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.     

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.     

Pembrolizumab with R-CHOP in previously untreated diffuse large B-cell lymphoma: potential for biomarker driven therapy

Tumor programmed death-ligand 1 (PD-L1) expression in diffuse large B-cell lymphoma (DLBCL) is associated with inferior outcomes. The first-line immunologically-replete setting may be an opportune time for PD-1 inhibition. We evaluated pembrolizumab in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in untreated patients with DLBCL. Eligible patients were age 18 or older, had adequate organ function, and had DLBCL requiring full-course therapy. Patients received pembrolizumab 200 mg/cycle with R-CHOP, primarily to assess toxicity. Response assessment utilized standard criteria, and PD-L1 staining was performed at a validated central laboratory. Among 30 patients, toxicity was comparable to standard R-CHOP but with two grade ≥3 immune related adverse events (rash, pneumonitis). The overall and complete response rate was 90% and 77%. With 25·5 months of median follow-up, 2-year progression-free survival (PFS) is 83%. PD-L1 expression was associated with non-GCB subtype, and improved PFS and survival. Pembrolizumab can safely be added to R-CHOP, and is associated with a high CR rate and 2-year PFS. Improved PFS with PR-CHOP in PD-L1 expressing tumors contradicts historical data in R-CHOP treated patients, supporting evaluation of PD-L1 as a biomarker to identify DLBCL patients who may benefit from this first-line strategy.     

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.     

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     

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。     

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.     

Vitreoretinal lymphoma occurring after systemic chemotherapy for primary conjunctival diffuse large B cell lymphoma: A case report

Introduction:Ocular adnexal lymphoma and vitreoretinal lymphoma are rare forms of non-Hodgkin lymphoma. They are regarded as distinct disease entities due to the differences in molecular mechanism, management, and outcome. We present a rare case of conjunctival diffuse large B cell lymphoma (DLBCL) that developed to vitreoretinal lymphoma after systemic chemotherapy.Patient concerns:A 60-year-old man presented with a left salmon-colored conjunctival mass.Diagnosis:A biopsy was performed, and histopathologic examination showed DLBCL. Immunohistochemical staining was positive for CD20 with increased κ to λ light chain ratio.Interventions:Bone marrow biopsy also revealed DLBCL. Gallium-67 scintigraphy showed abnormal uptake only in the left orbital lesion. Ann Arbor stage was estimated as IV. The patient underwent systemic combination chemotherapy and immunotherapy.Outcomes:Four months after the last course of chemotherapy, primary conjunctival DLBCL relapsed, manifesting vitreous opacity. Diagnostic vitrectomy confirmed a diagnosis of vitreoretinal lymphoma.Lessons:Conjunctival DLBCL and vitreoretinal lymphoma are both DLBCL. After systemic chemotherapy for conjunctival DLBCL, the lymphoma may relapse in intraocular sites as secondary vitreoretinal lymphoma.     

Correlations between BCL6 rearrangement and outcome in patients with diffuse large B-cell lymphoma treated with CHOP or R-CHOP

Background

BCL6 gene rearrangement is the most frequent chromosomal abnormality in diffuse large B-cell lymphoma, a malignancy characterized by genetic heterogeneity and wide variability in clinical outcome. The prognostic significance of BCL6 rearrangement has not been evaluated in the context of rituximab therapy for diffuse large B-cell lymphoma. We analyzed the effect of the BCL6 rearrangement on survival in patients with diffuse large B-cell lymphoma treated with CHOP and CHOP plus rituximab (R-CHOP).

Design and Methods

BCL6 rearrangement status was analyzed by fluorescence in situ hybridization with break-apart probes in 164 patients with diffuse large B-cell lymphoma treated with CHOP (n=65) or R-CHOP (n=99). Cell-of-origin immunophenotype including BCL6 protein expression were determined by immunohistochemistry on a tissue microarray.

Results

BCL6 rearrangement was detected in 19.5% of cases. The presence of the gene rearrangement was associated with a non-germinal center B-cell immunophenotype (P=0.006), and showed no correlation with BCL6 protein expression. A trend toward inferior overall survival was observed in association with the BCL6 rearrangement among patients treated with R-CHOP (P=0.08), but not among patients treated with CHOP (P=0.64). However, BCL6 rearrangement also correlated with a high International Prognostic Index score (P=0.02), and did not demonstrate independent prognostic value by multivariate analysis.

Conclusions

The introduction of rituximab may have altered the prognostic impact of BCL6 gene rearrangement in patients with diffuse large B-cell lymphoma. However, prospective analysis within large randomized clinical trials will be needed to clarify the prognostic significance of this biomarker in the rituximab era.     

Late relapse in patients with diffuse large B-cell lymphoma: impact of rituximab on their incidence and outcome

Diffuse large B-cell lymphoma (DLBCL) constitutes 25–35% of all non-Hodgkin lymphomas in Western countries. Approximately two thirds of the patients can be cured with standard immuno-chemotherapy. Most relapses occur within 1–2 years from diagnosis, however, the occurrence of relapses after 5 years or more has been described. We aimed at defining the incidence and clinical features of late relapses. Data of 1113 DLBCL patients were analysed. Among the 196 patients relapsing after a first complete remission, 36 (18% of relapses and 3% of all DLBCLs) experienced a recurrence more than 5 years from diagnosis. Late relapsing patients, in comparison with those relapsing earlier, showed a more favourable risk profile at presentation: normal lactate dehydrogenase levels (P = 0·002), early Ann Arbor stage (P = 0·006) and low International Prognostic Index (P = 0·003). The risk of late relapse was lowered by the introduction of rituximab as part of the front-line treatment (P < 0·001). Cause-specific survival (CSS) from the time of relapse was significantly better for late relapsing patients compared to those relapsing early: 5-year CSS rates were 53% and 31%, respectively (P = 0·033). A trend toward a better overall survival was also observed, with 5-year rates after relapse of 47% and 25%, respectively (P = 0·054).     

Tissue microarray is inappropriate for analysis of BCL6 expression in diffuse large B-cell lymphoma

OBJECTIVE: In this study, our aim was to investigate how different immunohistochemical techniques may influence the result of BCL6 positivity and categorization in germinal center (GC) and non-GC derived diffuse large B-cell lymphoma (DLBCL), as it has been proposed that classification of DLBCL according to cell-of-origin by immunohistochemistry may be performed as a routine procedure in the diagnostic work-up. However, a number of technical issues need to be solved before introducing this as a standard technique. METHODS: Tumor specimens from 122 patients with de novo stage II-IV disease, adequately treated with anthracycline-containing chemotherapy regimens were collected. Immunohistochemical expression of BCL6, CD10, and MUM-1/IRF4 was examined using a tissue microarray (TMA) technique. BCL6 and CD10 were also evaluated on whole tissue sections. RESULTS: Due to profound tissue heterogeneity, BCL6 showed a wide range of positivity, with a high number of false negative results by TMA (25% positive), compared to 53% on whole tissue sections (WTS). CD10 was more homogeneously expressed, and TMA results corresponded better to WTS. Consequently, the results from categorization into GC and non-GC DLBCL differed considerably by use of the two methods, and resulted in very different outcome in terms of overall survival. CONCLUSION: Immunohistochemical GC-status determined on TMA is not reliable enough to be used for individual treatment decisions in DLBCL, mostly due to difficulties in interpreting BCL6 status.     

Cost-effectiveness of rituximab (MabThera) in diffuse large B-cell lymphoma in The Netherlands

OBJECTIVE: To determine the incremental cost-effectiveness ratio (ICER) of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) vs. CHOP plus rituximab (R-CHOP) in diffuse large B-cell lymphoma (DLBCL) patients in the Netherlands. METHODS: A state transition model was developed to estimate the clinical course, costs and quality of life of patients with stage II, III or IV DLBCL receiving initial treatment with CHOP or R-CHOP to arrive at the ICER. The base year for the cost analysis was 2002 and was performed from the societal perspective. Only direct medical costs were included. The time horizon of the model was 15 yr and both costs and effects were discounted at 4%. Sensitivity analyses were performed to determine the effect of varying base-line assumptions of the model. RESULTS: The incremental gain in quality adjusted life years (QALYs) was 0.88 in both the younger and the older patient groups. The costs were 12 343 higher in the younger group of patients and 15 860 in the older patients. This resulted in an ICER of 13 983 for the younger and 17 933 for the older patients per QALY gained. These results were sensitive to the time horizon of the model, other variations had a marginal impact on the outcome. CONCLUSION: The addition of rituximab to standard therapy for DLBCL results in a gain of 0.88 QALYs. The ICER of 13 983 for younger and 17 933 for older patients per QALY gained should, seen in the light of disease severity, be considered acceptable by most policy makers in priority setting for budget allocation.