patients.     

牛磺酸上调基因1在弥漫性大B细胞淋巴瘤患者中的表达及其与预后的关系

目的:探讨牛磺酸上调基因1（taurine upregulated gene 1, TUG1）在弥漫性大B 细胞淋巴瘤（diffuse large B-cell Lymphoma,DLBCL）患者组织标本中的表达,分析TUG1 表达与DLBCL患者临床特征及其预后的关系。方法：收集108 例2011 年1 月至2016 年12 月在西南医科大学附属第一医院血液科确诊为DLBCL 的初诊患者和同期47 例反应性淋巴结增生（reactive lymphoid hyperplasia,RLH）患者的组织标本,通过qPCR方法检测DLBCL和RLH患者组织标本中TUG1 的表达,采用Chi-Square 检验、Kaplan-Meier 法和单因素及多因素分析法分别分析TUG1 mRNA表达水平与DLBCL患者临床病理特征的关系和影响DLBCL患者生存时间及预后的因素。结果：TUG1 mRNA在DLBCL患者组织中的表达显著高于RLH患者（6.108±0.332 vs 1.231±0.095,P<0.01）,TUG1 mRNA表达与DLBCL患者的疾病分期、肿瘤大小、B细胞症状、IPI 指数、GCB亚型及化疗敏感性显著相关（均P<0.01）,TUG1 表达量、疾病分期及肿瘤大小是影响DLBCL患者总生存时间（overall survival, OS）的因素。TUG1 mRNA表达、疾病分期、IPI 指数和化疗敏感性是影响DLBCL患者预后的因素。结论：TUG1 mRNA在DLBCL组织中高表达,是影响患者预后的独立因素,TUG1有可能成为DLBCL患者新的预后评估标志物和基因治疗DLBCL的潜在靶点。     

Diffuse large B-cell lymphoma: is there a place for autologous hematopoietic stem cell transplant in first remission in the era of chemo-immunotherapy?

Abstract While rituximab-based chemo-immunotherapy has improved response and long-term survival rates in diffuse large B-cell non-Hodgkin lymphoma (DLBCL), relapse and death from recurrent disease is still the eventual outcome in a significant proportion of patients, especially those with high-risk disease. Autologous hematopoietic stem cell transplant (AHSCT) in first remission, which was studied mainly before the advent of rituximab, has lost its appeal due to several small negative trials. However, definitive data do not exist to determine the role of AHSCT in first remission. In this review, we critically evaluate studies investigating AHSCT in DLBCL in first remission. Most available studies have shortcomings that limit the applicability of their findings. AHSCT in first remission may have a role in selected patients with high-risk DLBCL, but a carefully designed prospective study is required to appropriately evaluate this concept.     

Clinicopathologic evaluation of subgroups of diffuse large B cell lymphoma by immunohistochemistry

Diffuse large B cell lymphoma (DLBCL) has become an emerging epidemic in recent years. Striking heterogeneity in its clinical, biological and treatment responses prompted us to identify variation in our study group. The aim was to classify the DLBCL into prognosis-based subgroups according to the WHO classification and to evaluate their relation to clinical parameters (age, gender, anatomic location and B symptoms), as well as bcl 2 and Ki 67 status. Patients and Methods: A cross sectional study was carried out on 42 DLBCL patients, classified histologically and immunophenotypically into germinal center B cell like (GCB) or non-GCB type. Immunohistochemistry (IHC) was performed using antibodies against CD 10, MUM-1 and bcl 6; additionally anti-apoptotic protein bcl 2 and proliferative marker Ki 67 (using cutoff value of 70%) were also assayed by IHC. Results: Of the total 27/42 (64%) were males and 15/42 (36%) females, with a mean age of 44.1±15 years. 15/42 (36%) cases were of GCB type as compared to 27/42 (64%) of non GCB type. Extranodal involvement and B symptoms were seen in 18/27 (66.6%) and 20/27(74%) of the non GCB type, whereas bcl 2 protein expression and Ki 67 proliferative index (PI) <70% were each noted in 22/27 (81.4%). Conclusion: We document an astonishingly high number of non-GCB type DLBCL in our population. It is alarming to see such an aggressive tumor proliferating in our region. Significant association of non-GCB type with extranodal origin, B symptoms and low Ki 67 PI (<70%) is another concern.     

Correlation Between Immunophenotype Classification and Clinicopathological Features in Chinese Patients with Primary Gastric Diffuse Large B-Cell Lymphoma

Recent studies have shown that diffuse large B-cell lymphoma (DLBCL) can be classified into germinal center B-cell–like (GCB) and non-GCB phenotypes by immunohistochemical staining. The aim of this study was to investigate the correlation of immunophenotypic classification with clinicopathological features in Chinese patients with primary gastric DLBCL to further our knowledge of this disease. Seventy-three patients with a histopathological diagnosis of primary gastric DLBCL were studied. Immunohistochemistry was carried out using the EnVision method to detect the expression of CD10, Bcl-6, and MUM1. The clinicopathologic features and follow-up data were analyzed using the Kaplan–Meier method, log-rank test, and χ ² test. Expression of CD10 was observed in 21.9 % (16/73) of patients, Bcl-6 in 72.6 % (53/73), and MUM1 in 74.0 % (54/73). According to these data, 32.9 % (24/73) of the cases belonged to GCB subtype and 67.1 % (49/73) belonged to non-GCB subtype. There was a significant difference in tumor size and local lymph node metastasis between the GCB and non-GCB groups (P?<?0.05). Complications in the GCB group (4.2 %) occurred less frequently than those in the non-GCB group (18.4 %); however, this difference was not significant (P?>?0.05). Survival analysis revealed that patients in the GCB group had an increased 5-year survival rate compared to those in the non-GCB group (58.5 % vs 35.7 %, χ ²?=?3.939, P?<?0.05). The 5-year survival rate of patients undergoing R-CHOP chemotherapy was significantly longer than that of patients in the CHOP group (74.7 % vs 37.5 %, χ ²?=?4.185, P?<?0.05). The immunophenotype classification of primary gastric DLBCL, which is closely related to the tumor size and local lymph nodes metastasis, was found to have prognostic significance.     

p53 、Ki-67 在弥漫性大B 细胞淋巴瘤中的表达及相互关系

 目的 探讨p53和Ki-67在DLBCL免疫类型中的表达及相互关系。方法 采用免疫组化MaxVision法检测p53和Ki-67在DLBCL免疫类型中和反应性增生的淋巴结中的表达。结果 25例GCB中p53的阳性率为16．0％，35例non-GCB中p53的阳性率为45．7％，两者之间P〈0．01；25例GCB中Ki-67高表达4例，35例non-GCB中Ki-67高表达18例，两者之间P〈O．01；p53阳性DL-BCL20例中ki-67高表达12例，p53阴性DLBCL40例中Ki-67高表达10例，两者正相关。结论 p53、Ki-67的表达与DLBCL的免疫类型相关，GCB类型中低表达，non-GCB类型中高表达。     

Prognostic impact of tumor infiltrating FOXP3 positive regulatory T cells in diffuse large B-cell lymphoma at diagnosis.

Tumor-infiltrating immune cells perform a crucial function in host immune reactions against diffuse large B-cell lymphoma (DLBCL). In this study, we have identified a subset of tumor-infiltrating FOXP3-positive regulatory T cells (Tregs) in the initial DLBCL biopsy specimens, and have evaluated their prognostic significance. Ninety six patients with DLBCL were evaluated retrospectively. The pattern of FOXP3 protein expression was evaluated using standard immunohistochemistry in paraffin-embedded tissue samples. Sixty seven of all 96 specimens were stained with antibodies for CD-10, bcl-6 and MUM1 via tissue microarray (TMA) to classify the cases into a germinal center B-cell like (GCB) group and a non-GCB group. The median overall survival (OS) was 28 months. As compared with the others, the patients with higher percentages of FOXP3-positive Tregs on initial tumor biopsy evidenced a significantly longer OS (p = 0.003). Patients classified into the GCB group evidenced a significantly longer OS as compared with the non-GCB group (p = 0.008). When the prognostic factors were evaluated via a multivariate model, the international prognostic index and the percentage of infiltrating FOXP3-positive Tregs in the initial biopsy were identified as independent predictors of OS. In conclusion, the presence of an increased percentage of FOXP3-positive Tregs in DLBCL is predictive of better prognoses.     

Gene expression profiling of diffuse large B-cell lymphoma

Initial gene expression profiling studies of diffuse large B-cell lymphoma (DLBCL) revealed that this single diagnosis actually encompasses two distinct diseases that differ in the expression of hundreds of genes. One subtype, germinal center B-cell-like (GCB) DLBCL, strongly resembles normal germinal center B-cells and has a good prognosis following chemotherapy, whereas activated B-cell-like (ABC) DLBCL resembles mitogenically activated blood B cells and has a poor outcome. An expanded analysis of 274 DLBCL cases confirmed the existence of the GCB and ABC subgroups, but demonstrated that additional subgroups exist. Furthermore, two recurrent oncogenic events in DLBCL, t(14;18) and amplification of the c-rel locus on chromosome 2p, were only observed in GCB DLBCL, whereas constitutive activation of NF-kappaB was seen in ABC DLBCL, showing that the gene expression subgroups represent pathogenetically distinct diseases. Gene expression profiling has also been used to identify individual genes that predict overall survival in DLBCL, the majority coming from gene expression signatures that reflect the cell of origin, proliferation rate, and host immune response to the tumor. A multivariate model including 17 genes representing these biological features divided patients with DLBCL into quartiles with strikingly distinct 5-year survival rates, ranging from 73% to 15%. The use of gene expression profiling should eventually lead to an integration of molecular diagnosis and consequent selection of the most appropriate treatment.     

CDC7 MCM2在弥漫大B细胞淋巴瘤预后和治疗中的作用

弥漫大B细胞淋巴瘤(DLBCL)是最常见的非霍奇金淋巴瘤, 占成人淋巴瘤发病率的30%~40%。由于受预后危险因素和生物学特性的影响, 不同患者的5年生存率差异很大。DLBCL的发病率呈逐年上升趋势, 仅40%~45%的患者可经CHOP方案治愈, 美罗华联合CHOP方案可以显著延长患者的生存期。临床工作中发现IPI评分不能准确预测DLBCL患者的预后, 所以急需找到能反映其生物学行为的特异性分子指标来准确预测患者的预后并指导个体化治疗方案的制定。CDC7是一种丝氨酸/苏氨酸激酶, 最早在酵母中发现, 与DNA复制有关。人CDC7通过磷酸化微小染色体维持蛋白2(MCM2)来启动DNA的复制。许多恶性肿瘤细胞中存在CDC7的高表达, 包括DLBCL。CDC7高表达是DLBCL患者的预后不良因素之一, 可作为DLBCL的特异性预后指标指导患者预后; 靶向抑制CDC7基因通路可以诱导DLBCL细胞的凋亡, 与美罗华联合有协同增效作用。CDC7和MCM2在指导DLBCL的预后及临床治疗方面具有重要的临床意义。CDC7基因通路可以成为治疗DLBCL患者的新的治疗靶点。CDC7抑制剂与美罗华联合可以有效提高难治性DLBCL患者的疗效。      

De Novo CD5+ Diffuse Large B-Cell Lymphoma: Biology,Mechanism, and Treatment Advances

Despite its low frequency in all variants of diffuse large B-cell lymphoma (DLBCL), CD5⁺ DLBCL has gradually gained the attention it deserves, the result of its poorer outcomes compared to DLBCL without the CD5 signature. CD5⁺ DLBCL is classified as activated B-cell–like (ABC)/non–germinal-center B-cell–like (GCB) DLBCL with elusive genetic features, and patients are frequently characterized as being older and female, and as having Eastern Cooperative Oncology Group performance status > 1, high International Prognostic Index score, tendency to develop B symptoms, and advanced-stage disease with high central nervous system relapse and bone marrow involvement rate. The mechanism underlying the poor prognosis in CD5⁺ DLBCL has not been fully explored, and we summarize the reported potential mechanisms, including CD5-mediated B-cell receptor (BCR)-dependent and -independent pathways. The former involves the inhibition of BCR signaling, and the latter involves the BCR-independent overexpression of interleukin 10, Bcl-2 (antiapoptotic B-cell leukemia/lymphoma 2), cyclin D2, and CXCR4 (C-X-C motif chemokine receptor 4). The efficacy of traditional regimen R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is currently not satisfied in CD5⁺ DLBCL. Therapies of larger doses, such as R-DA-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab), R-ACVBP (rituximab plus doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone), R-DA-EPOCH plus central nervous system prophylaxis, can improve the overall survival in CD5⁺ DLBCL patients, while allogeneic hematopoietic stem-cell transplantation still remains controversial as a salvage treatment. In addition, some novel drugs, such as lenalidomide, CXCR4 antagonists, Bruton tyrosine kinase inhibitors, Bcl-2 inhibitors, and immunotherapy, have been reported to have encouraging results and may improve the outcomes of these patients. In the present review, we comprehensively summarize the biology, mechanism, and treatment of CD5⁺ DLBCL.