|Year : 2016 | Volume
| Issue : 1 | Page : 41-46
|C-MYC and BCL2 translocation frequency in diffuse large B-cell lymphomas: A study of 97 patients
Bahar Akkaya1, Ozan Salim2, Hampar Akkaya3, Mualla Ozcan1, Orhan Kemal Yucel2, Ramazan Erdem2, Utku Iltar2, Levent Undar2
1 Department of Pathology, Akdeniz University, Antalya, Turkey
2 Department of Hematology, School of Medicine, Akdeniz University, Antalya, Turkey
3 Department of Pathology, School of Medicine, Baskent University, Antalya, Turkey
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|Date of Web Publication||9-Mar-2016|
| Abstract|| |
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.
Keywords: BCL2, diffuse large B-cell lymphoma, double-hit lymphoma, FISH, MYC
|How to cite this article:|
Akkaya B, Salim O, Akkaya H, Ozcan M, Yucel OK, Erdem R, Iltar U, Undar L. C-MYC and BCL2 translocation frequency in diffuse large B-cell lymphomas: A study of 97 patients. Indian J Pathol Microbiol 2016;59:41-6
|How to cite this URL:|
Akkaya B, Salim O, Akkaya H, Ozcan M, Yucel OK, Erdem R, Iltar U, Undar L. C-MYC and BCL2 translocation frequency in diffuse large B-cell lymphomas: A study of 97 patients. Indian J Pathol Microbiol [serial online] 2016 [cited 2019 Nov 20];59:41-6. Available from: http://www.ijpmonline.org/text.asp?2016/59/1/41/178220
| Introduction|| |
Most common type of lymphoma is diffuse large B-cell lymphoma (DLBCL) with 40% of all B-cell non-Hodgkin lymphomas in Western countries.
DLCBL includes various groups of lymphoid neoplasms and has heterogeneous clinical, histological, immunophenotypic, cytogenetic, and molecular features.  The patients with DLBCL have widely various clinical outcomes because of these revealing prognostic markers, which accurately predict outcome as a fascinating area of investigation. Genetic and molecular analyses on the heterogeneity of DLBCL have been recognized in clinical presentation and morphology as well as in molecular and cytogenetic features during the past decade. 
The addition of rituximab (R) to the classic cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy has significantly improved the outcome of these patients. Nevertheless, 30-40% of them die of the disease usually within 1-2 years after the diagnosis. Thus, it is necessary to identify the alternative treatment strategies on such patients with worse prognosis. Numerous studies have attempted to assess the prognostic value of individual biomarkers. More recent reports describe molecular classifications for DLBCL. Gene expression profiling was first described in the study of DLBCL in 2000 and has identified two major prognostic types based on cell of origin, i.e., germinal center B-cell (GCB) and activated B-cell (ABC). The first and best-known algorithm proposed by Hans et al. is used CD10, BCL6, and multiple myeloma oncogene (MUM)/interferon regulatory factor 4 (IRF4) to subclassify DLBCL into prognostically significant GCB-like DLBCL and ABC-like DLBCL subtypes.  Both CD10 and BCL6 are considered as germinal center markers whereas MUM-1 is expressed in ABCs and plasma cells. Recent studies showed that GCB profile predicts better survival than an ABC-like profile among DLBCL patients treated using chemotherapy with or without rituximab. However, relapses occur at nearly the same rates in patients with GCB-like DLBCL and in patients with ABC-like DLBCL, suggesting the existence of additional oncogenic events of importance in resistance to therapies. DLBCLs show considerable molecular genetic heterogeneity. Chromosomal translocations are diagnostic and pathogenic hallmarks of B-cell lymphomas. Several cytogenetic translocations have been found in DLBCL with the most common involving the BCL2, BCL6, and MYC loci, though the prognostic relevance of these translocations is controversial. BCL2 gene rearrangement is associated with GCB-DLBCL and has been identified as an adverse prognostic factor in this DLBCL subtype. , MYC translocation is a characteristic feature for Burkitt lymphoma (BL) and is required for the diagnosis. MYC translocation is showed that MYC gene aberrations are found not only in BLs but also in DLBCLs and other lymphomas. In previous studies MYC translocation has been reported in DLBCL with a frequency of 5-10%,  because such cases have unfavorable prognoses in DLBCL patients, who had an unfavorable prognosis and in almost 20% at first relapse. 
In this study, we used tissue microarray (TMA) analysis to evaluate the prognostic value of immunohistochemical markers classification based on the cell-of-origin. We also investigated the status of BCL2 and MYC breakpoints using fluorescence in situ hybridization (FISH) and assessed their prognostic significance.
| Materials and methods|| |
Biopsies were obtained from 121 DLBCL patients between January 2002 and June 2014. The diagnosis of DLBCL was confirmed based on the 2008 WHO classification criteria. FISH analyses were available in 97 out of 121 cases (61 males and 60 females) with a mean age of 54.8 years (range, 22-86) [Table 1]. Clinical data were obtained from the referring medical records. Ninety-seven patients were determined eligible for survival analysis. The median follow-up was 65.7 ° 3.9 months (range 8-96 months). At the time of analysis, 31 (31.9%) of 97 patients had died, and 66 (68%) were reported to be alive. This retrospective study was approved by the University Medical School Research Ethics Board and the study was performed in accordance with ethical standards of the Helsinki Declaration.
|Table 1: Clinicopathological characteristics of patients with MYC, BCL2 rearranged in DLBCL (n=121) |
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Hematoxylin and eosin-stained slides from each tumor block were reviewed, and representative areas with the highest percentage of tumor cells were selected for TMA construction. TMA blocks were constructed with a TMA. Immunohistochemistry was performed on 3 μ TMA sections using CD10, BCL6, and MUM-1/IRF4. We used heat-induced antigen retrieval and an automated immunostainer (Ventana, Tucson, AZ, USA). Antibodies reactive with the following antigens were used: CD10 (mouse, 1:40; Novocastra, Vector Labs, Burlingame, CA, USA), BCL6 (mouse, 1:50; Novocastra, Vector Labs, Burlingame, CA, USA), and MUM-1 (mouse, 1:100; Novocastra, Vector Labs, Burlingame, CA, USA). Detection was performed with biotinylated secondary antibody, horseradish peroxidase, and 3,3 ?-diaminobenzidine as a chromogen. Slides were counterstained with hematoxylin. Appropriate negative and positive control slides were run in parallel. Immunoreactivity was determined without any knowledge of survival or other clinical data. The cases were then subclassified as GCB and ABC phenotype using the algorithm described by Hans et al.  For evaluation of CD10, BCL6, and MUM-1/IRF4, the staining was interpreted as positive if 30% or more of the tumor cells showed expression.
Interphase FISH analyses were performed on 3 micron TMA tissue sections using dual-color break apart probes for an MYC (Abbott Molecular/Vysis) and dual-color fusion probes for IGH-BCL2 (Abbott Molecular/Vysis) rearrangements. The slides were analyzed using an Olympus BX61 fluorescence microscope (Olympus, Tokyo, Japan), and images were captured with a charge-coupled device camera using an image analysis system (Applied Imaging, Grand Rapids, MI, USA). A total of 100 interphase nuclei were analyzed for each probe. A neoplasm assessed using fixed, paraffin-embedded tissue sections was considered positive if observed signals were clearly >10%. This cutoff was used because of the known difficulty of providing an exact count in tissue sections in which nuclei are in or out of the plane of section. Among 121 cases, only 97 cases were available for FISH analysis.
Overall survival (OS) was calculated from diagnosis until death (all causes, events) or last contact. Survival analysis was performed using Kaplan-Meier method and compared by the log-rank test. All statistical analyses were performed using SPSS IBM Statistics 20 (IBM Corporation, Chicago, USA). A P value of <0.05 was considered significant.
| Results|| |
Demographic and clinical characteristics of the patients are shown in [Table 1]. FISH analysis was successfully performed in 97 cases, 47 (48.4%) were male, and 50 (51.5%) were female. The age at diagnosis ranged from 22 to 86 years (mean age, 55.6 years) [Table 2]. A ABC phenotype was found in 47 (48.4%) and ABC phenotype in 50 (51.5%) biopsies, as defined by the Hans' algorithm. No significant differences were observed regarding age (<60 vs. ≥60 years), sex, primary site of presentation (nodal vs. extranodal), stage (I-II vs. III-IV), GCB, and ABC subgroups.
|Table 2: Analysis of the clinicopathological characteristics in 97 DLBCL patients |
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MYC and BCL2 rearrangements
MYC rearrangements were observed in 11 (11.3%) of 97 DLBCL patients. There was no association with other clinical features including age, sex, and nodal/extranodal disease. MYC rearrangements were more common in nodal than in extranodal presentations. MYC rearrangement was associated with significantly worse OS (P < 0.001). MYC rearrangement was more common in cases with GCB phenotype (9 cases GCB; 2 cases ABC).
BCL2 rearrangements were observed in 14 (14, 4%) of 97 DLBCL patients. Six of them were extranodal lymphoma, and eight cases were nodal lymphoma. BCL2 rearrangements were more common in nodal than in extranodal presentations. There was no association with other clinical features including age, sex, and stage. BCL2 rearrangement had prognostic impact on outcome (P < 0.001). No significant differences were observed regarding age (<60 vs. ≥60 years), sex, primary site of presentation (nodal vs. extranodal), stage (I-II vs. III-IV) among GCB and ABC subgroups. No significant differences were observed regarding BCL2 rearrangement among GCB and ABC phenotype.
MYC and BCL2 rearrangements were observed in three out (3.09%) of 97 cases. There was no significant difference between GCB and ABC phenotype cases with regard to MYC and BCL2 rearrangements. Three cases were 53 (female), 53, and 63 years old, respectively. Of these three cases, two of them were GCB type of DLBCL. These three patients died after 24, 18, and 35 months, respectively, after the diagnosis. Double-hit lymphoma (DHL) patients included one female and two males with a median age of 56 years (range: 53-63). Two cases had primary nodal and one case primary extranodal presentations. The majority of patients had stage IV disease [Figure 1] [Figure 2] [Figure 3].
|Figure 1: Diffuse large B-cell lymphoma, not otherwise specified (H and E, ×400)|
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|Figure 2: Split signals demonstrating the presence of MYC rearrangement (×1000)|
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| Discussion|| |
DLBCL, the most frequent lymphoma in adults, forms a highly heterogeneous type with different clinical, morphological, immunological, cytogenetic characteristics, treatment responses, and prognosis.  Numerous studies have examined the prognostic factors for predicting survival and determining optimal therapeutic strategies in DLBCL. Relapses occur at nearly the same rates in patients with GCB-like DLBCL and in patients with ABC-like DLBCL, suggesting the existence of additional oncogenic events of importance in resistance to therapies. Since the predictive value of the immunohistochemically defined GCB and ABC phenotypes remains controversial, molecular classification is not feasible in routine clinical practice.  Cytogenetic and molecular cytogenetics in DLBCL showed that tumor cells carry nonrandom chromosomal aberrations, most frequently chromosomal translocations, deletions, or amplifications, as well as gene alterations and somatic hypermutations. DNA probes are used to identify specific genetic abnormalities that provide insight into the pathogenesis of this complex disease and to define distinct subgroups with variable prognoses. Recurrent chromosomal translocations involving the BCL6, BCL2, and/or MYC genes occur in approximately 50% of DLBCL cases.  In our series, BCL2 rearrangements were detected in 14.4% of DLBCL (14/97) cases, a result consistent with those reported by other groups. ,, BCL2 gene alteration (rearrangement and/or amplification) was not significantly correlated with cell-of-origin. Seven (50%) samples with BCL2 translocation were of GCB subtype, 7 (50%) samples with BCL2 translocation were of an ABC subtype. BCL2 rearrangements were more common in nodal than in extranodal presentations. There was no association with other clinical features including age, sex, stage, and nodal status. The prognostic role of BCL2 rearrangement is still controversial. In our study, BCL2 rearrangement had prognostic impact on outcome (P < 0.001). Barrans et al. demonstrated that GC-type DLBCL patients with t(14;18) had significantly worse survival.  Whereas in accordance with most reports BCL2 rearrangement was not predictive of OS in patients treated with rituximab plus CHOP (R-CHOP). ,
The c-MYC gene is located at 8q24. Translocation t(8;14) (q24;q32) was the first recurrent chromosomal abnormality ever reported in lymphoproliferative disorders.  It juxtaposes the c-MYC locus next to the IGH locus, resulting in overexpression of c-MYC protein, a key transcription factor that promotes cell cycling and tumor proliferation.  In our study, the frequency of MYC rearrangement was 11.3%, which is comparable to the previous studies, which have reported in 3-16% of DLBCL. ,,, Valera et al. reported that MYC rearrangement occurred as the sole abnormality (MYC single-hit) in 3% of cases, MYC and concurrent BCL2 and/or BCL6 rearrangements (MYC double/triple hit) in 4% in 219 cases of DLBCL. MYC double/triple hit was associated with unfavorable progression-free survival and OS.  Pedersen et al. have reported that all relapsed cases had previous follicular lymphoma and GCB immunophenotype.  Johnson et al. observed a very unfavorable impact of MYC rearrangements only when they were associated with either BCL2 breaks or protein overexpression.  In our series, none of the DH cases had previous follicular lymphoma and the distribution between GCB and ABC categories was even.
In DLBCL, the high Ki-67 proliferation index and positive BCL2 staining which is not typical BL should prompt FISH and cytogenetic analysis for MYC and BCL2 rearrangements to identify DHL, particularly if the results of tissue biopsy are unexpected. Recently, the prognostic impact of chromosomal translocations involving MYC, BCL2, and BCL6 genes has been widely investigated in DLBCLs. Several studies have reported the prognostic factors for predicting survival and determining optimal therapeutic strategies in DLBCL. Our data, although limited by a small sample size, indicate that DHLs are aggressive and have poor treatment response rates. The cases showing coexpression of MYC and BCL2 might be frequent in relapsed DLBCL than in primary cases.
Barrans et al. found patients with MYC-rearranged DLBCL were significantly associated with an advanced stage and a higher International Prognostic Index (IPI) score.  Niitsu et al. showed that patients with MYC-rearranged DLBCL significantly correlated with poor performance status, bone marrow involvement, high IPI score, and elevated lactate dehydrogenase levels. 
DLBCL with MYC rearrangements has a poor prognosis with outcomes that are inferior to both BL and other types of DLBCL. There is now a clear consensus of the presence of MYC rearrangement which retains its negative prognostic significance even in patients treated with rituximab and anthracycline-based immunochemotherapy and that the presence of MYC rearrangement is an independent predictor of outcome in DLBCL.  The poor clinical outcomes of patients with double-hit B-cell lymphomas treated with standard R-CHOP have been shown in publications of Johnson et al. and Green et al., suggesting the need for new therapeutic approaches in clinical trial settings in these patients. , On the basis of these findings, the routine screening for MYC rearrangements can be suggested in DLBCL cases, with high-risk features and/or a high proliferation rate. In our study, patients with MYC gene rearrangement showed significantly worse OS than nonrearranged patients. Akay et al. reported that patients with rearrangements of MYC tended to have shorter OS and BCL2 had a statistically significant negative influence on OS. There was also a trend toward worse OS with MYC expression.  Horn et al. investigated the prognostic relevance of MYC, BCL2- and BCL6-rearrangements with FISH in paraffin-embedded tumor samples from 442 de novo DLBCLs.  Horn reported that MYC translocation was detected in 8.8% of the cases, treated in a prospective trial with CHOP or rituximab plus CHOP R-CHOP.  They reported that did MYC protein expression have a significant prognostic impact in the univariate survival analyses. Savage et al. found that for DLBCL, MYC rearrangements had a negative prognostic impact by multivariate analysis for both progression-free survival and OS, as well as a higher risk of central nervous system relapse even when treated with R-CHOP. 
Even in pediatric patients with DLBCL, the presence of 8q24 rearrangements independently reduces event-free survival by 6-fold.  However, Copie-Bergman et al. found that the presence of MYC rearrangement did not predict shortened OS in DLBCLs treated with R-CHOP.  Three of our cases with MYC rearrangement also had BCL2. The poor clinical outcome of the group of tumors with MYC rearrangement is likely to be a consequence of the synergistic interaction between multiple dysregulated genes. The poor clinical outcomes of patients with double-hit B-cell lymphomas treated with standard R-CHOP have been shown in publications of Johnson et al. and Green et al., suggesting the need for new therapeutic approaches in clinical trial settings in these patients. , Double- and triple-hit lymphomas are rare neoplasms with estimated frequencies ranging from 1% to 12% of DLBCLs. BCL2/MYC DHLs (62%) formed the great majority of DHLs. ,,, In our study, MYC and BCL2 rearrangements were observed in 3 of 97 cases. Three cases were 53 (female), 53, and 63 years old, respectively. Our patients with DHL died after 24, 18, and 35 months after diagnosis. DHL patients included one female and two males with a median age of 56.3 years. Two cases had primary nodal and one case primary extranodal presentation. All of these patients had stage IV disease. In accordance with the reported cases in the literature, our patients presented as de novo DLBCL. Snuderl et al. reported that follicular low-grade follicular lymphoma history was reported in 6 (30%) of 20 BCL2/MYC DHL cases.  Our findings and other studies confirm that double- and triple-hit lymphomas are characterized by aggressive clinical behaviors. Patients usually present with poor prognostic parameters, including advanced stage, B symptoms, elevated lactate dehydrogenase, poor performance status, bone marrow and central nervous system involvement, high IPI score, and resistance to multiagent chemotherapy, even if treated with R-CHOP or high-intensity treatment regimens. In DLBCL, rearrangement of MYC is rarely found as the sole genetic abnormality, and the poor prognosis of these patients is likely related to inducing action of MYC growth promotion combined with the anti-apoptotic effect conferred by BCL2 overexpression. Some studies were reported that MYC rearrangement was significantly associated with a high proliferation rate. ,, All of DLBCL cases should be analyzed for MYC abnormality using FISH, especially if the proliferation index is >80%. The cases in which clinical, morphological, and immunohistochemical diagnosis are not adequate to discriminate DLBCL-BL, cytogenetic studies are beneficial. In this way, not only the patient will be able to reach the correct diagnosis but also will get the effective treatment.
Given the heterogeneous nature of the DLBCL, analysis of MYC, BCL2 alterations may support important prognostic information to know identify a high-risk group of patients who do not respond well to current treatment regimens and are most likely to benefit from novel therapeutic approaches. These findings need confirmation in additional series to clarify if this new assay (cell of origin assignment in formalin-fixed, paraffin-embedded tissue) is more effective than MYC and BCL2 analysis for identifying a subgroup of DLBCL patients with poor outcomes.
The authors would like to thank Dr K. Hakan Gulkesen for his excellent assistance in statistics for bringing out this manuscript successfully.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Akdeniz University School of Medicine Pathology Department, Antalya
Source of Support: None, Conflict of Interest: None
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[Table 1], [Table 2]
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