头颈部弥漫大B细胞淋巴瘤的免疫组织化学分型分析

目的:检测头颈部弥漫大B细胞淋巴瘤的免疫组织化学分型,并对Hans、Choi和Tally三种分型法进行比较,同时观察各蛋白的表达在各种分型法的意义.方法:收集我院2010年5月到2012年10月共103例头颈部弥漫大B细胞淋巴瘤,进行CD10、Bcl-6、MUM1、GCET1、FOXP1和LMO2蛋白表达的免疫组织化学检测,并进行Hans、Choi和Tally三种分型.结果:103例病例中,CD10、Bcl-6、MUM1、GCET1、FOXP1和LMO2的阳性例数分别为16例(15.53％)、68例(66.02％)、69例(66.99％)、21例(20.39％)、75例(72.82％)、50例(48.54％);Hans分型中,生发中心B细胞(GCB)型26例(25.0％),活化B细胞(ABC)型77例(75.0％);Choi分型中,GCB型25例(24.0％),ABC型78例(76.0％);Tally分型中,GCB型20例(19.4％),ABC型83例(80.6％).CD10、MUM1、GCET1、FOXP1和LMO2表达情况对于分型诊断结果均具有统计学意义(P＜0.05),而Bcl-6的表达对于Hans和Choi分型结果无统计学意义.结论:头颈部弥漫大B细胞淋巴瘤以ABC型多见;Hans、Choi和Tally三种分型法之间无明显差别;CD10、MUM1、GCET1、FOXP1和LMO2的表达情况对于诊断结果均具有意义.     

梭形细胞变异型弥漫性大B细胞淋巴瘤1例报道及文献复习

目的：探讨梭形细胞变异型弥漫性大B细胞淋巴瘤的临床病理特征、病变性质及鉴别诊断要点。方法：对1例梭形细胞变异型弥漫性大B细胞淋巴瘤的组织形态特征、免疫组化表型，结合临床预后进行分析。结果：1例23岁女性患者在半年内先后发生结肠肿瘤和乳腺肿瘤。HE切片显示肿瘤细胞弥漫性浸润肠壁和乳腺组织，瘤细胞有异型性和核分裂，并伴有显著的梭形细胞特征。免疫表型显示瘤细胞CD45 ，CD20 ，CD45RO-，CD30-，Vim ，Des-，SMA-，S-100-，CK-，EMA-。患者1年内死于肿瘤。结论：本例梭形细胞变异型大B细胞淋巴瘤是一种罕见的高度恶性肿瘤，在缺乏免疫组化标记的情况下易误诊为肉瘤或低分化癌。     

The Frequency of Double Expresser in Selected Cases of High Grade Diffuse Large B-Cell Lymphomas

Background: Diffuse large B-cell lymphomas (DLBCL) are fast-growing non-Hodgkin lymphomas that affect B-lymphocytes. Double expressor DLBCL is the concomitant expression of Myc and Bcl-2 proteins during lymphomas which results in poor prognosis of patients. This study aimed to determine the frequency of double expresser in high grade diffuse large B-cell lymphomas. Materials and Methods : The study was conducted on 74 cases (54 males (68.4%) and 20 females (25.3%)) of DLBCL between August 2018 to January 2019. The mean age of the 74 patients was 51.7 years + 18.5. Expression of proteins c-Myc, Bcl-2 and Bcl-6 were evaluated by immunohistochemistry. The involvement of primary lymph node was reported in 38 cases (51.3%) whereas, extra nodal site was observed in 22 cases (29.7%). Among the primary sites, the cervical lymph node enlargement was the most frequent site of presentation. Results: The rearrangement pattern was studied among 74 patients, 35 (47%) were found to have either one of the rearrangements i.e. Myc, Bcl-2, or Bcl-6. On the other hand, 14 (18.9%) had shown double rearrangements i.e. Bcl-2 and c-Myc (11 cases) and Bcl-6 and c-Myc (3 cases). The Bcl-2 and Bcl-6 rearrangements were demonstrated by 12 cases whereas 2 cases (2.7%) indicated all three types of rearrangements i.e. c-Myc, Bcl-2, and Bcl-6. In 11 cases the Bcl-2 and c-Myc rearrangements were found to be Bcl-2 > 50% and c-Myc > 40% and demonstrating the overall frequency of double expressers as 14.8%. The prognosis of the mentioned cases was extremely poor, median survival of 10 months. Conclusion: The concurrent expression of Bcl-2 and c-Myc was found to be 14% (level of expression for Bcl-2 > 50% and c-Myc > 40%) which is potentially a significant health burden and an emerging threat.     

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.     

Diffuse large B-cell lymphoma arising in nodular lymphocyte predominant hodgkin lymphoma. A report of 21 cases from the Nebraska Lymphoma Study Group

We sought to investigate the clinical characteristics and pathologic features and survival outcome of patients with diffuse large B-cell lymphoma (DLBCL) arising in nodular lymphocyte predominant Hodgkin's disease (NLPHL), since controversy regarding their prognosis exists in the literature. Twenty-one patients with DLBCL arising either concurrently with (n=7) or subsequent to (n=14) a diagnosis of NLPHL were identified in the Nebraska Lymphoma Study Group Registry. The clinical and pathologic features of the cases were evaluated, and survival analysis was performed from the time of diagnosis of DLBCL. The median time to the development of DLBCL in those with prior NLPHL was only one year (range, 0.5-24 years). The median age of the patients at the time of diagnosis of DLBCL was 46 years (range, 18-72 years) and the male to female ratio was 17:4. Ten patients presented with nodal DLBCL only, six patients presented with both nodal and extranodal involvement, and five patients presented with only extranodal DLBCL. Eleven patients had limited stage (I/II) disease and 10 had advanced stage (III/IV) disease. The median overall survival (OS) and failure-free survival (FFS) of the entire group was 35 months and 11 months, respectively, and the predicted five-year OS and FFS was 31 and 18%, respectively. There were no significant differences in the survival outcomes between patients with DLBCL arising in NLPHL and age- and sex- matched patients with de novo DLBCL. In conclusion, our findings suggest that patients with DLBCL arising in NLPHL have a prognosis similar to those with de novo DLBCL and should be treated aggressively.     

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.     

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.     

SOCS1 Mutation Subtypes Predict Divergent Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL) Patients

Suppressor of cytokine signaling 1 (SOCS1) is frequently mutated in primary mediastinal and diffuse large B-cell lymphomas (DLBCL). Currently, the prognostic relevance of these mutations in DLBCL is unknown. To evaluate the value of the SOCS1 mutation status as a prognostic biomarker in DLBCL patients, we performed full-length SOCS1 sequencing in tumors of 154 comprehensively characterized DLBCL patients. We identified 90 SOCS1 mutations in 16% of lymphomas. With respect to molecular consequences of mutations, we defined two distinct subtypes: those with truncating (major) and those with non-truncating mutations (minor), respectively. The SOCS1 mutated subgroup or the minor/major subtypes cannot be predicted on clinical grounds; however, assignment of four established gene-expression profile-based classifiers revealed significant associations of SOCS1 major cases with germinal center and specific pathway activation pattern signatures. Above all, SOCS1 major cases have an excellent overall survival, even better than the GCB-like subgroup. SOCS1 minor cases had a dismal survival, even worse than the ABC gene signature group. The SOCS1 mutation subsets retained prognostic significance in uni- and multivariate analyses. Together our data indicate that assessment of the SOCS1 mutation status is a single gene prognostic biomarker in DLBCL.     

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.     

Epirubicin Inhibits Soluble CD25 Secretion by Treg CellsIsolated from Diffuse Large B-cell Lymphoma Patients

Objective: To investigate the effect of epirubicin on soluble CD25 (sCD25) secretion by CD4+CD25+regulatory T (Treg) cells isolated from diffuse large B-cell lymphoma (DLBCL) patients. Methods: Treg cellswere isolated from the peripheral blood mononuclear cells isolated from the newly diagnosed DBLCL patients.The concentration of sCD25 in the supernatant was determined with a commercial sCD25 (IL-2R) enzyme-linkedimmunosorbent assay (ELISA) kit. The fluorescence intensity of CD25 was detected by flow cytometry. Results:Cell survival rate was significantly decreased along with the increase of epirubicin concentration after treatmentfor 24 h. There was also a significant difference in the concentration of sCD25 between the epirubicin group andthe control group (P<0.01). A positive correlation between the Treg cells survival rate and the concentration ofsCD25 was detected (r=0.993, P<0.01). When equal numbers of CD4+CD25+ Treg cells of the epirubicin groupand the control group were cultured for another 24 h without epirubicin the CD25 fluorescence intensity onthe surface of Treg cells was obviously higher in the epirubicin group than that in the control group (P<0.01),while the sCD25 concentration in the supernatant in the epirubicin group was significantly lower than that inthe control group (P<0.05). Conclusion: Epirubicin may improve the body’s immune functions by inhibiting thesCD25 secretion by Treg cells in DLBCL patients.     

免疫分型标记物和CD43在非特指弥漫性大B细胞淋巴瘤中的表达及临床意义

目的 探讨免疫分型标记物和CD43在非特指弥漫性大B细胞淋巴瘤(DLBCL NOS)中的表达及其临床意义.方法 收集120例DLBCL NOS临床病理资料进行分析.采用免疫组化法检测CD10、bcl-6、MUM-1和CD43的表达,根据Hans分型将其分为GCB型和non-GCB型.结果 120例DLBCL,NOS中GCB型和non-GCB型分别为38例和82例,Hans分型与DLBCL NOS预后无关(P＞0.05).120例DLBCL NOS中CD43阳性33例(27.5％),CD43表达与性别、临床分期和免疫分型均无关(P＞0.05),与年龄(P=0.036)和生存状态(P=0.004)有关.结论 DLBCL NOS预后差与CD43阳性表达有关,与Hans分型无关.     

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.     

Phase 2 Study of Daratumumab in Relapsed/Refractory Mantle-Cell Lymphoma,Diffuse Large B-Cell Lymphoma,and Follicular Lymphoma

BackgroundDaratumumab is a CD38 monoclonal antibody approved for treating relapsed/refractory and newly diagnosed multiple myeloma. Preclinical daratumumab studies demonstrated cytotoxic activity and reduced tumor growth in B-cell non-Hodgkin lymphoma (NHL) subtypes, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle-cell lymphoma (MCL).Patients and MethodsThis was a phase 2, open-label, multicenter, 2-stage trial. Patients with relapsed/refractory DLBCL, FL, or MCL with ≥ 50% CD38 expression were eligible for stage 1. Daratumumab (16 mg/kg; 28-day cycles) was administered intravenously weekly for 2 cycles, every 2 weeks for 4 cycles, and every 4 weeks thereafter. Overall response rate was the primary end point. Pharmacokinetic and safety were also evaluated. Stage 2 was planned to further assess daratumumab in larger populations of NHL subtypes if futility criteria were not met. The study was registered with ClinicalTrials.gov (NCT02413489).ResultsThe trial screened 138 patients resulting in accrual of 15 patients with DLBCL, 16 with FL, and 5 with MCL. Median CD38 expression across treated patients was 70%. Overall response rate was 6.7%, 12.5%, and not evaluable in DLBCL, FL, and MCL cohorts, respectively. The most common grade 3/4 treatment-emergent adverse event was thrombocytopenia (11.1%), and 4 (11.1%) patients discontinued treatment because of treatment-emergent adverse events. Infusion-related reactions occurred in 72.2% of patients (3 patients with grade 3; no grade 4).ConclusionIn NHL, the safety and pharmacokinetics of daratumumab were consistent with myeloma studies. Screen-fail rates were high, prespecified futility thresholds were met in 2 cohorts, and the study was terminated. Studies in other hematologic malignancies and amyloidosis are ongoing.     

Real-World Characteristics,Treatment Patterns,Health Care Resource Use,and Costs of Patients with Diffuse Large B-Cell Lymphoma in the U.S

BackgroundDiffuse large B‐cell lymphoma (DLBCL) represents the most common subtype of non‐Hodgkin lymphoma in the U.S., but current real‐world data are limited. This study was conducted to describe real‐world characteristics, treatment patterns, health care resource utilization (HRU), and health care costs of patients with treated DLBCL in the U.S.Materials and MethodsA retrospective study was conducted using the Optum Clinformatics Data Mart database (January 2013 to March 2018). Patients with an International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis for DLBCL after October 2015 and no prior International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis for unspecified DLBCL or primary mediastinal large B‐cell lymphoma were classified as incident; those with such codes were classified as prevalent. An adapted algorithm identified lines of therapy (e.g., first line [1L]). All‐cause HRU and costs were calculated per‐patient‐per‐year (PPPY) among patients with a ≥1L.ResultsAmong 1,877 incident and 651 prevalent patients with ≥1L, median age was 72 years and 46% were female. Among incident patients, 22.6% had at least two lines (2L), whereas 38.4% of prevalent patients had ≥2L. The most frequent 1L therapy was rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP). Incident patients had 1.3 inpatient and 42.0 outpatient (OP) visits PPPY, whereas prevalent patients had 0.8 and 31.3 visits PPPY, respectively. Total costs were $137,156 and $81,669 PPPY for incident and prevalent patients, respectively. OP costs were the main driver of total costs at $88,202 PPPY, which were higher within the first year.ConclusionThis study showed that a large portion of patients require additional therapy after 1L treatment to manage DLBCL and highlighted the substantial economic burden of patients with DLBCL, particularly within the first year following diagnosis.Implications for PracticePatients diagnosed with diffuse large B‐cell lymphoma (DLBCL) carry a substantial clinical and economic burden. A large portion of these patients require additional therapy beyond first‐line treatment. There is significant unmet need among patients with DLBCL who require additional therapy beyond first‐line treatment. Patients who do not respond to first‐line therapy and are not eligible for transplants have very high health care resource utilization and costs, especially in the first 12 months following initiation of treatment.     

Molecular Subtypes,Apoptosis and Proliferation Status in Indonesian Diffuse Large B-Cell Lymphoma Cases

Objective: The diffuse large B-cell lymphoma (DLBCL) has two major molecular subtypes, germinal center B-cell-like (GCB) and non-GCB. These have differing behavior which affects overall patient survival. However, immunohistochemistry based molecular subtyping of Indonesian DLBCLs has been limited. This was the focus of the present study, with a focus of attention on the apoptotic index (AI) and the proliferation index (PI) of the two molecular subtypes. Materials and Methods: During the study period of 3.5 years, a total of 98 cases of DLBCL were identified. Molecular subtypes and PI were determined by immunohistochemistry and TUNEL method was used to determine the AI. Result: GCB accounted for 31 cases (31.6%) and non-GCB the remainder (68.4%). Gender showed a slight male predominance (54 cases, 55.1%), with a higher incidence in the extra-nodal region (57 cases, 58.2%). The AI and PI were significantly higher in GCB (pConclusion: The findings indicate that the non-GCB subtype is more common than GCB in Indonesian DLBCL. GCB features significantly higher PI and AI, which themselves appear linked.