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. Author manuscript; available in PMC: 2013 Jul 1.
Published in final edited form as: Curr Opin Hematol. 2012 Jul;19(4):299–304. doi: 10.1097/MOH.0b013e328353bbbd

Biology of Double-Hit B Cell Lymphomas

R Coleman Lindsley a,b, Ann S LaCasce a
PMCID: PMC3389520  NIHMSID: NIHMS384771  PMID: 22504522

Abstract

Purpose of review

Mature B cell lymphomas bearing concurrent chromosomal rearrangement of MYC/8q24 and BCL2/18q21 are associated with an aggressive clinical course and resistance to conventional chemotherapy. This review summarizes the recent literature regarding the clinical and pathologic features of Double-hit lymphomas and outlines current questions about the most accurate and inclusive definition of the disease.

Recent findings

Comprehensive evaluation of large series of aggressive mature B cell neoplasms reveals recurrent chromosomal aberrations in the majority of cases. A subset of these lymphomas harbors multiple rearrangements, including MYC/8q24 in combination with BCL2/18q21 and/or BCL6/3q27, and displays a particularly aggressive clinical course. Recent data suggest that consideration of additional features, such as copy number alteration, quantitative protein expression, and biologic pathway activation may be important in deriving a more accurate definition of Double-hit lymphoma. Despite the poor prognosis associated with this subset of lymphomas, there remains no evidence for a risk-adapted treatment strategy and no clinical, pathologic, or genetic factors predict response to therapy.

Summary

“Double-hit lymphoma” remains an incompletely characterized disease entity. Large, multicenter studies are needed to define relevant clinical, genetic, and pathologic variables and to characterize appropriate risk-adapted treatment strategies.

Keywords: Lymphoma, double-hit, MYC, BCL2, BCL6

INTRODUCTION

The term ‘double-hit’ lymphoma was initially used to describe mature B cell neoplasms bearing concurrent rearrangements of the BCL2/18q21 and MYC/8q24 loci. Though relatively rare, double-hit lymphomas have been the subject of intensified investigation due to their aggressive clinical course and resistance to conventional chemotherapy [1–8]. As clinical and molecular evidence accumulates, ‘double-hit lymphoma’ has been broadened to include any aggressive, mature B cell neoplasm with a chromosomal breakpoint affecting the MYC locus and one or more additional rearrangements recurrently associated with lymphoma, most commonly BCL2, BCL6 or CCND1 [9,10]. Moreover, recent analysis of copy number alterations and pathway mutations prompt consideration of an expanded definition of clinically relevant double-hit lesions [8,11*,12, 13**].

THE INCIDENCE AND EVOLVING DEFINITION OF DOUBLE-HIT LYMPHOMA

Initial case series have proven invaluable in defining double-hit lymphoma as an important disease entity with distinctive clinical behavior. However, recent data from larger series of unselected patients suggest that the true incidence of double-hit lymphomas may be revealed only by comprehensive molecular analysis. Barrans, et al. evaluated the frequency of MYC, BCL2, and BCL6 rearrangements in a population-based cohort of 303 patients with previously untreated, de novo diffuse large B cell lymphoma, the majority of whom received R-CHOP chemotherapy [14**]. 245 were evaluable at the MYC locus and of these 35 (14%) were found to have MYC/8q24 rearrangements. Of those with MYC rearrangements, 83% (29/35) had concurrent abnormalities of BCL2/18q21 and/or BCL6/3q27. The majority of multiple-hit cases in this series were ‘classic’ MYC/BCL2 double-hit (19/29), while the remaining were either MYC/BCL6 double-hit (3/29) or MYC/BCL2/BCL6 triple-hit (7/29).

Foot and colleagues provided an unbiased assessment of MYC/8q24, BCL2/18q21, and BCL6/3q27 status in a prospective, sequential series of aggressive and high-grade B cell non-Hodgkin lymphomas (n = 162) [13**]. Using comprehensive FISH analysis on formalin-fixed paraffin-embedded tissue sections, they evaluated for rearrangement and increased copy number (ICN), with a 99% technical success rate. Importantly, all new cases of aggressive B cell NHL, regardless of histology, were included in the study, with the exception of those meeting current WHO criteria for Burkitt Lymphoma. The majority of cases were defined per current WHO classification as DLBCL, not otherwise specified (n = 121) with other cases representing a range of histologies, including Intermediate BL/DLBCL (n = 23) and DLBCL as post-transplant lymphoproliferative disorder (n = 9). It should be noted that in this study, all cases of double-hit lymphoma were automatically classified as intermediate BL/DLBCL based on genetic features, independent of morphology.

In this study, abnormalities of MYC/8q24, BCL2/18q21, or BCL6/3q27 were remarkably common, with rearrangements and/or ICN detectable in 74% of cases of cases. Rearrangements involving MYC/8q24 (22%) were most frequent, followed by BCL6/3q27 (18% conclusive; 5% abnormal but not conclusive) and IGH-BCL2 (18%). Double-hit lymphomas, defined by concurrent rearrangements of MYC and either BCL2 or BCL6, were diagnosed in 14% of cases. The prevalence of copy number increase (3–6 copies) or amplification (>6 copies) was striking, and was found at MYC/8q24 in 19% of samples, BCL2/18q21 in 31%, and BCL6/3q27 in 22%. Since clinical data were not included in this analysis, the clinicopathologic features and prognostic implications of ICN relative to chromosomal rearrangement are unknown. Further, the frequency of cases harboring concurrent copy number alterations at multiple loci or a combination of rearrangement and ICN was not reported.

These studies raise important questions about the most accurate, inclusive, and clinically relevant definition of double-hit lymphoma. Indeed, there is some evidence to suggest that copy number alteration of MYC/8q24 and BCL2/18q21 may have clinical consequences that are indistinguishable from rearrangements of these loci [8,11*,12]. Increased MYC copy number has been correlated with increased mRNA level in DLBCL, suggesting that the functional consequence of enforced MYC expression, independent of the specific genetic lesion, is most relevant to disease biology [15].

Results from the recent next generation sequencing studies have raised similarly provocative questions about a more biologic definition of double-hit lymphoma. Using whole exome sequencing followed by targeted resequencing, a number of recurrent point mutations were identified in DLBCL [16*]. Among these, oncogenic mutations in MYC (6.3%) and mutations in BCL2 (9.0%) were identified, confirming previous results showing accumulation of mutations in MYC and other proto-oncogenes [17]. Though mutations in BCL6 were not reported in this study, 11.7% of cases harbored inactivating mutations in PRDM1, a target of BCL6 repression required for terminal B cell differentiation. Notably, biallelic inactivation of PRDM1 was found to be mutually exclusive of BCL6 rearrangement, suggesting a functional equivalence of enforced BCL6 expression and abrogated PRDM1 activity.

B cell lymphomas with more than two lymphoma-specific chromosomal abnormalities, so called triple- or quadruple-hit lymphomas have been described [12, 13**,14**,18–20]. In their unselected series, Foot and colleagues reported that among cases with multiple abnormalities (14.4% of total), 30% harbored concurrent aberrancies of MYC, BCL2, and BCL6 [13**]. Similarly, Tomita, et al. found additional BCL6 rearrangements in 26% of cases of MYC/BCL2 double-hit lymphoma [18].

CLINICOPATHOLOGIC FEATURES

Double-hit lymphomas bearing concurrent rearrangements of MYC/8q24 and BCL2/18q21 are clinically distinct from Burkitt Lymphoma and DLBCL. The median age of diagnosis of MYC/BCL2 double-hit lymphomas is in the 6th–7th decade, significantly older than sporadic BL (4th decade) and younger than DLBCL (7th decade) [3,7,8,21]. Across series, MYC/BCL2 double-hit lymphomas tend to present with advanced stage (Ann Arbor III/IV), high or high-intermediate International Prognostic Index (IPI), and increased LDH. There is a high frequency of extranodal disease, most commonly involving bone marrow/peripheral blood, central nervous system, or pleural effusions. When compared to IPI-matched DLBCL, only younger age (64 vs. 71 years), higher median LDH at presentation (727 U/L vs. 366 U/L), and increased frequency of bone marrow involvement (59% vs. 23%) are significantly associated with MYC/BCL2 double-hit lymphomas [8].

On routine cytogenetic analysis, double-hit lymphomas nearly always possess complex karyotypes, as defined by >2 numerical and/or structural aberrations [8,11*,18]. This context of chromosomal complexity is thought to be critical in determining the biological and clinical effects of MYC rearrangement. In fact, aggressive B cell lymphomas with MYC rearrangement and complex karyotype are associated with poor clinical outcomes, independent of documented second-hit lesions [22]. However, a subset of these patients may harbor cryptic second-hit lesions that escape detection by FISH and routine cytogenetics, as suggested by recent RNA-sequencing analysis [23*].

The median proliferation index of double-hit lymphomas approaches 90% [10]. Recent series have confirmed this observation, but noted a wide range of proliferative index (40–100%), even in disease that otherwise behaves in a clinically aggressive manner [11*]. In an unselected series, nearly 20% of samples with MYC rearrangements had a proliferative index <80% [13**]. Together, these data suggest that a relatively low proliferative index should not itself deter full evaluation for double-hit lesions.

With increasing recognition of the incidence and prognostic importance of double-hit lymphomas, several groups have performed comprehensive FISH analysis in specific populations of B cell NHL. In a retrospective study of aggressive B cell lymphomas of the GI tract, MYC rearrangements were identified in 22% of cases, 61% of which were Burkitt Lymphoma. MYC rearrangements were rarely associated with concurrent rearrangement of BCL6 (8%) and never with BCL2 [24*], suggesting a restricted distribution of extranodal disease sites in double-hit lymphoma. In a population-based pediatric cohort, MYC rearrangements were found in 44% (7/16) of cases not meeting criteria for Burkitt lymphoma, only two of which were found to have concurrent BCL6 ICN [25*]. No cases with aberrancies of the BCL2 locus were identified, consistent with previous reports demonstrating absence of t(14;18)(q32;q21) in pediatric DLBCL [26].

MORPHOLOGIC CLASSIFICATION

Double-hit lymphomas are, in principle, defined genetically and represent a morphologic continuum between Burkitt Lymphoma and DLBCL. In series unselected by histology, between 30–40% of MYC/BCL2 double-hit lymphomas are classified as DLBCL, with rare cases classified as B-lymphoblastic lymphoma/leukemia or Follicular lymphoma [2,8,11*]. The majority of cases, however, display morphologic or immunophenotypic characteristics inconsistent with established diagnostic entities. In fact, no unifying pathologic features of double-hit lymphomas have been identified. Based on characteristic genetics, adverse clinical outcomes, and ‘gray-zone’ histology, the 2008 WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues assigned a new category aimed in part at capturing double-hit lymphomas. This category, B cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BCLU), comprises a heterogeneous array of lymphomas with variable clinical behavior and a range of genetic lesions [21].

The diagnosis of BCLU is invoked to classify aggressive, mature B cell neoplasms that fail to meet classical morphologic, immunophenotypic, and genetic definitions of Burkitt lymphoma or DLBCL. BCLU includes lymphomas that represent “true biologic” BL, so-called molecular Burkitt Lymphoma (mBL), that are distinguished from “true biologic” DLBCL and double-hit lymphomas by gene expression signature [22]. In their recent BCLU series, Lin and colleagues confirmed that double-hit lymphomas are enriched within this morphologic category, with 46% of cases harboring concurrent MYC/BCL2 rearrangements. However, 42% of BCLU cases lacked chromosomal aberrancy at the MYC locus, precluding a diagnosis of double-hit lymphoma or perhaps suggesting other mechanisms of MYC or BCL2 pathway activation [27*].

Among patients with double-hit lymphoma, morphology alone has not reliably been demonstrated to carry prognostic significance [2,8,11*]. Further, diagnosis of BCLU does not alone warrant intensified therapy, independent of genetics [27*]. The WHO BCLU assignment thus serves primarily as a provisional category upon which to base studies aimed at defining improved therapies and elucidating fundamental disease biology. It should be emphasized that BCLU should not be viewed as a morphologic proxy for double-hit genetics.

ONTOGENY

Most MYC rearrangements in mature B cell neoplasms occur as an unwanted consequence of AID-dependent class switch recombination and somatic hypermutation during the germinal center reaction. In Burkitt lymphoma, IG/MYC translocation is the primary, transforming event and is not typically associated with other chromosomal abnormalities. By contrast, rearrangement of MYC in double-hit lymphomas is thought to be a secondary event, arising in the context of pre-existing, lymphoma-associated lesions and relative chromosomal complexity. The increased frequency of immunoglobulin light chain (IGL) and non-immunoglobulin MYC translocation partners in double-hit lymphoma is invoked to support this concept of tumor ontogeny. Whereas the MYC translocation partner is within the immunoglobulin heavy chain (IGH) locus in 80–90% of Burkitt Lymphoma [8,22], the majority of MYC partners in double-hit lymphoma are at ‘alternative’ sites, such as IGL or non-IG loci [8,11*,13**,22].

MYC/BCL2 double-hit lymphomas commonly display a germinal center B cell (GCB) phenotype, with immunohistochemistry positive for CD10 and BCL6 and negative for MUM1/IRF4 [8,11,14**]. This finding is consistent with the known enrichment of t(14;18)(q32;q21) translocations in the GCB subset of DLBCL [28]. An important caveat, however, is the incomplete clinicopathologic characterization of double-hit lymphomas that harbor second-hit chromosomal aberrancies other than IGH/BCL2. Specifically, both BCL6 rearrangement and increased BCL2 copy number are found more commonly in large B cell lymphomas of non-GCB origin [13**,29]. As existing evidence suggests that BCL6 rearrangement and BCL2 copy number alteration confer an adverse clinical risk similar to conventional BCL2 rearrangements [8,11*], it remains to be determined whether the prognostic implications of cell of origin assignment in DLBCL also apply to double-hit lymphoma.

Most double-hit lymphomas arise without history or evidence of indolent lymphoma. In fact, 80–85% of double-hit lymphomas represent de novo diagnoses, while 15–20% are found in patients with a prior diagnosis of indolent lymphoma, most often follicular lymphoma (FL) [8,11*]. The molecular ontogeny of MYC-related transformation of FL is well demonstrated by two recent case reports of patients who developed B cell lymphomas with foci of high-grade “Burkitt-like” morphology in the setting of otherwise histologically low-grade FL [30,31]. In both cases, the high-grade component harbored MYC/8q24 and BCL2/18q21 rearrangements, while the low-grade component had t(14;18)(q32;q21) alone. In one study, the clonal relationship of the disparate disease morphologies was demonstrated by sequencing of the immunoglobulin heavy chain variable region [31]. These reports are consistent with established data implicating MYC as a rare, though prognostically important, progression factor in FL [5,32–34]. Lastly, concurrent MYC/BCL2 rearrangements have been identified in cases of FL with blastoid morphology and are associated with adverse clinical outcomes [35,36].

TREATMENT OUTCOMES

Double-hit lymphomas are highly resistant to standard chemotherapy, independent of regimen intensity or inclusion of rituximab. Median survival in recently published series ranges widely from 4.5 to 18.5 months [2,4,7,8,11*,14**,18], but is significantly shorter compared to survival of patients with Burkitt lymphoma or IPI-matched DLBCL [8].

In their study of 303 patients with DLBCL, Barrans, et al. showed that overall survival at 2 years was significantly worse in patients with MYC/8q24 rearrangements compared to those with unrearranged MYC/8q24 (35% vs. 61%) [14**]. Importantly, 83% of patients with MYC rearrangements in this series also harbored rearrangement of BCL2 and/or BCL6, suggesting that in this study “MYC-rearranged DLBCL” may serve primarily as a surrogate for “double-hit DLBCL”. Patients in this study were treated uniformly with R-CHOP, leaving unanswered the question of whether risk-adapted intensification of therapy may attenuate the observed survival difference.

In a retrospective analysis of 52 patients with MYC/BCL2 double-hit lymphoma, Li and colleagues reported a median overall survival of 18.6 months. Importantly, no difference in survival was observed between patients with rearranged MYC or BCL2 loci when compared to those with increased copy number. This again suggests that enforced oncogene expression, regardless of genetic mechanism, may be most clinically and biologically relevant. The majority of patients in this study received high-intensity chemotherapy regimens (primarily R-hyper-CVAD), while the remaining received a moderate-intensity regimen (R-CHOP). 21% of patients received consolidation with either allogeneic stem cell transplantation or high-dose chemotherapy with autologous stem cell rescue. While elevated LDH, >1 extranodal site, and IPI > 2 were associated with shorter survival in univariate analysis, neither intensity of treatment regimen nor stem cell transplantation impacted outcomes [11*].

PROGNOSTIC AND PREDICTIVE FACTORS

Among patients with double-hit lymphomas, few prognostic variables have been identified consistently across studies. As in DLBCL without double-hit lesions, the International Prognostic Index (IPI), LDH, extent of extranodal disease, and performance status are informative regarding prognosis [2,11*]. Several studies have found that in MYC/BCL2 double-hit lymphoma, non-DLBCL morphology portends shorter survival than DLBCL morphology [2,8], while another found no association between survival and morphology [11*], There is similar inconsistency regarding the prognostic importance of BCL2 protein expression, non-IG/MYC translocations, and history of indolent lymphoma [2,11*,27*], Several small series suggest that lymphomas bearing three (MYC/BCL2/BCL6) or four (MYC/BCL2/BCL6/CCND1) concurrent rearrangements may fare even worse than double-hit lymphomas, but with small numbers and lack of uniform treatment protocols, it is difficult to draw conclusions regarding definitive differences in clinical outcomes [18,20].

Unfortunately, no clinical or pathologic features currently provide prospective guidance regarding risk-adapted intensification (or de-intensification) of therapy. Larger, multicenter studies are required to determine whether specific clinical, pathologic, or genetic variables might offer reliable information about prognosis or predict response to specific therapies.

CONCLUSION

Double-hit B cell lymphomas have a poor prognosis and are associated with early relapse or primary resistance to conventional chemotherapy. In addition to the well-characterized implications of dual rearrangement of MYC/8q24 and BCL2/18q21, recent studies suggest future analysis should focus on additional loci (i.e. BCL6/3q27) and on more diverse mechanisms of pathway dysregulation (i.e. copy number alterations, aberrant protein expression, somatic point mutation, small insertion/deletions). Population-based studies will allow the most accurate and clinically relevant definition of double-hit lymphomas and prospective clinical trials will determine whether intensified therapeutic approaches can improve outcomes.

Key points.

  • Double-hit lymphomas are mature B cell neoplasms with concurrent chromosomal abnormalities affecting MYC/8q24 and one or more additional loci that are recurrently affected in lymphoma, most commonly BCL2/18q21 or BCL6/3q27.

  • Double-hit B cell lymphomas have a poor prognosis and are associated with primary resistance to conventional chemotherapy or early disease relapse.

  • Recent studies suggest that the incidence of double-hit lymphomas is currently underestimated.

  • Prospective clinical trials are required to determine whether intensification of therapy will yield improved clinical outcomes.

Acknowledgements

RCL is supported by the National Institutes of Health (T32 CA009172-37).

Abbreviations

DLBCL

diffuse large B cell lymphoma

ICN

increased copy number

IPI

International Prognostic Index

GCB

germinal center B cell

LDH

lactate dehydrogenase

IGH

immunoglobuling heavy chain

IGL

immunoglobulin light chain

BL

Burkitt lymphoma

FL

follicular lymphoma

BCLU

B cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma

R-CHOP

rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone

Footnotes

Conflicts of interest: none

References and Recommended Reading

  • 1.Bertrand P, Bastard C, Maingonnat C, et al. Mapping of MYC breakpoints in 8q24 rearrangements involving non-immunoglobulin partners in B-cell lymphomas. Leukemia. 2007 Mar.21(3):515–523. doi: 10.1038/sj.leu.2404529. [DOI] [PubMed] [Google Scholar]
  • 2.Johnson NA, Savage KJ, Ludkovski O, et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood. 2009 Sep.114(11):2273–2279. doi: 10.1182/blood-2009-03-212191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Kanungo A, Medeiros LJ, Abruzzo LV, Lin P. Lymphoid neoplasms associated with concurrent t(14;18) and 8q24/c-MYC translocation generally have a poor prognosis. Mod Pathol. 2006 Jan.19(1):25–33. doi: 10.1038/modpathol.3800500. [DOI] [PubMed] [Google Scholar]
  • 4.Le Gouill S, Talmant P, Touzeau C, et al. The clinical presentation and prognosis of diffuse large B-cell lymphoma with t(14;18) and 8q24/c-MYC rearrangement. Haematologica. 2007 Oct.92(10):1335–1342. doi: 10.3324/haematol.11305. [DOI] [PubMed] [Google Scholar]
  • 5.Macpherson N, Lesack D, Klasa R, et al. Small noncleaved, non-Burkitt's (Burkit-Like) lymphoma: cytogenetics predict outcome and reflect clinical presentation. J. Clin. Oncol. 1999 May;17(5):1558–1567. doi: 10.1200/JCO.1999.17.5.1558. [DOI] [PubMed] [Google Scholar]
  • 6.Niitsu N, Okamoto M, Miura I, Hirano M. Clinical features and prognosis of de novo diffuse large B-cell lymphoma with t(14;18) and 8q24/c-MYC translocations. Leukemia. 2009 Jan.23(4):777–783. doi: 10.1038/leu.2008.344. [DOI] [PubMed] [Google Scholar]
  • 7.Tomita N. BCL2 and MYC dual-hit lymphoma/leukemia. J Clin Exp Hematop. 2011;51(1):7–12. doi: 10.3960/jslrt.51.7. [DOI] [PubMed] [Google Scholar]
  • 8.Snuderl M, Kolman OK, Chen Y-B, et al. B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma. Am. J. Surg. Pathol. 2010 Mar.34(3):327–340. doi: 10.1097/PAS.0b013e3181cd3aeb. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Salaverria I, Siebert R. The gray zone between Burkitt's lymphoma and diffuse large B-cell lymphoma from a genetics perspective. Journal of Clinical Oncology. 2011 May 10;29(14):1835–1843. doi: 10.1200/JCO.2010.32.8385. [DOI] [PubMed] [Google Scholar]
  • 10.Aukema SM, Siebert R, Schuuring E, et al. Double-hit B-cell lymphomas. Blood. 2011 Feb.117(8):2319–2331. doi: 10.1182/blood-2010-09-297879. [DOI] [PubMed] [Google Scholar]
  • 11. Li S, Lin P, Fayad LE, Lennon PA, et al. B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome. Mod Pathol. 2011 Oct. doi: 10.1038/modpathol.2011.147. This case series confirms the histologic heterogeneity and adverse clinical outcome of double-hit lymphomas. Importantly, they demonstrate that copy number gain of MYC or BCL2 confers a poor prognosis that is indistinguishable from rearrangement of the same loci.
  • 12.Yoon SO, Jeon YK, Paik JH, et al. MYC translocation and an increased copy number predict poor prognosis in adult diffuse large B-cell lymphoma (DLBCL), especially in germinal centre-like B cell (GCB) type. Histopathology. 2008 Aug.53(2):205–217. doi: 10.1111/j.1365-2559.2008.03076.x. [DOI] [PubMed] [Google Scholar]
  • 13. Foot NJ, Dunn RG, Geoghegan H, et al. Fluorescence in situ hybridisation analysis of formalin-fixed paraffin-embedded tissue sections in the diagnostic work-up of non-Burkitt high grade B-cell non-Hodgkin“s lymphoma: a single centre”s experience. Journal of Clinical Pathology. 2011 Sep.64(9):802–808. doi: 10.1136/jclinpath-2011-200015. This systematic survey of aggressive, mature B cell neoplasms found a 14% incidence of double-hit lymphoma and frequent additional copy number alterations of MYC, BCL2, and BCL6. This suggests that double-hit lymphomas may currently be underdiagnosed.
  • 14. Barrans S, Crouch S, Smith A, et al. Rearrangement of MYC Is Associated With Poor Prognosis in Patients With Diffuse Large B-Cell Lymphoma Treated in the Era of Rituximab. Journal of Clinical Oncology. 2010 Jul.28(20):3360–3365. doi: 10.1200/JCO.2009.26.3947. This large study identified double- or triple-hit rearrangements in at least 12% of DLBCL cases. Adverse outcomes associated with MYC-rearrangement in this study may reflect the large proportion of double-hit lesions (83%) in MYC-rearranged cases.
  • 15.Stasik CJ, Nitta H, Zhang W, et al. Increased MYC gene copy number correlates with increased mRNA levels in diffuse large B-cell lymphoma. Haematologica. 2010 Apr.95(4):597–603. doi: 10.3324/haematol.2009.012864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 2011 Jul.43(9):830–837. doi: 10.1038/ng.892. Whole exome sequencing of DLBCL samples demonstrates recurrent somatic point mutation in proto-oncogenes, tumor suppressors, suggesting multiple mechanisms of core lymphoma pathway activation.
  • 17.Pasqualucci L, Neumeister P, Goossens T, et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature. 2001 Jul.412(6844):341–346. doi: 10.1038/35085588. [DOI] [PubMed] [Google Scholar]
  • 18.Tomita N, Tokunaka M, Nakamura N, et al. Clinicopathological features of lymphoma/leukemia patients carrying both BCL2 and MYC translocations. Haematologica. 2009 Jun.94(7):935–943. doi: 10.3324/haematol.2008.005355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Tibiletti MG, Martin V, Bernasconi B, et al. BCL2, BCL6, MYC, MALT 1, and BCL10 rearrangements in nodal diffuse large B-cell lymphomas: a multicenter evaluation of a new set of fluorescent in situ hybridization probes and correlation with clinical outcome. Human Pathology. 2009 May;40(5):645–652. doi: 10.1016/j.humpath.2008.06.032. [DOI] [PubMed] [Google Scholar]
  • 20.Bacher U, Haferlach T, Alpermann T, et al. Several lymphoma-specific genetic events in parallel can be found in mature B-cell neoplasms. Genes Chromosomes. Cancer. 2011 Jan.50(1):43–50. doi: 10.1002/gcc.20831. [DOI] [PubMed] [Google Scholar]
  • 21.Kluin P, Harris N, Stein H, Leoncini L. B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008. pp. 265–266. [Google Scholar]
  • 22.Hummel M, Bentink S, Berger H, et al. A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling. N Engl J Med. 2006 Jun.354(23):2419–2430. doi: 10.1056/NEJMoa055351. [DOI] [PubMed] [Google Scholar]
  • 23. Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011 Jul.476(7360):298–303. doi: 10.1038/nature10351. RNA-sequencing demonstrates that DLBCL may harbor cryptic rearrangements that escape detection by FISH and routine cytogenetics, suggesting potential underdiagnosis of double-hit lymphomas.
  • 24. Choi S-Y, Kim SJ, Kim WS, et al. Aggressive B cell lymphomas of the gastrointestinal tract: clinicopathologic and genetic analysis. Virchows Arch. 2011 Nov.459(5):495–502. doi: 10.1007/s00428-011-1153-3. Double-hit lymphomas are rarely identified in GI tract lymphomas, suggesting a restricted distribution of extranodal sites of disease.
  • 25. Lu B, Zhou C, Yang W, et al. Morphological, immunophenotypic and molecular characterization of mature aggressive B-cell lymphomas in Chinese pediatric patients. Leuk Lymphoma. 2011 Dec.52(12):2356–2364. doi: 10.3109/10428194.2011.602772. This study confirms the low incidence of double-hit lymphoma in pediatric patients.
  • 26.Oschlies I, Klapper W, Zimmermann M, et al. Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal-center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (Berlin-Frankfurt-Munster) Multicenter Trial. Blood. 2006 May 15;107(10):4047–4052. doi: 10.1182/blood-2005-10-4213. [DOI] [PubMed] [Google Scholar]
  • 27. Lin P, Dickason TJ, Fayad LE, et al. Prognostic value of MYC rearrangement in cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Cancer. 2011 Aug. doi: 10.1002/cncr.26433. Although MYC/BCL2 double-hit lymphoma is enriched (35%) within the provisional WHO category "B cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma", this morphologic assignment is not a proxy for double-hit genetics.
  • 28.Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jun.346(25):1937–1947. doi: 10.1056/NEJMoa012914. [DOI] [PubMed] [Google Scholar]
  • 29.Nogai H, Dörken B, Lenz G. Pathogenesis of non-Hodgkin's lymphoma. Journal of Clinical Oncology. 2011 May 10;29(14):1803–1811. doi: 10.1200/JCO.2010.33.3252. [DOI] [PubMed] [Google Scholar]
  • 30.Hwang YY, Loong F, Chung LP, Chim CS. Atypical Burkitt's lymphoma transforming from follicular lymphoma. Diagn Pathol. 2011;6:63. doi: 10.1186/1746-1596-6-63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Kobayashi H, Ichikawa M, Hangaishi A, et al. Concurrent development of “Burkitt-like” lymphoma and BCL-2-rearranged low-grade B cell lymphoma sharing the same germinal center origin. Int. J. Hematol. 2011 Jan.93(1):112–117. doi: 10.1007/s12185-010-0741-3. Using IGVH sequencing, this report demonstrates the clonal relationship of concurrently diagnosed low-grade and double-hit lymphomas.
  • 32.Christie L, Kernohan N, Levison D, et al. C-MYC translocation in t(14;18) positive follicular lymphoma at presentation: An adverse prognostic indicator? Leuk Lymphoma. 2008 Mar.49(3):470–476. doi: 10.1080/10428190701836845. [DOI] [PubMed] [Google Scholar]
  • 33.Johnson NA, Al-Tourah A, Brown CJ, et al. Prognostic significance of secondary cytogenetic alterations in follicular lymphomas. Genes Chromosomes Cancer. 2008 Dec.47(12):1038–1048. doi: 10.1002/gcc.20606. [DOI] [PubMed] [Google Scholar]
  • 34.Relander T, Johnson NA, Farinha P, et al. Prognostic Factors in Follicular Lymphoma. Journal of Clinical Oncology. 2010 Jun.28(17):2902–2913. doi: 10.1200/JCO.2009.26.1693. [DOI] [PubMed] [Google Scholar]
  • 35.Mohamed AN, Palutke M, Eisenberg L, Al-Katib A. Cancer Genet. Cytogenet. 1. Vol. 126. Elsevier; 2001. Chromosomal analyses of 52 cases of follicular lymphoma with t (14; 18), including blastic/blastoid variant; pp. 45–51. [DOI] [PubMed] [Google Scholar]
  • 36.Vaidyanathan G, Ngamphaiboon N, Hernandez-Ilizaliturri FJ. Clinical spectrum and prognosis of follicular lymphoma with blastoid transformation: case series and a review of the literature. Annals of Hematology. 2011 Aug.90(8):955–962. doi: 10.1007/s00277-011-1162-y. [DOI] [PubMed] [Google Scholar]

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