Published online 16 June 2009
Haematologica, Vol 94, Issue 7, 935-943 doi:10.3324/haematol.2008.005355
Copyright © 2009 by Ferrata Storti Foundation

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Malignant Lymphomas

Clinicopathological features of lymphoma/leukemia patients carrying both BCL2 and MYC translocations

Naoto Tomita¹, Mami Tokunaka², Naoya Nakamura², Kengo Takeuchi³, Junki Koike⁴, Shigeki Motomura⁵, Ko Miyamoto⁶, Ako Kikuchi⁷, Rie Hyo⁸, Yoshihiro Yakushijin⁹, Yasufumi Masaki¹⁰, Soichiro Fujii¹¹, Takamasa Hayashi¹², Yoshiaki Ishigatsubo¹, Ikuo Miura¹³

¹ Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama;
² Department of Pathology, Tokai University School of Medicine, Kanagawa;
³ Department of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo;
⁴ Department of Pathology, St. Marianna University School of Medicine, Kawasaki;
⁵ Department of Chemotherapy, Kanagawa Cancer Center, Yokohama;
⁶ Division of Hemato-oncology, St. Marianna University School of Medicine, Yokohama City Seibu Hospital, Yokohama;
⁷ Department of Hematology, Tokai University School of Medicine, Kanagawa;
⁸ Department of Hematology, Yokohama City University Medical Center, Yokohama;
⁹ Cancer Center, Ehime University Graduate School of Medicine, Ehime;
¹⁰ Department of Hematology and Immunology, Kanazawa Medical University, Ishikawa;
¹¹ Department of Internal Medicine, Okayama Red Cross General Hospital, Okayama;
¹² Division of Hematology, Tenri Hospital, Nara and
¹³ Division of Hematology and Oncology, St. Marianna University School of Medicine, Kawasaki, Japan

Correspondence: Naoto Tomita, M.D., Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan E-mail:cavalier{at}ch-yamate.dlenet.com

TOP ABSTRACT Introduction Design and Methods Results Discussion Acknowledgments: References

 
Background: Lymphoid neoplasm with 18q21.3/BCL2 and 8q24/MYC translocation to immunoglobulin (IG) genes as dual-hit lymphoma/leukemia is very rare and known to have a poor clinical outcome.

Design and Methods: To clarify the clinicopathological characteristics of this malignancy, we analyzed 27 cases of cytogenetically proven dual-hit lymphoma/leukemia.

Results: Dual-hit lymphoma/leukemia was diagnosed at presentation in 22 cases and at relapse or disease progression in 5 cases. At the time of diagnosis of dual-hit lymphoma/leukemia, extranodal involvement was found in 25 cases (93%) and central nervous system involvement occurred in 15 cases (56%). The median survival and 1-year survival rate of the 27 cases were only 6 months and 22%, respectively, after diagnosis of the dual-hit lymphoma/leukemia. Seven cases of triple-hit lymphoma/leukemia (dual-hit lymphoma/leukemia with 3q27/BCL6 translocation) were included; the median survival of these patients was only 4 months from the diagnosis of the dual-hit lymphoma/leukemia. The duration of survival of the patients with a triple-hit malignancy was shorter than that of the other 20 cases of dual-hit lymphoma/leukemia (p=0.02). The translocation partner of MYC subdivided the dual-hit cases into two groups; 14 cases of IGH and 13 cases of IGK/L. The MIB-1 index was investigated in 14 cases with aggressive B-cell lymphoma, and was higher in the group with MYC-IGH translocation (n=7) than in the MYC-IGK/L group (n=7) (p=0.02). Overall survival was not different between the MYC-IGH translocation group (n=14) and the MYC-IGK or MYC-IGL translocation group (n=13).

Conclusions: Dual-hit lymphoma/leukemia is a rare but distinct mature B-cell neoplasm with an extremely poor prognosis characterized by frequent extranodal involvement and central nervous system progression with either of the translocation partners of MYC.

Key words: BCL2, MYC, dual-hit lymphoma/leukemia.

TOP ABSTRACT Introduction Design and Methods Results Discussion Acknowledgments: References

 
Translocation of the BCL2 gene on chromosome band 18q21.3 results in consistent expression of the apoptosis inhibitor of the Bcl2 protein.¹ BCL2 usually translocates to the immunoglobulin heavy chain (IGH) gene as t(14;18)(q32;q21.3) and rarely to IG light chain (IGK, IGL) loci as t(2;18)(p11;q21.3) or t(18;22)(q21.3;q11).² The t(14;18) is observed in 70% to 95% of cases of follicular lymphoma (FL)^3,4 and 20% to 30% of cases of diffuse large B-cell lymphoma.^5,6 The MYC gene on chromosome band 8q24 acts as an accelerator of cell proliferation.⁷ MYC translocates to 14q32/IGH as t(8;14) (q24;q32) or less commonly to 2p11/IGK as t(2;8) (p11;q24) or 22q11/IGL as t(8;22)(q24;q11).² The 8q24/MYC translocation is detected in most cases of Burkitt’s lymphoma and up to 10% of cases of diffuse large B-cell lymphoma.⁸

The World Health Organization (WHO) classification² translates the fruit of work in immunology and molecular biology to morphology. Lymphoid neoplasms are classified into two groups based on B or T/NK cell origin and further classified into precursor or mature cell types. Most mature B-lymphoid neoplasms show disease-specific chromosome abnormalities. Lymphoma/leukemia cases with both 18q21.3/BCL2 and 8q24/MYC translocations to IG genes are rarely identified and most of them are classified as B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt’s lymphoma (IL). These lymphomas are termed as BCL2/MYC dual-hit lymphoma/leukemia (DHL). Although DHL has been reported to have a poor prognosis,² the clinicopathological characteristics of this conditions have not been sufficiently studied thus far.

Here, we report the clinicopathologic and genetic features of 27 cases with translocations of both 18q21.3/BCL2 and 8q24/MYC identified by chromosome analysis. We examined differences between cases with translocation of MYC-IGH and cases with translocation of MYC-IGK/L, and also studied the prognosis of patients with triple-hit lymphoma/leukemia (THL) involving 18q21.3/BCL2, 8q24/MYC, and 3q27/BCL6.

TOP ABSTRACT Introduction Design and Methods Results Discussion Acknowledgments: References

 
We identified cases of mature B-cell neoplasms (lymphoma/leukemia) in which the translocations of both 18q21.3/BCL2 and 8q24/MYC were found in identical cells by chromosome analysis. Clinical data relating to 27 cases of DHL were collected from 20 institutions. Pathological specimens from 20 cases were reviewed by three pathologists (NN, KT, and JK). Cases in which the two translocations were observed separately by fluorescent in situ hybridization analysis were not included in this study. Clinical data such as gender, International Prognostic Index (IPI),⁹ age, serum lactate dehydrogenase (LDH) levels, performance status, clinical stage, number and site of extranodal involvements, B symptoms, and presence of a bulky mass (defined as a tumor with a minimum diameter of at least 10 cm or one-third the transverse thoracic diameter) were analyzed. Histological diagnosis involved hematoxylin-eosin staining and immunohistochemistry. The data collection procedure was submitted to the ethical committee or institutional review board of each institute. The procedures of this study were conducted in accordance with the Helsinki Declaration.

Statistical analysis
Fisher’s exact probability test and the Mann-Whitney test were used to determine statistically significant differences between groups. A survival curve was constructed using the Kaplan-Meier method. p values less than 0.05 were considered to indicate statistical significance.

TOP ABSTRACT Introduction Design and Methods Results Discussion Acknowledgments: References

 
Clinical data review
The characteristics of the 27 patients with DHL are shown in Table 1. All data were obtained at the onset of DHL. The median age (range) of the patients at the onset of DHL was 51 years (36–79 years). There were 23 cases of B-lymphoma (lymphoma-type DHL) and four of B-leukemia (leukemia-type DHL). All 11 tested cases were negative for human immunodeficiency virus. Most (25/27) patients had elevated serum LDH. Patients with leukemia-type DHL had higher serum LDH levels than those with lymphoma-type DHL (p=0.01). Among the 23 lymphoma-type DHL patients, 22 were at an advanced clinical stage and 15 patients had involvement of two or more extranodal sites. Only two patients had no extranodal involvement. In the 23 cases of lymphoma-type DHL, bone marrow (65%) was the most frequent site of extranodal involvement at the onset of DHL, followed by peripheral blood (30%) and pleural effusion (30%), as shown in Table 2. The IPI was high or high-intermediate in 87% (20/23) of the patients with lymphoma-type DHL.

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Table 1. Clinical features and karyotype of patients with dual-hit lymphoma/leukemia.

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Table 2. Extranodal sites of involvement among 23 cases of lymphoma-type dual-hit lymphoma/leukemia.

The cases were divided into two subgroups depending on the timing of the diagnosis of DHL, as shown in Table 1. Twenty-two cases (18 with lymphoma-type DHL and 4 with leukemia-type DHL) who presented with DHL initially were classified as DHL-1. The other five cases (all with lymphoma-type DHL) who exhibited DHL at relapse or disease progression after treatment of the initial lymphoma/leukemia were classified as DHL-2. The clinical data of the DHL-2 cases refer to the onset of DHL, instead of the initial lymphoma/leukemia. In the DHL-2 group, four of the initial lymphoma/leukemia cases were diagnosed as FL and one as IL. The time from the diagnosis of the initial lymphoma/leukemia to the onset of DHL in the five DHL-2 cases was 3, 3, 3, 25, and 31 months.

All 27 patients received systemic chemotherapy. Multi-agent induction chemotherapy such as CHOP, CODOX-M/IVAC, or HyperCVAD, with (n=14) or without (n=8) rituximab, was given to most (22/23) patients with lymphoma-type DHL. Patients with leukemia-type DHL underwent combination chemotherapy for acute lymphocytic leukemia. Complete remission or complete remission-uncertain was observed in six of the 23 patients with lymphoma-type DHL and two of the four patients with leukemia-type DHL. However, seven (5 lymphoma-type and 2 leukemia-type) of the eight patients who achieved a complete remission (confirmed or uncertain) relapsed. No patients received up-front autologous or allogeneic transplantation at first remission. The overall survival curve is depicted in Figure 1A. The median survival and 1-year survival rate were only 6 months and 22%, respectively. Involvement of the central nervous system (CNS) was observed in up to 56% of patients (15/27) including two patients at the onset of DHL-1. The cause of death was progression of DHL in 87% of the patients who died.

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Figure 1. Overall survival of 27 cases of DHL. (A) The 1-year survival rate is only 22%. In the five type-2 DHL cases, the survival duration is measured from the diagnosis of DHL. The two patients with the longest survival were those without extranodal involvement at the diagnosis of DHL. (B) The survival duration of patients with THL (DHL with BCL6 translocation) was shorter than that of the other 20 DHL cases (p=0.02).

Chromosomal data review
The results of chromosome analysis are summarized in Table 1 and listed in detail in Table 3. All cases were analyzed by examining the G-banding after trypsin exposure, except UPN21, for whom Q-banding was used. UPN23, bearing a complex translocation, was analyzed by G-banding and spectral karyotyping. Chromosome analysis revealed BCL2-IGH and MYC-IG translocations in all but one case (UPN13) in which BCL2-IGK and MYC-IG translocations were detected. The translocations detected in 11 cases were t(14;18) and t(8;14); in nine cases, t(14;18) and t(8;22); in four cases, t(14;18) and t(2;8); in one case, t(2;18) and t(8;14); and in two cases (UPN12, UPN23), a t(8;14;18) 3-way translocation.^10–12 Trisomy (or tetrasomy) 7 and trisomy 12 were detected in nine and eight cases, respectively. An additional translocation involving 3q27/BCL6 was detected in seven cases (UPN9, UPN13, UPN20, UPN21, UPN23, UPN24, UPN25), and among them, the BCL6-IG translocation was identified in five cases. These seven cases were regarded as having THL. Of our 27 cases, six have been previously reported.^13–18

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Table 3. Chromosomal analysis.

Pathological review
The results of the pathological review are summarized in Table 4. A reviewed diagnosis of the 20 DHL cases revealed 1 case of grade 3a FL (UPN10), one case of grade 3b FL (UPN17), 15 cases of IL, and three cases of composite lymphoma that showed different lymphoma histologies synchronously in identical lymph nodes (UPN1, UPN23) or at different sites (UPN16). UPN1, belonging to the DHL-1 group, exhibited FL and IL in identical lymph nodes synchronously. UPN16, belonging to the DHL-1 group, exhibited FL in a lymph node and IL in the bone marrow synchronously. UPN23, belonging to the DHL-2 group, exhibited FL as the initial lymphoma/leukemia and FL and IL in identical lymph nodes at relapse, as shown in Figure 2A. The typical histology of DHL is shown in Figures 2B–D. Pathological diagnoses were made according to the WHO classification.² No cases showed the typical phenotype of Burkitt’s lymphoma/Burkitt’s leukemia (CD10⁺, Bcl6⁺, Bcl2^–, MIB-1 index >95%).¹⁹ CD20 immunostaining was positive in 18 of 19 cases, with the degree of positivity varying from partial (positive in less than 30% of tumor cells) to diffuse (positive in more than 30% of tumor cells). UPN9 was CD20-negative by immunostaining but CD20-positive by flow cytometry. Other immunohistochemical analyses revealed positive/negative results of 18/1 for CD10 (negative in UPN7), 19/1 for Bcl2 (negative in UPN27), 11/4 for Bcl6, and 2/16 for MUM-1. The MIB-1 index was lower than 90% in 13 of 14 tested cases (except for follicular lesions in composite lymphomas).

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Table 4. Pathological review at the diagnosis of dual-hit lymphoma/leukemia.

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Figure 2. Pathological review: hematoxylin-eosin staining or peroxidase immunostaining (antigen addressed). Original magnification was x400 in all panels unless otherwise stated. (A) Composite lymphoma of grade 1 follicular lymphoma and B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitts’ lymphoma (IL) (UPN23). The resected lymph node is effaced by nodular proliferation of the lymphoma cells (A-1, original magnification x40), which exhibits a small-cleaved nucleus (A-2), indicating follicular lymphoma, grade 1. They are CD20-positive (A-3), CD10-positive (A-4), and BCL2-positive (A-5). The ki-67 index of the follicular lymphoma cells is about 10% (A-6). In the adipose tissue around the lymph node, there is diffuse proliferation of the lymphoma cells with medium to large-sized nuclei with scattered starry sky macrophages, indicating IL (A-7). The lymphoma cells are positive for CD20 (A-8), CD10 (A-9), and Bcl2 (A-10). The ki-67 index of the IL cells is approximately 60% (A-11). (B) Follicular lymphoma, grade 3b (UPN17). The lymph node shows a nodular and diffuse proliferation of the lymphoma cells (B-1, original magnification x100). The lymphoma cells have a large-sized round nucleus with a prominent nucleolus (B-2). They are positive for CD20 (B-3, original magnification x100, B-4), CD10 (B-5), and Bcl2 (B-6). The ki-67 index of the lymphoma cells is approximately 50% (B-7). (C) IL (UPN6). The bone marrow biopsy specimen shows diffuse proliferation of the lymphoma cells that have a large-sized round or cleaved nucleus with prominent nucleoli and vesicular chromatin (C-1). The lymphoma cells are positive for CD20 (C-2), CD10 with weak staining (C-3), and Bcl2 (C-4). The ki-67 index of the lymphoma cells is 82.6% (C-5). The translocation partner of MYC is IGH. (D) IL (UPN19). The bone marrow biopsy specimen shows diffuse proliferation of the leukemia cells with medium to large-sized nuclei (D-1). The lymphoma cells are partially CD20 positive (D-2), CD10 positive (D-3), and Bcl2 positive (D-4). The ki-67 index of the leukemia cells is 64.7% (D-5). The translocation partner of MYC is IGL.

According to the criteria of Hans et al.,²⁰ 17 of the 19 tested cases showed diffuse CD10 positivity (more than 30% of tumor cells) on immunostaining and were classified as the germinal center B cell-like (GCB) subtype. UPN18 showed partial CD10 positivity (less than 30% of tumor cells), Bcl6 positivity, and MUM-1 negativity and was also classified as the GCB subtype. Only UPN7 was classified as the non-GCB subtype as this patient was negative for CD10, Bcl6, and MUM-1. CD10 immunostaining was not performed in the case of UPN9.

Partner of the MYC translocation
The translocation partner of MYC consisted of IGH in 14 cases and IGK/L in 13. Cases with more than one extranodal site involved were more common in the MYC-IGH group (p=0.04). The other factors were similarly distributed. The MIB-1 index was investigated in 14 cases among the 20 pathologically reviewed cases shown in Table 4. It was higher in the MYC-IGH translocation group (n=7) than in the MYC-IGK/L group (n=7) (p=0.02). Overall survival was not different between patients with MYC-IGH translocation (n=14) and those with the MYC-IGK/L translocation (n=13) (data not shown).

Triple-hit lymphoma/leukemia
There were seven cases of THL. All of them died and their median survival was only 4 months from the diagnosis of DHL. Variables of clinical factors were similarly distributed in DHL without BCL6 translocation and THL, as shown in Table 1. The duration of survival of patients with THL was shorter than that of the other 20 DHL cases, with a median survival of 6 months (p=0.02), as shown in Figure 1B.

TOP ABSTRACT Introduction Design and Methods Results Discussion Acknowledgments: References

 
We accessed chromosomally proven DHL cases having both 18q21.3/BCL2 and 8q24/MYC translocations to analyze their clinicopathological features. This report is the largest case-series study conducted.^21–29 BCL2/MYC DHL account for most of the double hit lymphomas, which contain a MYC breakpoint in combination with a BCL2 and/or BCL6 breakpoint, as defined in the WHO classification.²

Whether the BCL2-IG translocation and MYC-IG translocation arise concurrently or separately has not yet been determined. In the DHL-2 group (UPN23-27), the initial lymphoma/leukemia was FL in four cases and IL in one case (UPN24). At least in four of these cases the BCL2-IG translocation definitely preceded the MYC-IG translocation. The interval from the onset of the initial lymphoma/leukemia to the onset of DHL ranged from 3 to 31 months. In the DHL-1 group, there were two cases of composite lymphoma with FL and IL (UPN1 and UPN16). These two cases suggest the transformation of FL into diffuse lymphoma. In UPN1, detailed examination using fluorescent in situ hybridization analysis of paraffin-embedded tissue and DNA sequencing in the immunoglobulin heavy chain gene by the microdissection technique³⁰ confirmed that the BCL2-IG translocation occurred before the MYC-IG translocation.¹³ These data indicate that the BCL2-IG translocation occurs first and is followed by the MYC-IG translocation at least in some cases of DHL. It is also possible that an additional 8q24/MYC translocation occurs in non-neoplastic circulating B-cells with the t(14;18),^31,32 resulting in DHL-1 features. As for the patterns of 8q24/MYC translocation, 13 cases (48%) showed translocation to IG light chain gene. This is different from the frequency observed in usual Burkitt’s lymphoma in which up to 85% of the cases show 8q24/MYC translocation to an IGH gene, resulting in t(8;14). This is a characteristic of DHL. It might be attributable to the fact that only one IGH gene would remain as the partner of MYC in the presence of the BCL2-IGH translocation.

Typical Burkitt’s lymphoma histology was not observed in any of the 20 pathologically reviewed cases. The MIB-1 index reflects the cell ratio in the cell cycle and might fluctuate depending on the degree of cell proliferation in the presence of MYC overexpression in DHL. In most cases of DHL, the index was below 90%. This differs considerably from typical Burkitts’ lymphoma, in which it is almost 100%. The group with the MYC-IGH translocation showed a higher MIB-1 index than the group with the MYC-IGK/L translocation. In DHL, the proliferation potential might differ according to the translocation partner of the MYC, although its impact on survival is not apparent. It is reported that in most cases of MYC-IGH translocation, the breakpoints of MYC are located 5’ of the coding region, either in the first intron, within the first exon, or 5’ of the first exon, while in cases with MYC-IGK/L translocation, they may be at considerable distances centromeric or telomeric from the MYC coding exons.³³ The breakpoint of MYC might have a role in determining the proliferation potential in DHL.

The prognosis of DHL is extremely poor. Most patients died within 1 year of the diagnosis of DHL despite chemotherapy. Extranodal involvement, a transient response to chemotherapy, repeated relapses, highly aggressive disease, and frequent CNS progression were characteristic of DHL. High-dose chemotherapy followed by stem cell transplantation should be indicated for DHL. In seven of our 27 cases of DHL, the 3q27/BCL6 translocation was also detected. Because of the very short survival of patients with this translocation, one should pay attention to the presence or absence of the 3q27/BCL6 translocation during the diagnosis of DHL. In our series, the longest surviving (beyond 7 years) patient was UPN4.¹⁴ UPN4 initially had DHL with t(14;18) and t(8;14) as diffuse large B-cell lymphoma and reached complete remission with CHOP chemotherapy. After 55 months, relapse occurred only as FL with a t(14;18) chromosome abnormality. This suggests the mechanism of additional acquisition of t(8;14) to the original clone with t(14;18) and disappearance of the clone carrying both t(14;18) and t(8;14) as a result of chemotherapy. The second longest survival (beyond 2 years) was noted in the case of UPN18. UPN18 initially had DHL also with t(14;18) and t(8;14) as diffuse large B-cell lymphoma and achieved complete remission with CHOP and MACOP-B chemotherapy with rituximab. UPN18 is still in first complete remission beyond 2 years. Interestingly, they were the only two patients without initial extranodal involvement at the onset of DHL among our 27 patients. This might suggest the possible mechanism of controlling nodal DHL.

In this study, DHL was defined as a lymphoma/leukemia with chromosome translocations of both BCL2-IG and MYC-IG. DHL is a rare but distinct subgroup among the mature B-cell neoplasms; it is characterized by extranodal involvement and CNS progression with an extremely poor prognosis.

TOP ABSTRACT Introduction Design and Methods Results Discussion Acknowledgments: References

 
we gratefully appreciate the contribution of Masako Toyosaki (Tokai University School of Medicine), Keiko Hodohara (Shiga University of Medical Sciences), Takeshi Shimomura (Hiroshima-Nishi Medical Center), Naoto Takahashi (Akita University School of Medicine), Isamu Sugiura (Toyohashi Municipal Hospital), Tomofumi Yano (Okayama Rosai Hospital), Hideho Wada (Kawasaki Medical School), Saburo Tsunoda (Tochigi Cancer Center), Makoto Takeuchi (Minami-Okayama Medical Center), Akira Tamekane (Hyogo Prefectural Amagasaki Hospital), Kunihiro Tsukasaki (Atomic Bomb Disease Institute Nagasaki University Graduate School of Biomedical Science), Yoshikazu Ito (Tokyo Medical University), Chizuko Hashimoto (Kanagawa Cancer Center), and Atsuko Fujita (Yokohama City University Medical Center) in the collection of clinical and pathological data. We also thank Kumiko Tsuyama and Yukiko Natsukari for secretarial work.

 
Authorship and Disclosures

NT: designed the research, collected and analyzed data and wrote the paper; MT: performed the pathological research; NN: designed the research, analyzed and interpreted data, and performed the pathological review; KT and JK: performed the pathological review; SM, KM AK, RH, YY, YM, SF and TH: collected data and performed the clinical research; YI: finally approved the submission; MI: critically reviewed the manuscript and gave an important intellectual contribution. All authors gave their approval to the manuscript submission.

The authors report no potential conflicts of interest.

Received for publication December 29, 2008. Revision received February 24, 2009. Accepted for publication February 25, 2009.

TOP ABSTRACT Introduction Design and Methods Results Discussion Acknowledgments: References

 

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