B-cell lymphoma associated with haemophagocytic syndrome: a clinical, immunological and cytogenetic study

B-cell lymphoma associated with haemophagocytic syndrome (HPS) is extremely rare in Western countries but has recently been increasingly reported in Asian countries. We describe seven patients with B-cell lymphoma associated with HPS, six males and one female, age range 41-82 years (median 63 years). All patients had fever and splenomegaly, and six of the seven patients had hepatomegaly with no associated lymphadenopathy. The bone marrow showed haemophagocytosis and an infiltration of lymphoma cells. All patients showed increased levels of lactate dehydrogenase, C-reactive protein, ferritin and soluble interleukin-2 receptor. Lymphoma cells were positive for CD19. CD20 and surface immunoglobulin in all patients examined, and positive for CD5 in four of seven patients. Cytogenetic analyses of bone marrow cells showed a complex structural abnormality including chromosome 14q32 in two patients, 19q13 in three patients and deletion of the terminal part of 8p21 in six patients. The prognosis was poor; only two of the seven patients have survived in complete remission with a median survival of 11 months. These data suggested that B-cell lymphoma associated with HPS might constitute a distinct biological and clinical disease entity. Abnormality of chromosome 19q13 and loss of 8p21 might be involved in the pathogenesis of this disease.     

Intravascular lymphoma associated with haemophagocytic syndrome: a very rare entity in western countries

Intravascular lymphoma (IVL) is a rare and aggressive disorder, characterised by frequent cutaneous and neurological involvement and medullary infiltration. In rare cases particularly in Asia, IVL can be associated with haemophagocytic syndrome (IVL-HS). Here, we report the case of a 61-year-old Caucasian female who presented with IVL-HS. Bone marrow biopsy showed haemophagocytic features and medullary localisation of a diffuse large B-cell lymphoma. Liver biopsy showed exclusive sinusoidal infiltration by large B cells. Treatment by polychemotherapy associated with rituximab induced a rapid complete remission. Unfortunately, death occurred as a consequence of septic shock. Early recognition of IVL-HS by performing bone marrow biopsy is critical to start rapidly appropriate treatment. The role of rituximab in the management of IVL-HS remains to be established.     

Specificity of polymerase chain reaction-based clonality analysis of immunoglobulin heavy chain gene rearrangement for the detection of bone marrow infiltrate in B-cell lymphoma-associated haemophagocytic syndrome

As a wide range of disorders underlie haemophagocytic syndrome, a rapid distinction between benign polyclonal and malignant monoclonal lymphoid proliferations is critical. We investigated whether polymerase chain reaction (PCR) amplification of immunoglobulin heavy chain gene rearrangement could efficiently detect clonal B-cell populations in non-diagnostic marrow for B-cell lymphoma-associated haemophagocytic syndrome (B-LAHS). On amplifying two DNA samples per biopsy, no reproducible monoclonal PCR result was found in reactive haemophagocytic marrows. In contrast, four out of nine assessable B-LAHS patients with histomorphologically and immunohistochemically lymphoma-free bone marrow showed a reproducible monoclonal immunoglobulin heavy chain gene rearrangement. At the molecular level, two B-LAHS patients had lymphoma-free marrow as demonstrated by patient-specific PCR, suggesting that haemophagocytic marrow is not always associated with lymphoma involvement. PCR-based demonstration of clonal B-cell populations in marrow would add an extra dimension to B-LAHS diagnosis.     

Transformation of follicular lymphoma to diffuse large B-cell lymphoma proceeds by distinct oncogenic mechanisms

This study was undertaken to further elucidate the biological mechanisms underlying the frequent event of transformation of follicular lymphoma (FL) to diffuse large B-cell lymphoma (t-FL). The gene expression profiles of 20 paired lymph node biopsies, derived from the same patient pre- and post-transformation, were analysed using the Lymphochip cDNA microarray. TP53 mutation analysis was performed and copy number alterations at the c-REL and CDNK2A examined. Immunohistochemistry was performed on an independent panel of paired transformation paraffin-embedded samples. Transformed follicular lymphoma was predominantly of the germinal centre B-like phenotype both at the mRNA and protein level. Despite this homogeneity, transformation proceeded by at least two pathways. One mechanism was characterised by high proliferation, as assessed by the co-ordinately expressed genes of the proliferation signature. This group was associated with the presence of recurrent oncogenic abnormalities. In the remaining cases, proliferation was not increased and transformation proceeded by alternative routes as yet undetermined. Genes involved in cellular proliferation prevailed amongst those that were significantly increased upon transformation and T cell and follicular dendritic-associated genes predominated amongst those that decreased. t-FL is a germinal centre B (GCB)-like malignancy that evolves by two pathways, one that is similar in proliferation rate to the antecedent FL and the other that has a higher proliferation rate and is characterised by the presence of recognised oncogenic abnormalities.     

老年弥漫大B细胞淋巴瘤50例患者的临床特征和预后分析

目的 探讨老年弥漫大B细胞淋巴瘤（DLBCL）患者的临床特征及预后因素。方法 回顾性分析2010年1月至2013年1月,第四军医大学西京医院血液内科收治的50例年龄≥70岁的老年DLBCL患者,收集整理年龄、Ann-Arbor分期、B症状、国际预后指数（IPI）、乳酸脱氢酶（LDH）、β2?微球蛋白、Ki-67等资料进而分析临床特点;采用Kaplan-Meier法进行生存分析,并进行单因素分析评估预后。结果 50例初发老年DLBCL患者中,60%患者为Ⅲ～Ⅳ期,54% IPI评分为3～5分,52%有B症状,75%原发部位为结外。在老年患者中,调整剂量的化疗疗效优于放疗及对症支持治疗。利妥昔单抗联合剂量调整化疗（R-CHOP）组完全缓解（CR）率优于不包括利妥昔单抗的剂量调查化疗（CHOP/COP）组。患者中位生存时间为 8个月,1、2、3年总生存率分别为48.5%、30.8%、11.5%。生存分析发现Ki-67对患者生存有显著的影响,尤其是Ki-67＞80%患者预后差。结论 老年患者以疾病分期晚,易合并其他系统疾病,生存期短为特征,具有更高的DLBCL发病率,Ki-67是一个重要的不良预后指标。R-CHOP方案可明显提高CR率,并且足够疗程的化疗将显著改善超高龄患者的生存期。     

Gain of chromosome 7 marks the progression from indolent to aggressive follicle centre lymphoma and is a common finding in patients with diffuse large B-cell lymphoma: a study by FISH

Gain of chromosome 7 represents one of the most frequent cytogenetic findings in B-cell lymphomas with a follicular growth pattern. We used fluorescence in situ hybridization (FISH) and a probe specifying chromosome 7 on lymph node imprints and/or bone marrow (BM) and peripheral blood (PB) smears from six consecutive patients with follicle centre lymphomas (FCLs) grade I or II (low-grade lymphomas), four patients with FCLs grade III and 11 patients with diffuse large B-cell lymphomas (DLBCLs) (high-grade lymphomas). We found gains of chromosome 7 in 14/18 successfully analysed cases (i.e. 2/6 FCLs grade I–II, 3/3 FLCs grade III and in 9/9 DLBCLs) using lymph node imprints. Moreover, the FISH technique demonstrated gains of chromosome 7 in 1/4 BM and 0/4 PB samples from FCLs grade I–II, in 2/4 BM and 2/4 PB specimens from FCLs grade III and in 4/9 BM and 2/9 PB samples from the DLBCLs. In contrast, morphologically recognizable lymphoma cells were seen in only 1/4 BM and 0/4 PB samples from the FCLs grade III and in 1/11 BM and 1/11 PB samples from the DLBCLs. We conclude that: (i) gain of chromosome 7 marks the progression from indolent to aggressive FCL and would appear to be a common finding in patients with FCLs grade III and in DLBCLs, (ii) clonal lymphoid cells occur frequently in BM and PB in high-grade lymphomas, making traditional staging by cytomorphology uncertain, and (iii) using gains of chromosome 7 as a marker of lymphoma cells, FISH is a useful method to detect minimal residual disease in FCLs grade III and DLBCLs.     

Primary diffuse large B-cell lymphoma of the uterus: A SEER database analysis

Uterine diffuse large B-cell lymphoma (DLBCL) is a rare clinical condition. Most studies for uterine DLBCL are derived from case reports and series. Our main objective was to present a new case while also investigating the demographic, clinical characteristics, and survival of women with primary uterine DLBCL as compared to non-uterine DLBCL using the Surveillance, Epidemiology, and End Results incidence database. We queried the Surveillance, Epidemiology, and End Results database for women aged 18 years or older with a diagnosis of primary DLBCL from 1975 to 2017. The most common site of primary uterine DLBCL is the cervix uteri not otherwise specified, followed by endometrium, uterus not otherwise specified, corpus uteri, myometrium and isthmus uteri. Non-uterine DLBCL cases tend to be older than uterine DLBCL cases. Uterine DLBCL is most common among women aged 40 to 64 years. Patients with uterine DLBCL showed greater survival than non-uterine DLBCL patients, and patients treated in the rituximab era also exhibited a survival benefit. Both the elderly and African American cohorts experienced worse overall survival.     

Recent advances in the understanding and management of diffuse large B-cell lymphoma in children

Diffuse large B-cell lymphomas (DLBCL) are neoplasms of transformed mature B cells, accounting for approximately 10% of non-Hodgkin lymphomas (NHL) of childhood. Increasing evidence indicates that DLBCL are composed of biologically distinct subsets. Clinical features of children with DLBCL differ from those with other NHL entities, e.g. by a lower frequency of bone-marrow and central nervous sytem involvement. Treatment strategies originally designed for Burkitt lymphoma appear to be efficacious for children with DLBCL. However, children with primary mediastinal large B-cell lymphoma may need a more specific treatment approach, given their inferior outcome in recent studies. The addition of the monoclonal anti-CD20 antibody rituximab to standard CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy improved outcome of adults with DLBCL significantly. However, preliminary data suggest differences between DLBCL of children and adults concerning cell of origin, genetic abnormalities and responsiveness to current treatments. Thus, the potential role of monoclonal antibodies in the treatment of children with DLBCL remains to be determined. The availability of new methodological tools, such as gene expression profiling, will greatly enhance our insights into the biology of childhood DLBCL and its similarities and disparities compared to adult DLBCL. Furthermore, these tools may enable a more risk-adapted and rationally targeted subtype-specific therapy in the future.     

De novo CD5-positive diffuse large B-cell lymphoma: clinical characteristics and therapeutic outcome

To determine the clinical significance of CD5 expression in diffuse large B-cell lymphoma (DLBL) without a clinical history of low-grade B-cell lymphoma, we have reviewed the clinical features and therapeutic outcome of 25 patients with de novo CD5-positive DLBL, and compared the results with those of 87 patients with CD5-negative DLBL and 22 patients with mantle cell lymphoma (MCL). The patients with de novo CD5-positive DLBL had clinical characteristics of elderly onset (median age 63, range 37-91), and female predominance (male/female 10/15). 21 (84%) of these patients had extranodal involvement at presentation, with great variation in the sites. In comparison with the patients with CD5-negative DLBL, the treatment outcome for the patients with de novo CD5-positive DLBL was very poor with frequent relapse. The failure-free survival curve was almost identical to that of patients with MCL, showing that standard chemotherapy for DLBL was not effective for most of the patients with de novo CD5-positive DLBL. These findings suggest that de novo CD5-positive DLBL forms a distinct subgroup of DLBL.     

双侧卵巢非霍奇金淋巴瘤弥漫大B细胞型2例

1病历资料例1.女,57岁,以"下腹胀痛、尿频、食欲不振1个月余为主诉"于2008-04-14就诊我院妇产科,拟诊为多发子宫肌瘤。行"经腹全子宫及双附件切除术+病灶切除术"后病理检查诊断双侧卵巢非霍奇金淋巴瘤。住我院血液科,予以CHOP(氟美松10 mg,每日1次静脉滴注,连用     

Role of CD21 antigen in diffuse large B-cell lymphoma and its clinical significance

Recent advances in immunological and molecular technology have prompted proposals to change tumour classification and treatment strategies. Cell surface antigens are now easy to access, and tumour origins and clinical characteristics are now readily identifiable. However, in diffuse large B-cell lymphoma (DLBCL), one of the heterogeneous forms of haematological malignancy, the clinical significance of tumour surface antigens has not been well documented. We analysed the tumour surface antigens of 50 tumours from newly diagnosed DLBCL patients by flow cytometry in accordance with their clinical characteristics and followed the patients for a median 3.7 years. Statistical analysis showed that CD21 expression was significantly negatively associated with mortality in DLBCL (CD21 negative versus positive; relative risk = 2.36, P < 0.05). As a result of these clinical observations, we generated CD21-overexpressed (CD21(+)) lymphoma cell lines after gene transfection and analysed tumour cell growth in vivo in immunocompromised mice. Mice challenged with vector-only transfectants and parental cells as controls died within 50 d. In contrast, mice injected with CD21(+) transfectants exhibited significantly reduced tumour growth and 83% survived long term (versus control groups; P < 0.05). Interestingly, all established CD21(+) transfectants (six clones from different bulks) showed homotypic aggregation during in vitro cell culture, and anti-CD21 antibodies did not block this aggregation. Expression of CD21 is strongly associated with increased survival in DLBCL in vivo. CD21 expression may be indirectly concerned with the expression of additional cell adhesion molecules.     

MicroRNA signatures characterize diffuse large B-cell lymphomas and follicular lymphomas

MicroRNAs (miRNA, miR) are negative regulators of gene expression that play an important role in diverse biological processes such as development, cell growth, apoptosis and haematopoiesis, suggesting their association with cancer. Here we analysed the expression signatures of 157 miRNAs in 58 diffuse large B-cell lymphoma (DLBCL), 46 follicular lymphoma (FL) and seven non-neoplastic lymph nodes (LN). Comparison of the possible combinations of DLBCL-, FL- and LN resulted in specific DLBCL- and FL-signatures, which include miRNAs with previously published function in haematopoiesis ( MIRN150 and MIRN155 ) or tumour development ( MIRN210 , MIRN10A , MIRN17-5P and MIRN145 ). As compared to LN, some miRNAs are differentially regulated in both lymphoma types ( MIRN155 , MIRN210 , MIRN106A , MIRN149 and MIRN139 ). Conversely, some miRNAs show lymphoma-specific aberrant expression, such as MIRN9/9* , MIRN301 , MIRN338 and MIRN213 in FL and MIRN150 , MIRN17-5P , MIRN145 , MIRN328 and others in DLBCL. A classification tree was computed using four miRNAs ( MIRN330 , MIRN17-5P , MIRN106a and MIRN210 ) to correctly identify 98% of all 111 cases that were analysed in this study. Finally, eight miRNAs were found to correlate with event-free and overall survival in DLBCL including known tumour suppressors ( MIRN21 , MIRN127 and MIRN34a ) and oncogenes ( MIRN195 and MIRNLET7G ).