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Objective:To investigate the clinicopathologic characteristics, gene mutation profile and prognostic influencing factors of diffuse large B-cell lymphoma (DLBCL) complicated with follicular lymphoma (FL) (DLBCL/FL).Methods:The clinicopathological data of 50 DLBCL/FL patients admitted to Rui Jin Hospital Affiliated of Shanghai Jiao Tong University School of Medicine from February 2018 to November 2021 were retrospectively analyzed. Targeted sequencing was performed to assess the mutation profile of 55 lymphoma-related genes. The clinicopathological characteristics were summarized to evaluate the short-term therapeutic efficacy of all patients. Kaplan-Meier method was used to analyze the overall survival (OS) and progression-free survival (PFS) of patients. Cox regression risk models were used to assess the factors affecting the OS and PFS.Results:Among 50 DLBCL/FL patients, 23 cases (46%) were male, 22 cases (44%) had an international prognosis index (IPI) score ≥ 2 points, 16 cases (32%) were double-expression lymphoma (DEL) and 4 cases (8%) were double-hit lymphoma (DHL). The complete response (CR) and overall response rates were 68% (34/50) and 78% (39/50), respectively after the first-line therapy. The median follow-up time was 23.3 months (5.1-50.9 months). The 2-year OS rate was 82.1% and 2-year PFS rate was 67.1%; and the median OS and PFS were not reached. Targeted sequencing results showed that the mutation frequencies of KMT2D, MYD88, TP53, BTG2, DTX1, EZH2, CD70, CREBBP, DUSP2, HIST1H1C, HIST1H1E and PRDM1 genes in this cohort were more than 15%. Multivariate Cox regression analysis showed that male ( HR = 4.264, 95% CI 1.144-15.896, P = 0.031) and IPI score ≥ 2 points ( HR = 6.800, 95% CI 1.771-37.741, P = 0.007) were independent risk factors of PFS in newly diagnosed DLBCL/FL patients, and TP53 mutation ( HR = 4.992, 95% CI 1.027-24.258, P = 0.046) was an risk influencing factor of OS. Conclusions:The proportion of male and female DLBCL/FL patients is similar, with a small proportion of DHL. Mutations of KMT2D, MYD88 and TP53 genes are commonly found in DLBCL/FL patients. Generally, DLBCL/FL patients can have a high overall response and good prognosis. Male and IPI score ≥ 2 points are the independent risk factors of PFS, and TP53 mutation is an independent risk factor of OS in DLBCL/FL patients.
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High grade B-cell lymphoma was defined as an independent disease in the 2016 new version of the World Health Organization lymphoma classification, including double-hit high grade B-cell lymphoma with myc and bcl-2 or bcl-6 gene rearrangements and high grade B-cell lymphoma, not otherwise specified without myc and bcl-2 or bcl-6 gene rearrangements, both of them are invasive in clinical features. In recent years, there have many studies on it, double-hit lymphoma (DHL) has relatively unique clinical features and poor prognosis. Although high-intensity chemotherapy can prolong the survival of patients, current treatment options have poor efficacy, and specific targeted drug therapies are still required. Single-agent or combination therapy of signal pathway inhibitors can improve the poor prognosis of patients. Immunotherapy is expected to become the direction of future research. This article reviews the definition, diagnosis, prognosis, and latest treatment progress of DHL.
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Objective To study the frequency of diffuse large B-cell lymphoma (DLBCL) with multi-genetic alteration, and its correlation with c-myc, bcl-2 and bcl-6 protein expression. Methods 50 cases diagnosed with DLBCL from January 2012 to December 2016 were collected. The expression of c-myc, bcl-2 and bcl-6 was analyzed by immunohistochemistry. Interphase fluorescence in situ hybridization (I-FISH) analysis was performed to identify the genetic alteration of c-myc, bcl-2 and bcl-6. Results In all cases, there were 27 males and 23 females with a median age of 50 years (range: 3-85 years). 23 (46.00 %) cases were defined as primary nodal DLBCL and 27 (54.00 %) cases were primary extra-nodal DLBCL, with gastrointestinal tract (48.15 %, 13/27) being the most common site of involvement. c-myc protein expression was detected in 94.00 % (47/50) cases, in which 82.00 % (41/47) cases exhibited high levels of c-myc expression with positive nuclear staining observed in over 40.00 % of tumor cells. The positive rate of bcl-2 protein was 84.00 % (42/50), 76 % (38/50) cases presented with high-level bcl-2 expression. Concurrent high expression of c-myc and bcl-2 were presented in 18 cases (36.00%). FISH analysis demonstrated c-myc gene rearrangement in 7 cases (14.00 %) and amplification in 2 cases (4.00 %). bcl-2 gene rearrangement was detected in 6 cases (12.00 %) and 4 cases (8.00 %) exhibited gene amplification. bcl-6 gene rearrangement was identified in 8 cases (16.00%), amplification in 3 cases (6.00%), and 1 case concomitantly harbored the rearrangement and amplification of bcl-6. Multi-genetic alterations were defined in 4 cases with 3 cases fulfilling the criteria for double-hit lymphoma (DHL) and 1 case for triple-hit lymphoma (THL). For the cases with concomitant high-level expression of c-myc and bcl-2 proteins, 3 cases (16.67 %) was detected with multi-genetic alterations, including 2 cases for DHL and 1 case for THL. Conclusions The proportion of DLBCL with multi-genetic alterations is 8.00 % in this study. The genetic alterations are not consistently correlated with the protein expression. The molecular genetic testing is reliable for the identification of DHL.
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Purpose: Diffuse large B‑cell lymphoma (DLBCL) is an aggressive non‑Hodgkin lymphoma with marked biologic heterogeneity. MYC and BCL2 rearrangements have been reported in a proportion of DLBCLs, where they may be associated with an adverse clinical outcome. The aim of this study was to determine the frequency of MYC and BCL2 translocations in DLBCL and assess the prognostic impact in DLBCL patients. Materials and Methods: In the present study, we evaluated the expression patterns of CD 10, BCL6, and MUM 1 by immunohistochemistry in 121 cases with DLBCL in tissue microarray (TMA): 62 cases in germinal center B‑cells (GCBs); and 59 cases in activated B‑cells (ABCs) of which 60 were females and 61 were males. MYC and BCL2 rearrangements were investigated by interphase fluorescence in situ hybridization on TMAs in 97 DLBCLs. Result: MYC rearrangements were observed in 11 of 97 cases. There was no association with other clinical features, including age, sex, and nodal/extranodal disease. MYC rearrangement was associated with significantly worse overall survival (P < 0.01). BCL2 rearrangements were observed in 14 of 97 cases. There was no association with other clinical features including age and sex. BCL2 rearrangement had a worse outcome (P < 0.01). MYC and BCL2 rearrangements were observed in 3 of 97 cases with the age of 53 (female), 53, 63 years old, respectively, died in 24, 18, and 35 months after the diagnosis. Two cases had primary nodal and one case primary extranodal presentations. All these patients had stage IV disease. Conclusion: We concluded that C‑MYC and BCL2 may contribute to aggressive transformation, and more mechanism‑based therapy should be explored. Targeted therapies involving these rearrangements and its associated pathways may change the fate of DLBCLs. Analysis of MYC gene rearrangement along with BCL2 is critical in the identification of high‑risk patients with poor prognosis.
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Double-hit lymphoma is usually defined to be large B-cell lymphoma with MYC gene rearrangement combined with bcl-2 and/or bcl-6 gene rearrangement.It is highly aggressive with poorer prognosis after R-CHOP treatment and so far,its optimal therapy has not been developed.This article reviewed new advances in diagnosis,biology,prognostic factors and treatment of DHL in order to deepen insights,optimize therapy and improve prognosis of DHL.
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Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of non-Hodgkin's lymphoma.An uncommon subset with myc and either bcl-2 or bcl-6 rearrangement,also known as ‘double-hit’ lymphomas,is considered very aggressive clinical course and poor prognosis despite high-intensity chemotherapy.Recently,these lymphomas have received increased attention.This review explores the existing literatures for the involved genes with their functions,clinical features,diagnosis and treatment.
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Recently, double-hit lymphoma (DHL) was clarified to be a molecular category of B-cell lym-phoma, which was mainly related to MYC and Bcl-2 genes translocation. Fluorescence in situ hybridization (FISH) is the gold standard of diagnosis and it is controversial to detect the expression of MYC and Bcl-2 protein by immuno-histochemistry. DHL, which was found to be aggressive according to many retrospective analyses, mainly develops in patients with diffuse large B-cell lymphoma and grey zone lymphoma. Both rituximab combination and transplant consolidation were not able to signiifcantly overcome the poor prognosis of DHL. Novel and speciifc molecular targeted agents need to be explored and investigated in order to improve the treatment outcome.
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Double-hit lymphoma (DHL) is a kind of disease with features intermediated between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL),usually accompanied by myc gene breakpoint with other recurrent chromosomal breakpoint and mainly involving myc and bcl-2 translocation.The presentation of this disease is characterized by elevated serum lactate dehydrogenase levels,B symptoms,bone marrow involvement,advanced stage disease,extranodal involvement,and central nervous system involvement.Because its features are similar with DLBCL and BL,it's difficult to distinguish them by pathological diagnosis.At present,the differential diagnosis is mainly by chromosomal analysis (G-banding),FISH and immunohistochemistry.This subtype received a poor response to conventional chemotherapy for DLBCL,and has a poor prognosis.The median survival time is only 0.2-1.5 years.Currently,the main regimens include RCHOP,RICE,RCVD,methotrexate prophylaxis for central nervous system involvement,high-dose chemotherapy and bone marrow transplantation.