Diffuse large B-cell lymphoma of the breast: a distinct entity?

The management of squamous cell carcinoma arising in the lungis markedly different than squamous cell carcinoma of the skin,cervix, or larynx. Likewise, the optimal management of diffuselarge B-cell lymphoma sometimes varies by the primary site ofinvolvement. Knowledge of the unique clinical behavior of lymphomaarising in certain extranodal sites is necessary. Examples ofthis include the requirement for specialized evaluation andtreatment of diffuse large B-cell lymphoma arising in the eye,brain, and testicle. It has also been questioned whether primarydiffuse large B-cell     

T-cell/histiocyte-rich large B-cell lymphoma: a distinct clinicopathologic entity.

PURPOSE: Although it has proven difficult to delineate diagnostically reproducible and clinically relevant subgroups, the heterogeneity of diffuse large B-cell lymphomas (DLBCL) is widely acknowledged. In 1992, we reported on six cases that suggested that large B-cell lymphoma rich in stromal histiocytes and T cells may be identified as a distinct clinicopathologic entity within DLBCL. PATIENTS AND METHODS: An integrated clinicopathologic study of 40 cases of this DLBCL subtype is presented. RESULTS: Distinguishing a DLBCL rich in histiocytes and reactive T cells, designated T-cell/histiocyte--rich large B-cell lymphoma (THR-BCL), may be justified from a clinical point of view. The disease typically affects middle-aged male patients who usually present with advanced-stage disease that is not adequately managed with current therapeutic strategies. Whereas proliferation fraction and p53 overexpression, in addition to the clinical variables incorporated in the International Prognostic Index (IPI), significantly correlate with response to treatment and survival in a univariate analysis, only the IPI score identifies relevant prognostic THR-BCL subpopulations in a multivariate model. The morphologic and immunophenotypic profile of the neoplastic B cells in THR-BCL suggests that they may originate from a germinal center ancestor. CONCLUSION: THR-BCL constitutes a distinct clinicopathologic entity that is characterized by an aggressive behavior. Experimental therapeutic strategies may be indicated to obtain a more favorable response to treatment in this disease.     

Bronchial infiltration with diffuse large B-cell lymphoma

Non-Hodgkin's lymphoma (NHL) refers to a heterogeneous group of lymphoproliferative diseases with a diversity of clinical courses, including involvement in another organs. NHL frequently involves the thoracic structures, and particularly the mediastinum and lung parenchyma. Several clinical reports have described bronchial-associated lymphoid tissue (BALT) lymphoma as an endobronchial lesion, but endobronchial infiltration with diffuse large B-cell lymphoma is extremely rare. Here, we provide the first report of this condition confirmed by a histopathological study and the presence of an immunoglobulin heavy chain (IgH) gene rearrangement detected by a polymerase chain reaction (PCR).     

微小RNA与弥漫大B细胞淋巴瘤

微小RNA（miRNA）是一类小分子非编码RNA,通过与目标mRNA互补序列结合,在转录水平调控基因的表达。研究发现,包括弥漫大B细胞淋巴瘤在内的不同恶性肿瘤中存在特定的miRNA表达谱。因此,体液、组织标本中miRNA的表达将有望成为评估弥漫大B细胞淋巴瘤的新指标。     

弥漫大B细胞淋巴瘤研究最新进展

弥漫大B细胞淋巴瘤(DLBCL)是成年人发生率最高的淋巴瘤亚型,是一组高度异质性的肿瘤,不同亚型有不同的生物学特征、临床表现及治疗反应,患者预后差别很大,尽管目前的标准治疗R-CHOP方案为基础的免疫化疗使DLBCL治愈率提高,但仍有约40％的患者治疗早期即出现耐药或达到缓解后复发,预后差.本文结合第59届美国血液学会(ASH)年会有关报道,对DLBCL的新分子分型、新靶点药物研发、复发难治患者治疗等的研究进展进行总结.     

Treatment of diffuse large B-cell lymphoma: a risk-based approach

Advances in molecular biology have provided an increased understanding of the heterogeneity of diffuse large B-cell lymphoma, allowing multiple clinical and biologic prognostic factors to be elucidated. Recently, the addition of rituximab to CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) has been adopted as the new standard of care, representing the first major improvement in therapy in 2 decades. Although outcomes have markedly improved, patients with lymphoma that is not cured with this standard first-line therapy continue to pose a difficult challenge. Early identification of patients at high risk would allow alternative treatment strategies to be considered in a risk-based management approach. Accurate risk assessment will require all previously recognized prognostic indicators to be revalidated in the era of immunochemotherapy. Although the International Prognostic Index remains predictive, it no longer distinguishes a subgroup with < 50% chance of survival. Many molecular prognostic markers, such as Bcl-2 and Bcl-6 protein expression, no longer appear predictive of outcome. Early positron emission tomography scanning is a powerful independent predictive tool that will likely be relied on more frequently in the future. Finally, the role of increased dose intensity or dose density will need to be reevaluated for combinations that include rituximab. Alternative treatment strategies and newer therapies will need to be explored in the context of clinical trials.     

原发中枢神经系统小B细胞淋巴瘤合并胃弥漫大B细胞淋巴瘤一例并文献复习

目的:探讨原发中枢神经系统淋巴瘤合并胃弥漫大B细胞淋巴瘤（DLBCL）的临床特征及治疗。方法:回顾分析武汉大学人民医院收治的1例原发中枢神经系统小B细胞淋巴瘤（PCNSL-SBC）合并胃DLBCL患者临床资料及诊疗经过,并复习相关文献。结果:患者初诊为PCNSL-SBC,经手术、大剂量甲氨蝶呤化疗及局部放疗,颅内病变完全缓解并持续22个月。诊断为胃DLBCL时颅内磁共振成像无异常,CHOP（环磷酰胺、长春地辛、吡柔比星、泼尼松）方案化疗4个周期胃部病灶缓解,但颅内病灶出现进展,再予大剂量甲氨蝶呤+大剂量阿糖胞苷化疗4个周期,神经系统症状缓解,颅内病灶缩小,但合并Ⅳ级骨髓抑制且胃部病灶进展,出现多浆膜腔积液,病情迅速恶化。结论:复合型淋巴瘤临床少见,针对一种类型淋巴瘤有效的治疗方案对另一种类型基本无效,由于严重骨髓抑制,患者不能耐受两种方案同时应用。     

State-of-the-art therapeutics: diffuse large B-cell lymphoma.

This article is a review of the improvement in the treatment of patients with diffuse large B-cell lymphoma made during the last 10 years. Patients with diffuse large B-cell lymphoma now have a better outcome with longer survival because of two major developments: (1) increasing the dose of active drugs with shortening the time between cycles, resulting in dose-dense and/or dose-intense regimens; and (2) combining rituximab with chemotherapy. Both strategies were associated with higher response rates, lower relapse rates, longer event-free survival, longer time to progression, and longer overall survival, particularly in patients without adverse prognostic parameters. A combination of dose-dense, dose-intense regimens plus rituximab is currently being tested for poor-risk patients with diffuse large B-cell lymphoma. However, much work has to be done for patients with high-risk lymphoma. It may come with a better definition of genetic abnormalities specifically associated with refractoriness to chemotherapy.     

弥漫大B细胞淋巴瘤治疗进展

弥漫大B细胞淋巴瘤(DLBCL)是最常见的恶性淋巴瘤.虽然R-CHOP标准治疗方案改善了DLBCL患者的整体生存,但高危患者5年总生存率仍<50%.因此DLBCL一直是研究和关注的热点,如新药的联合治疗、以嵌合抗原受体T细胞(CAR-T)和抗体治疗为代表的免疫靶向治疗、如何降低治疗的长期不良反应以及寻找新的预后生物学标志物和分型系统等.文章就第60届美国血液学会年会上DLBCL的最新进展进行概述.     

Conditional survival of patients with diffuse large B-cell lymphoma

BACKGROUND: Prognosis of lymphoma patients is usually estimated at the time of diagnosis and the estimates are guided by the International Prognostic Index (IPI). However, conditional survival estimates are more informative clinically, as they consider those patients only who have already survived a period of time after treatment. Conditional survival data have not been reported for lymphoma patients. METHODS: Conditional survival was estimated for 1209 patients with diffuse large B-cell lymphoma (DLBCL) from the population-based LYFO registry of the Danish Lymphoma Group. The Kaplan-Meier method was used to estimate conditional survival at 0-5 years after diagnosis. RESULTS: The probability of surviving 5 years increases with each year survived for the first 3 years after diagnosis, after which the increase is minimal. The median survival increases from 38 months for all patients to between 108 and 120 months, conditioned on survival for at least 3-5 years. The prognostic capacity of the IPI and the age-adjusted IPI was high at diagnosis, but the significance gradually declined in the first years after diagnosis. Furthermore, the prognostic impact of the individual clinical variables of the IPI was also significant at diagnosis, but 2 years after diagnosis only age had prognostic impact. Multivariate analysis of patients who survived > or = 3 years identified only age as a prognostic factor. CONCLUSION: For patients with DLBCL who have survived more than 1 year after diagnosis, the conditional survival probability provides more accurate prognostic information than the conventional survival rate estimated from the time of diagnosis.     

弥漫性大B细胞淋巴瘤临床病理分析

 目的　探讨弥漫性大 B细胞淋巴瘤（DLBCL）的临床病理特征、免疫表型,以提高对DLBCL的诊断水平。方法　对22例DLBCL患者进行回顾性分析,复习组织形态和临床表现,补充完善所有患者CD20、CD3、CD10、bcl-6、MUM-1、Ki-67免疫表型测定,为与其他肿瘤相鉴别,对精原细胞瘤、间变性大细胞性淋巴瘤、母细胞型套细胞淋巴瘤部分病例检测AE1／3、PLAP、CD30、ALK、CD5和CyclinD1。结果　22 例患者均为原发DLBCL,男性14例,女性8例,年龄21～71岁,平均48岁;13例结内,9例结外。生发中心细胞（CGB）型13 例（结内7例,结外6例）,非CGB（non-CGB）型9例（结内6例,结外3例）,结合临床和组织形态学17例可诊断,再结合免疫组织化学22例均可诊断。结论　DLBCL形态学、免疫表型及临床表现有一定的特征性,三者相结合能较准确诊断。     

Management of relapsed diffuse large B-cell lymphoma

Despite more effective front-line regimens, a substantial portion of patients with diffuse large B-cell lymphoma relapse and require further therapy. Several trials have established the efficacy of autologous stem cell transplantation for relapsed diffuse large B-cell lymphomas, but the benefit has been largely restricted to patients with chemosensitive disease and low-risk features at the time of relapse. In an effort to improve outcomes following an autologous transplant, researchers are exploring several avenues, including improvement of salvage regimens, addition of radioimmunotherapy to preparative regimens, and application of posttransplant treatments to eliminate minimal residual disease. Allogeneic stem cell transplantation also appears promising, but there is much to learn about optimal patient selection and timing. This review outlines the current approach to the management of relapsed diffuse large B-cell lymphoma, with an emphasis on newer peritransplant therapies.     

Treatment of elderly patients with diffuse large B-cell lymphoma

With the implementation of rituximab, tremendous progress has been achieved in the treatment of diffuse large B-cell lymphoma (DLBCL). Nevertheless, the majority of patients with DLBCL are over the age of 65 years and the management of these patients is often suboptimal. Standard chemo-immunotherapy with curative approach should be appropriate for all elderly patients who can tolerate it. Therefore, a careful evaluation of each patient is mandatory prior to treatment allocation. R- CHOP regimen (rituximab, cyclophosphamide doxorubicin, vincristine, prednisolone) remains the standard of care, but special attention has to be paid to rigorous supportive care. Patients not fit enough for R-CHOP are candidates for dose-reduced therapy or other palliative strategies.     

T-cell-rich B-cell lymphoma: a clinicopathologic study of 21 cases and comparison with 43 cases of diffuse large B-cell lymphoma

Clinicopathologic features of 21 patients with T-cell-rich B-cell lymphoma (TCRBCL) were reviewed and compared to 43 patients with diffuse large B-cell lymphoma (DLBCL) to determine if there were distinguishing clinical characteristics and differences in response or survival to CHOP therapy. For the diagnosis of TCRBCL, the current WHO criteria was used. In all of our cases, the majority of cells are non-neoplastic T cells and <10% large neoplastic B cells are present. The initial pathologic diagnosis was nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) in two cases. Patients with TCRBCL were significantly younger (median: 46 years) and had a significantly higher incidence of B symptoms (62%), hepatomegaly (33%) and marrow infiltration (33%) at presentation when compared to DLBCL (P<0.03). The CR rate after treatment was 48% for TCRBCL patients versus 79% for the DLBCL (P<0.003). Although the CR rates in between the two groups are significant, the difference in 3 years survival rates in each CR groups was insignificant (80% versus 77%). The overall survival time in the two groups was 17 months. Event-free survival time in TCRBCL was 12 months, compared with 17 months in the DLBCL (P>0.05). The frequency of patients with TCRBCL achieving CR was 52.6% whereas that of patients with DLBCL was 79% (P<0.003). The TCRBCL 3 years event-free survival 48% and overall survival 64% were 63 and 72% for DLBCL, respectively.     

弥漫大B细胞淋巴瘤两种预后亚型患者的外周血T细胞亚群动态监测

 　目地　检测弥漫大B细胞淋巴瘤（DLBCL）患者两种预后亚型（生发中心型和非生发中心型）不同治疗阶段的T细胞亚群分布,评估患者的T细胞免疫功能状态。方法　采用流式细胞术（FCM）检测34例DLBCL患者发病初、化疗期间、疗程结束后外周血中的CD+3、CD+4、CD+8和CD+4 CD+25 T细胞的分布情况。以16名健康人外周血作为对照。结果　DLBCL两种预后亚型患者化疗前外周血中CD+4 T细胞比例和CD4／CD8比值分别为（32.27±2.00）%和（0.81±0.39）,明显低于正常水平;CD+8 T细胞、CD+4 CD+25 T细胞比例分别为（40.80±6.23）%和（5.68±5.45）%,明显增高。而CD+3 T细胞比例则在整个治疗过程中保持稳定状态,与正常水平比较差异均无统计学意义（均P＞0.05）。化疗3个周期后CD+8 T细胞逐渐减少,而CD+4、CD+4 CD+25 T细胞、CD4／CD8比值则明显上升,至化疗6个周期结束后除了CD+4 CD+25 T细胞仍明显高于正常及化疗前水平外,余各项指标与正常水平比较差异均无统计学意义（均P＞0.05）。至化疗结束3个月后,CD+4 CD+25 T细胞逐渐下降至接近正常,除了化疗前生发中心型CD+3 和CD+8 T细胞比例[分别为（74.83±3.59）%和（40.80±6.23）%]高于非生发中心型[分别为（68.26±3.56）%和（33.76±5.46）%],不同治疗时期DLBCL患者两种预后亚型间各项指标差异均无统计学意义（t值分别为2.039、2.419,P值分别为0.041、0.018）。不同时期DLBCL患者两种预后亚型间各指标差异均无统计学意义（均P＞0.05）。结论　不同基因亚型DLBCL患者不同治疗时期均存在不同程度的细胞免疫受抑,动态监测T细胞亚群的变化可以实时了解患者的T细胞免疫功能状况。     

Venous thromboembolism in patients with diffuse large B-cell lymphoma

We conducted a retrospective record review to determine the frequency of venous thromboembolism (VTE) in patients with diffuse large B-cell lymphoma (DLBCL). All records from 1990 to 2001 of patients with the diagnosis of DLBCL at a tertiary care hospital were reviewed. Those with transformation from low-grade lymphoma, central nervous system lymphoma, HIV-related lymphoma or with incomplete records were excluded. All episodes of symptomatic VTE confirmed by imaging studies that were either present at diagnosis or occurred during initial treatment were identified. VTE occurred in 27 of 211 patients (12.8%). Stage I disease was associated with a low risk, whereas a high international prognostic index score increased risk. Of patients with VTE, thrombosis was present at diagnosis in 37% and occurred during the first chemotherapy cycle in 22% and during the first three cycles in 82%. The median survival of patients with VTE was 1.04 years [95% confidence interval (CI) = 0.75 - 1.33] compared to 5.2 years (95% CI 1.8 - 8.6) for those without VTE (P = 0.038). We conclude that VTE is a frequent complication of DLBCL that occurs particularly at diagnosis and during initial therapy, and it is associated with a worse prognosis.     

Improving outcomes for patients with diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world. Until the mid 1990s the incidence of DLBCL increased in both sexes, across racial categories, and across all age groups except the very young, the etiology of most cases remains unknown. DLBCL is associated with an aggressive natural history, but it can be cured with combination chemotherapy regimens like cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), which has been the mainstay of therapy for several decades. Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy. Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses, and the addition of the monoclonal antibody, rituximab, to CHOP has markedly improved outcomes. Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease.     

弥漫性大B细胞淋巴瘤的治疗选择

弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphpma,DLBCL）是非霍奇金淋巴瘤中最常见的类型,在分子遗传学、免疫表型等方面具有高度异质性,患者临床预后也截然不同。R-CHOP方案为DLBCL标准治疗方案,如何进一步提高DLBCL疗效是近年来的研究热点。2015年美国临床肿瘤学会（ASCO）提出基于细胞起源分型进行R-CHOP+X方案治疗的策略,但这些方案相继失败。基于更加精准的分层方法,筛选出不同DLBCL亚组并进行针对性治疗,是未来DLBCL治疗的方向。此外,抗体-药物偶联物、双特异性抗体和嵌合抗原受体T细胞（chimeric antigen receptor T-cell,CAR-T）等免疫治疗近年来取得突破性进展,为DLBCL患者带来新的希望。本文针对基于精准分层的DLBCL靶向治疗、免疫治疗的最新进展及遗传学检测方法予以综述。      

Rituximab and chemotherapy in diffuse large B-cell lymphoma

Rituximab is an anti-CD20 chimeric monoclonal antibody with activity in nearly all subtypes of B-cell lymphomas. Association of rituximab with chemotherapy (mostly the cyclophosphamide, doxorubicin, vincristine and prednisolone [CHOP] regimen) in diffuse large B-cell lymphoma (DLBCL) represents an extraordinary revolution in the prognosis of DLBCL, and is the new standard of therapy in elderly and young, low-risk patients. Despite the lack of randomized, clinical trials in younger patients with high risk, rituximab is also a standard of care in these patients in clinical practice, at least in North America. The practice is based on observational trials (e.g., the British Columbia Registry) and the missing logic in classifying patients as ‘younger’ or ‘older’: 60 years old or 65 years old. In Europe, trials are ongoing to establish the best treatment for young, high-risk patients. Association of rituximab and chemotherapy deeply modifies prognostic factors defined before the rituximab era.