Primary Diffuse Large B-Cell Lymphoma of the Urinary Bladder: Update on a Rare Disease and Potential Diagnostic Pitfalls

Diffuse large B-cell lymphoma (DLBCL) represents the most frequent type of non-Hodgkin lymphoma. Globally, DLBCL is an aggressive disease, requiring an accurate diagnosis and prompt treatment. The diagnosis is often made on biopsy samples of a nodal mass, however, approximately 40% of DLBCL cases arise at extranodal sites. The most common extranodal site is the gastrointestinal tract, however any extranodal area may be primarily involved. Primary urinary bladder lymphoma represents only 0.2% of extranodal non-Hodgkin lymphomas, whereas secondary involvement of the urinary bladder by a systemic lymphoma is a more common event. Despite being rare, DLBCL is considered to represent the predominant primary urinary bladder lymphoma. The majority of cases reported in the bladder belong to the DLBCL, NOS group, and there are only rare cases of EBV-positive DLBCL, NOS. In this review, we summarize the current knowledge on DLBCL primarily occurring in the urinary bladder, with the aim of increasing clinician and pathologist awareness on this aggressive lymphoma rarely arising in the urinary bladder. Additionally, we focus on those entities which should be taken into consideration in the differential diagnosis, highlighting potential diagnostic pitfalls.     

29例 CD5阳性弥漫大B 细胞淋巴瘤患者的临床预后分析

目的：探讨 CD5阳性弥漫大 B 细胞淋巴瘤的预后影响因素。方法回顾性分析了29例 CD5阳性弥漫大 B 细胞淋巴瘤患者临床资料及随访数据,采用 Kaplan-Meier 法估算患者的生存时间,采用 COX 比例风险模型进行预后影响因素分析。结果29例 CD5阳性弥漫大 B 细胞淋巴瘤患者1、2年无事件生存率分别为483%、255%,中位疾病无进展生存时间为10个月。全组患者1、2、3年总生存率分别为586%、449%、318%,中位总生存时间为19个月。单因素分析结果显示：不同的 Ann Arbor 分期、LDH 水平、IPI评分、结外受累范围、病理分型、利妥昔单抗的使用与否对总生存时间有显著影响（P ＜005）。COX 多因素回归分析结果显示：影响总生存时间的独立预后因素为 Ann Arbor 分期、病理类型及利妥昔单抗的使用与否。结论 CD5表达是 DLBCL 的不良预后因素,病理类型、Ann Arbor 分期及利妥昔单抗的使用是 CD5阳性 DLBCL 影响患者总生存期的独立预后因素。     

Evaluation of Ki-67 as a Prognostic Marker in Diffuse Large B-Cell Lymphoma—A Single-Center Retrospective Cohort Study

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and prognostic information is essential in finding the right treatment. This study evaluated the prognostic significance of Ki-67 in patients with DLBCL. Methods: Patients with DLBCL, treated with first-line R-CHOP, were retrospectively analyzed in groups of high (>70%) and low (≤70%) Ki-67. Parameters of interest were the international prognostic index (IPI), treatment response, progression-free survival (PFS) and overall survival (OS). A chi-squared test or Fisher’s exact test was conducted to analyze categorical variables. Kaplan–Meier and log-rank tests were applied for survival analyses. Finally, a multivariate linear regression analysis was performed, including gender, Ki-67 ≤ 70% or >70%, IPI and presence of B symptoms. Results: Overall, 58 patients were included. No significant association was found between Ki-67 status and IPI (p = 0.148) or treatment response (p = 0.373). Survival in patients with high Ki-67 was significantly inferior with respect to OS (p = 0.047) but not PFS (p = 0.138). Multivariate linear regression, however, yielded only IPI as a risk factor for OS. Conclusion: Future studies with larger patient cohorts are needed in order to elucidate the prognostic role of Ki-67 in patients with DLBCL treated with R-CHOP.     

粘膜相关淋巴瘤和结外弥漫大B细胞淋巴瘤临床病理特征和预后分析

目的:比较粘膜相关淋巴瘤和结外弥漫大B细胞淋巴瘤的临床病理特征和预后,探讨两类淋巴瘤的预后影响因素.方法:94例结外B细胞淋巴瘤(粘膜相关淋巴瘤62例,结外弥漫大B细胞淋巴瘤32例),经诊断复查后,收集其临床病理和随访资料,进行统计学分析.结果:两类淋巴瘤相比较,MALT淋巴瘤发病的中位年龄、临床病理分期、复发率、淋巴结累及率和细胞增殖活性均偏低,5年生存率较高.94例结外B细胞淋巴瘤的生存影响因素分析:肿瘤细胞增殖指数＞20%的患者生存状况较＜20%的患者低,I E期以上患者生存状况较I E期患者差,伴有淋巴结累及的患者生存状况较无累及患者低.结论:粘膜相关淋巴瘤与结外弥漫大B细胞淋巴瘤在发病年龄、细胞增殖水平、临床分期、复发等临床病理特征上有明显差异.肿瘤细胞增殖活性、临床病理分期及淋巴结累及对两种淋巴瘤的生存状况和预后有明显影响.     

Utility of the Geriatric 8 for the Prediction of Therapy-Related Toxicity in Older Adults with Diffuse Large B-Cell Lymphoma

BackgroundThe management of severe adverse events (AEs) is important in safely and effectively providing chemotherapy to older adults with diffuse large B‐cell lymphoma (DLBCL). However, reports on simple and DLBCL‐specific predictive models for treatment‐related toxicity in elderly individuals are scarce. The aim of this study was to examine the usefulness of Geriatric 8 (G8) in predicting treatment‐related severe AEs, nonhematological toxicity, and febrile neutropenia in older adults with DLBCL in real‐world practice.Materials and MethodsWe conducted a multicenter, retrospective study on 398 consecutive patients with DLBCL (aged ≥65 years) who received standard therapy at three centers in Japan (University of Fukui Hospital, the Fukui Prefectural Hospital, and the Japanese Red Cross Fukui Hospital), between 2007 and 2017.ResultMultivariate logistic analysis demonstrated that the G8 score was an independent predictive factor for severe AEs. Moreover, a logistic regression model with restricted cubic spline showed a nonlinear association between the incidence of severe AEs and the G8 score. According to receiver operating characteristic analysis, the most discriminative cutoff value of the G8 for the incidence of severe AEs was 11, with an area under the curve value of 0.670. AEs occurred most often in the first course of chemotherapy and decreased as the course progressed.ConclusionThe G8 score, an easy‐to‐use geriatric assessment tool, can be a useful prediction model of treatment‐related severe AEs during standard therapy in older adults with DLBCL.Implications for PracticeIn older patients with diffuse large B‐cell lymphoma (DLBCL), to accurately predict the risk of severe adverse events (AEs) in advance is essential for safe and effective treatment. This study demonstrated that the Geriatric 8 score, a simple and established geriatric assessment tool, indicated a high predictive ability for occurrence of therapy‐related severe AEs in elderly patients with DLBCL who were treated with standard treatment.     

Diffuse Large B Cell Lymphoma Arising in Patients with Preexisting Hodgkin Lymphoma

The metachronic onset of diffuse large B-cell lymphoma (DLBCL) after classic Hodgkin lymphoma (cHL) is a rare event affecting patients’ outcomes. However, although several studies have investigated the prognostic role of this event, little is known about a hypothetical common origin of the two different neoplastic cells. Aims: To investigate a possible relationship between DLBCL and cHL, in this retrospective study of 269 patients with newly diagnosed cHL treated at Bari University Hospital (Italy) between 2007 and 2020, we analyzed data from 4 patients (3 male and 1 female) with cHL who subsequently developed DLBCL. Methods: Gene expression profile analysis, assessed by NanoString Lymphoma Subtype Assay, was performed to identify the cell of origin in the DLBCL cases, in addition to Hans’s algorithm. Results: Using Hans’s algorithm, all DLBCL cases showed a germinal center-B-Cell subtype. The gene expression profile evaluated by the NanoString Lymphoma Subtype Assay revealed two cases of the GCB molecular subtype, while the others were unclassified. After first-line chemotherapy, 1 patient achieved complete remission, 3 were non-responders (2 died of lymphoma within 6 months, whereas the other achieved complete remission after autologous and allogeneic stem cell transplantation and is still alive). Conclusions: The origin of the second neoplastic cell in patients with DLBCL with a previous history of cHL remains controversial, although the different immunophenotypic characteristics suggest that it may mainly arise de novo in a subject with a possible individual predisposition to develop lymphoid neoplasms.     

Clinical Efficacy and Safety in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Systematic Literature Review

This systematic literature review was designed to assess information on the clinical efficacy and safety of interventions used in the treatment of refractory or relapsed diffuse large B-cell lymphoma (R/R DLBCL) and to perform a meta-analysis if possible. We searched databases (PubMed, EMBASE, and Cochrane Library for articles from 1997 to August 2, 2012 reported in English), conference abstracts, bibliographic reference lists, and the ClinicalTrials.gov database for phase II to IV studies with results. Studies had to report on patients with R/R DLBCL who were not eligible to receive high-dose therapy (HDT) with stem cell transplantation (SCT) (autologous or allogeneic). Mixed-type non-Hodgkin lymphoma (NHL) studies were required to report R/R DLBCL outcomes separately. We identified 55 studies that presented outcomes data separately for patients with R/R DLBCL. Of 7 comparative studies, only 4 were randomized controlled trials (RCTs). In the 2 RCTs with a common regimen, the patient populations differed too greatly to perform a valid meta-analysis. The 48 single-arm studies identified were typically small (n < 50 in most), with 31% reporting median progression-free survival (PFS) or overall survival (OS) specifically for the R/R DLBCL population. In these studies, median OS ranged from 4 to 13 months. The small number of RCTs in R/R DLBCL precludes identifying optimal treatments. Small sample size, infrequent reporting of OS and PFS separated by histologic type, and limited information on patient characteristics also hinder comparison of results. Randomized studies are needed to demonstrate which current therapies have advantages for improving survival and other important clinical outcomes in patients with R/R DLBCL.     

Impact of Cell of Origin on Outcomes After Autologous Hematopoietic Cell Transplant in Diffuse Large B-Cell Lymphoma

Germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) at diagnosis is associated with superior long-term outcomes compared to non-GCB-DLBCL in patients treated with conventional chemo-immunotherapy. Whether cell of origin (COO) by Hans algorithm retains its prognostic significance in patients with (R/R) relapsed/refractory DLBCL undergoing autologous hematopoietic cell transplant (auto-HCT) is not well established. Three hundred and fifty-seven patients underwent auto-HCT between 2005 and 2018. The COO status was determined in 284 patients and these were included in the analysis. One hundred ninety-four patients had GCB-DLBCL while 90 had non-GCB-DLBCL. Median follow up was 1.7 (0-13) years. The GCB-DLBCL was associated with inferior 5-year overall survival at 44% (95%CI, 36-52) versus 64% (95%CI, 54-77) (P = .004) and a higher relapse incidence at 67% (95%CI, 58-74) versus 49% (95%CI, 35-60) (P = .01) in the non-GCB-DLBCL. The difference between GCB and non-GCB-DLBCL remained statistically significant in multivariate analysis. Additionally, response at the time of transplant was an independent prognostic factor. GCB-DLBCL was enriched in double-hit and triple hit phenotype based on available fluorescence in situ hybridization data. These results suggest an enrichment of high-risk genetic rearrangements in R/R GCB-DLBCL resulting in limited efficacy of auto-HCT.     

123例原发韦氏环弥漫大B细胞淋巴瘤临床特征与预后分析

目的 探讨原发韦氏环弥漫大B细胞淋巴瘤（Waldeyer’s ring diffuse large B-cell lymphoma, WR-DLBCL）的临床特征、预后因素及治疗策略。方法 回顾性分析天津医科大学肿瘤医院2006年1月至2014年6月收治的123例初治原发韦氏环DLBCL患者,对其临床特征、治疗方式及生存情况比较分析,Kaplan-Meier法计算3、5年生存率,Log rank检验单因素分析,Cox比例风险模型多因素分析。结果 123例患者中位年龄为56岁（16~80岁）,男72例。Ann Arbor分期：Ⅰ期20例,Ⅱ期63例,Ⅲ期23例,Ⅳ期17例。中位随访54月,3年和5年生存率分别为74.7%和56.3%,早期（Ⅰ/Ⅱ期）患者3年和5年生存率分别为84.2%和69.4%。单因素分析显示：年龄、体质状况、B症状、临床分期、国际预后指数（IPI）、乳酸脱氢酶（LDH）水平、近期疗效是影响预后的主要因素;多因素分析显示：IPI评分和近期疗效为独立预后因素。结论 原发韦氏环DLBCL多为早期,肿瘤负荷较轻,生存率较高,多数可长期生存。IPI评分和近期疗效是独立预后因素。     

Evaluation of BCL6 and MUM1 Expression in Patients with Diffuse Large B cell Lymphoma and their Correlations with Staging and Prognosis in Iran

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkins lymphoma(NHL), accounting for approximately 25% of NHL cases. The aim of this study was to evaluate the associationbetween the BCL6 and MUM1 gene expression and patient prognosis and stage. Materials and Methods: Afterethical approval, in a cross-sectional study, tissue samples of 80 patients with diffuse large B-cell lymphoma wereanalyzed for BCL6 and MUM1 gene expression. Immunohistochemical staining was performed with division intocategories of 0-5%, 5-25%, 26-50%, 51-75% and more than 75%. Other clinical and histological information suchas lymph node involvement, T-stage, B symptoms and patient outcome were also recorded. Data were analyzedwith SPSS version 16 and a P-value less than 0.05 was considered significant. Results: The patient mean agewas 46.9±10.5 years (47.6±10.7 and 46.1±9.6 for males and females, respectively). A significant association wasseen between lymphoma stage and BCL6 (p=0.045) but not MUM1 expression (p=0.09). However, the latterwas associated with mortality (p=0.006) as was also the BCL6 level (p=0.006). Conclusions: : Overexpression ofMUM1 and BCL6 is associated with poor prognosis in patients with diffuse large B-cell lymphoma.     

弥漫性大B细胞淋巴瘤预后相关因素的研究

目的分析弥漫性大B细胞淋巴瘤（DLBCL）患者的病理学特征以及影响其预后的相关因素。方法采用单因素及Cox多因素分析方法,对影响DLBCL预后的相关因素进行分析。结果60例DLBCL患者中共有47例（78．33％）侵犯淋巴结,13例（21．67％）结外侵犯。经单因素分析显示,影响DLBCL患者的预后因素包括年龄、临床分期、PS分级、结外病灶数、血清LDH、近期疗效。经Cox多因素分析显示患者年龄、近期疗效、临床分期是影响患者预后的独立危险因素。根据国际预后指数（IPI）将患者分为低危组、低中危组、高中危组及高危组,各组5年生存率分别为70．59％（12／17）、57．14％（12／21）、41．67％（5／12）、10．00％（1／10）,差异有统计学意义（P〈0．05）。联合治疗DLBCL患者的5年生存率显著高于单纯性放化疗或手术治疗患者。结论影响DLBCL患者预后的独立因素包括年龄、近期疗效、临床分期,采用多种方式联合治疗的方案能提高DLBCL患者临床治愈率。