High-Grade B-cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements
Kate Berry, MBBS, BBus (Hons), Pathology Queensland
High-grade B-cell lymphoma
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements
Definition/Description of Disease
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements is a clinically aggressive lymphoma with poor prognosis. It is defined as a distinct entity which includes mature B cell neoplasms harbouring both MYC and BCL2 and/or BCL6 rearrangements, as detected by a cytogenetic/molecular method such as FISH, except for cases of proven follicular lymphoma in the absence of a concurrent high-grade component, or where the disease is classified as B-lymphoblastic leukaemia/lymphoma.
“Double-Hit Lymphoma (HGBL-DH)” in cases with MYC and BCL2 OR BCL6 rearrangement.
“Triple-Hit Lymphoma (HGBL-TH)” in cases with MYC, BCL2 AND BCL6 rearrangement.
Obsolete: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma
- HGBL DH/TH accounts for 3-9% of diffuse large B-cell lymphoma and approximately 13.3% of the germinal centre B-cell-like subtype
- HGBL DH/TH accounts for approximately 1.7% of activated B-cell-like diffuse large B-cell lymphoma
- These tumours overwhelmingly show concurrent MYC and BCL6 translocations, and the existence of activated B-cell-like high grade B cell lymphoma with BCL2 translocation is controversial
- MYC translocations occur concurrently with BCL2 translocations in 57-87% of cases and with BCL6 translocations in 5-30% of cases. MYC, BCL2 and BCL6 translocations ("triple hit") are present in 7-15%
- The diagnosis is slightly more common in males
- Median age at diagnosis is 6th to 7th decade
Patients typically show Ann Arbor stage IV disease at diagnosis with involvement of more than one extra-nodal site and a high International Prognostic Index (IPI) score. B symptoms (fever, night sweats and weight loss) are common at diagnosis, as is poor performance status. Patients almost invariably show elevated serum lactate dehydrogenase and, less frequently, leucocytosis.
Sites of Involvement
· Lymph nodes
· Extra-nodal sites
· Bone marrow
· Central nervous system
The morphological appearances of HGBL-DH/TH are variable, and histology alone is an unreliable predictor of double- or triple-hit status. Recognised morphologies include features of diffuse large B cell lymphoma (DLBCL), NOS, with a diffuse growth pattern, variably sized nuclei with irregular nuclear contours, often with plentiful basophilic cytoplasm and variable numbers of mitotic figures and tingible-body macrophages; Burkitt-like cytomorphology, with a diffuse proliferation of medium-sized to large, often very monomorphic, lymphoid cells with intermixed tingible-body macrophages and plentiful mitotic and apoptotic figures, imparting a “starry-sky” appearance; or an intermediate appearance with sheets of medium-sized cells with finely granular blastoid-like nuclear chromatin, inconspicuous nucleoli and scant cytoplasm..
When classified by cell of origin based on immunohistochemistry according to the Hans algorithm, the vast majority (70-90%) of HGBL-DH/TH are of germinal-centre B-type. This is especially true of HGBL with MYC and BCL2 translocation which is overwhelmingly shown to be of germinal centre origin, as per the Hans algorithm or by cell of origin gene expression profiling. Some authors regard this entity, along with triple hit cases, to be exclusively germinal centre B-cell derived and believe the small numbers of ABC cases identified by some studies to have been misclassified as a result of cell of inaccurate cell of origin testing.
Although HGBL-DH/TH includes a significantly higher proportion of tumours with immunohistochemically detectable overexpression of MYC and BCL2 and/or BCL6 than DLBCL as a whole, in the absence of confirmed gene rearrangements this is insufficient for diagnosis. The high prevalence of C-MYC protein expression in DLBCL in the absence of chromosomal translocation suggests alternative mechanisms may lead to similar overexpression, such as MYC gene mutations or amplifications.
Although the proliferative index of these tumours is variable, in contrast to Burkitt lymphoma the Ki67 staining rate is is predominantly lower than 90% when measured by immunohistochemistry.
|Positive (almost universal)||CD20|
|Positive (typically)||CD10, BCL2, BCL6, MYC, MIB-1|
|Negative (almost universal)||CD3, cyclin D1, TdT|
|Negative (typically)||CD5, MUM1, EBER|
Chromosomal Rearrangements (Gene Fusions)
This subtype of B-cell lymphoma is defined by a rearrangement of the MYC proto-oncogene, located on chromosome 8q24. In 39-65% of cases the translocation partner is an immunoglobulin gene, most commonly the IGH region on chromosome 14q32 with the IGK (2p12) and IGL (22q11.2) gene loci less frequently involved. Non-IG gene partners include 9p13 and 3q27.3 (BCL6). Additionally, all cases must harbour a BCL2 (18q21.3) and/or BCL6 (3q27.3) rearrangement.
|Chromosomal Rearrangement||Genes in Fusion (5’ or 3’ Segments)||Pathogenic Derivative||Prevalence|
High-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements almost invariably display a complex karyotype with many cytogenetic abnormalities. Gains of chromosomes 8q and 12q are more common in HGBL-DH/TH than in cases with isolated MYC translocation. 12q12-q15 copy-number gain is significantly more common in HGBL with MYC and BCL2 translocation than in cases with BCL6 translocation.
Other common aberrations include
Gene Mutations (SNV/INDEL)
Due to the relatively recent classification of HGBL with MYC and BCL2 and/or BCL6 translocation as a specific pathological entity, combined with small sample sizes, comprehensive data on gene mutation prevalence is not currently available. However, several studies have shown the mutational profile of HGBL DH/TH to differ significantly from that of DLBCL, NOS. Frequently mutations are associated with apoptosis and cell cycle pathways known to be associated with poor prognosis in DLBCL patients, including SOCS1 non-truncating mutations and mutations in CREBBP and FOX01. HGBL DH/TH also shows a significantly higher number of IGH and MYC mutations than DLBCL with isolated MYC translocation. MYC hotspot mutations occur more frequently in cases in which the MYC translocation partner is an immunoglobulin gene, and are associated with high MYC protein expression. Amongst the most frequently mutated genes, somatic CREBBP mutations have been shown to inhibit TP53 tumour suppressor activity through activation of the BCL6 oncoprotein. KMT2D mutations consist primarily of frameshift deletions and stop gain alterations with subsequent loss of protein function.
Amongst HGBL DH/TH cases, the nature of the secondary translocation also affects the mutational landscape, with TP53 mutations, associated with significantly worse overall survival, occurring more frequently in HGBL with MYC and BCL2 translocation than cases with MYC and BCL6 translocations or triple-hit tumours.
In one study, both HGBL with MYC and BCL2 translocations and triple-hit cases had a higher mutational load and more frequent mutations in BCL2, KMTD2, CREBBP, EZH2 and TNFRSF14 than DLBCL with isolated MYC translocation. These mutations are cardinal features of follicular lymphoma and are also commonly seen in DLBCL, NOS. In addition, BCL2 translocated cases harboured additional mutations (MYC, GNA13, TP53, P2RY8, PIM1, CCND3, B2M, EBF1 and S1PR2) associated with high-grade transformation of follicular lymphoma, suggesting a possible derivation from follicular lymphoma following acquisition of a MYC translocation.
Overall, HGBL with MYC and BCL6 translocation shows a different and more heterogenous mutation profile to those with MYC and BCL2 translocation. BCL10 and NOTCH2 mutations are most commonly enriched in MYC/BCL6 translocated cases.
As HGBL is a genetically heterogenous disease, a multitude of gene mutations have been identified at varying levels of prevalence. The table below summarises the most common mutations identified from a number of studies, including only those with a prevalence greater than 20% in the data analysed.
|Gene||Oncogene/Tumor Suppressor/Other||Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)||Prevalence (COSMIC/TCGA/Other)|
|KMT2D||Tumour suppressor||LOF||54% (68/126)|
|CREBBP||Tumour suppressor||LOF||47% (59/126)|
|IGLL5||Not fully characterised||40% (8/20)|
|TNFRSF14||Tumour suppressor||LOF||33% (35/106)|
|SOCS1||Tumour suppressor/oncogene||LOF/GOF||29% (33/112)|
|TP53||Tumour suppressor||LOF||25% (27/106)|
|DTX1||Tumour suppressor||LOF||25% (23/92)|
|GNA13||Tumour suppressor||LOF||25% (26/106)|
|ID3||Tumour suppressor||LOF||23% (7/31)|
|BCL7A||Tumour suppressor||LOF||20% (1/5)|
|C10orf12||Not fully characterised||20% (1/5)|
Although the role of epigenomics in HGBL specifically has been incompletely described, many of the genes most frequently mutated in HGBL have been shown to be epigenetic determinants in DLBCL. Such genes include EZH2, KMT2D and CREBBP, which encode proteins that are involved in two epigenetic switches at the promoter and enhancer regions of genes involved in the germinal centre reaction. These switches regulate the movement of germinal centre B-cells between the dark and light zones of the germinal centre and require the addition or removal of specific histone post-translational modifications to up- or down-regulate the target gene.
BCL6 is an important regulatory gene, repressing, often in combination with EZH2, the expression of a multitude of genes involved in cell cycle regulation whilst affinity maturation is ongoing. EZH2 encodes a histone methyltransferase which affects H3K27 methylation and its most common gain-of-function mutation has been shown in mouse models to cause a global increase of H3K27 trimethylation but with accompanying decreased expression of H3K27me3 at multiple loci. When there is constitutive expression of BCL6 and a concurrent EZH2 mutation driving the repression of the promoter region of a common target gene, such as is sometimes observed in DLBCL, such repression may become permanent, leading to an oncogenic state.
Similarly, inactivating CREBBP mutations within germinal centre B-cells prevent enhancer reactivation and, due to the role of CREBBP in acetylation of BCL6 and p53, impairs the cells’ ability to regulate these genes. Thus, inactivating CREBBP mutations can trap cells in the germinal centre reaction, being unable to differentiate whilst being exposed to mutagenic and therefore potentially oncogenic conditions. CREBBP and EP300, both histone acetyltransferases, are frequently mutated in DBLCL and mutations have been shown to promote oncogenesis by both inducing H3K27 deacetylation and activating the NOTCH signalling pathway, which is critical to the regulation of B-cell proliferation, migration and survival in lymphoma.
KMT2D mutants promote lymphomagenesis in part by impeding H3K4 methylation, driving enhanced proliferation in germinal centres and impeding terminal differentiation of B cells. The extent to which KMT2D loss promotes lymphomagenesis appears to be affected by dysregulation of the expression of a number of other genes, including BCL2 and AICDA. KMT2D loss, in combination with increased BCL2 expression, has been shown in mouse models to increase lymphoma incidence from that of mice with wild type KMT2D, and the effect is greater for those with homozygous deletions. Similarly the overexpression of AICDA, which encodes activation-induced cytidine deaminase (AID), an enzyme involved in somatic hypermutation, class switch recombination and gene conversion in the process of immunoglobulin diversification, has been shown in mice models to be associated with increased lymphoma incidence only in combination with KMT2D loss, and to be associated with more aggressive phenotypes than tumours with KMT2D deletion alone.
Genes and Main Pathways Involved
MYC is a proto-oncogene located at chromosome 8q24.2 which has been implicated in a variety of human cancers through its role as a regulator of multiple functions including cellular proliferation, DNA and protein synthesis and metabolism. In the process of B cell maturation, MYC is involved in multiple different intracellular pathways governing angiogenesis, differentiation and metabolism. MYC, not normally expressed by naïve B cells, is upregulated upon antigen stimulation and is crucial for germinal centre development, but is then subsequently suppressed by BCL6 and BLIMP1. MYC translocation leads to increased MYC expression compared to non-translocated cases, regardless of translocation partner. Translocation of MYC to an immunoglobulin locus leads to overexpression of the MYC protein due to IG promoter driven constitutively active transcription. MYC expression in lymphoma promotes cell proliferation and induces genomic instability, however whilst MYC contributes to oncogenic changes, it can also paradoxically promote apoptosis and increase the expression of tumour suppressor TP53. MYC overexpression in isolation is insufficient to promote lymphomagenesis, and MYC translocation is postulated to occur as a secondary genetic abnormality contributing to oncogenesis and an aggressive phenotype.
BCL2, an oncogene at chromosome 18q21.3, acts to inhibit apoptosis to maintain cellular viability, but is, in normal cells, itself downregulated by the BH3 family of proteins. BCL2 overexpression resulting from chromosomal translocation confers apoptosis resistance to B-cells and allows them to proliferate within the germinal centre in which the BCL2 protein is not normally expressed. BCL2 dysregulation acts synergistically with increased MYC translation to drive oncogenesis.
BCL6, located on chromosome 3q27.3 encodes a protein which suppresses the activity of P53, MYC and BCL2 and thus acts as a transcriptional repressor, contributing to the regulation of activation, differentiation and apoptosis in the germinal centre reaction. In normal B-cell development, expression of the BCL6 protein is restricted to the germinal centre stage of differentiation. Chromosomal translocations of BCL6 involve promoter substitution, where heterologous promoters from other chromosomes are relocated to the 5' end of the BCL6 gene. Commonly, these promoters show persistent activity in post germinal centre B-cells, causing abnormal BCL6 expression by prevention of its physiological downregulation. It is postulated that deregulated BCL6 expression contributes to lymphomagenesis by promoting a tolerance to DNA damage and hence oncogenic mutations.
Diagnostic Testing Methods
Histologically, HGBL with MYC and BCL2 and/or BCL6 rearrangements is often indistinguishable from other high-grade lymphomas and the only method to ensure detection of all cases is universal investigation of DLBCL, NOS by MYC FISH with further testing for BCL2 and BCL6 translocations where MYC rearrangement is detected. In environments with restricted resources, limiting screening to GCB subtype tumours would limit FISH testing to 50-62% of the DLBCL population, whilst still detecting >99% of tumours with MYC and BCL2 translocation.
Use of a MYC break-apart probe or IG/MYC dual fusion probe as the sole method of detection of MYC rearrangement has the potential to yield false-negative results in cases of 8q24 breakpoints occurring very close to the MYC gene region and non-IG MYC-rearrangement partners, respectively, and concurrent use of both break apart and IGH/MYC dual fusion probes is therefore recommended if possible. Use of IGL/MYC and/or IGK/MYC dual fusion probes can follow, if required, to confirm the presence or absence of an IG fusion partner, which has implications for prognostication.
There are, however, limitations to FISH testing. A subset of HGBCL DH/TH harbour MYC and/or BCL2 rearrangements that are cryptic to FISH, for example via cryptic enhancer insertions near MYC of insufficient size to separate the break apart probes sufficiently for detection by FISH. Such cases, identified via whole genome sequencing, were in one study found to account for 19% of all HGBL DH/TH tumours, with the authors recommending the use of gene expression profiling rather than FISH to identify HGBL DH/TH cases. Furthermore, false-positive or false-negative FISH results can occur due to probe type or different numbers of malignant lymphoid cells in different specimens (eg BM aspirate vs FFPE tissue) as well as inter-observer variability.
Several authors have proposed refined molecular subtypes of DLBCL based on gene expression profiling and/or mutation status, within which subtypes not all tumours are double- or triple- hit on the basis of FISH. In addition to overcoming translocations cryptic to FISH, several of these gene signatures have been shown to provide additional information on prognosis with one study showing that double hit lymphomas lacking the molecular high grade signature showed outcomes no worse than other germinal centre B-cell like cases.
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
In general, patients with germinal centre B type DLBCL have been shown to have a better prognosis than those with ABC-type tumours. However, despite the fact that the majority of HGBL DH/TH tumours are of GCB subtype, concurrent MYC and BCL2 and/or BCL6 rearrangement confers significantly worse outcomes than tumours without concurrent translocations, with median progression free and overall survival of approximately 10 and 22 months, respectively, despite treatment. The extremely poor outcomes in these patients are postulated to result from the synergistic dysregulation of both genes, leading to MYC-induced growth promotion and inhibition of apoptosis resulting from BCL2 rearrangement. Amongst HGBL DH/TH patients, advanced stage, central nervous system involvement, leucocytosis and LDH>3 times the upper limit of normal are all associated with poorer outcomes There appears to be no significant survival difference between patients with double hit (either BCL2 or BCL6) tumours and those with a triple hit.
The partner gene involved in MYC translocation also affects prognosis, with an IG partner gene conferring a significantly shorter progression free and overall survival. Patients with double hit lymphoma with an IG-MYC translocation have significantly worse survival than patients with a non-IG partner gene and patients without a double hit, even in studies in which double hit has not shown to be independently associated with poorer outcomes overall. Several studies  have shown that, regardless of double or triple hit status, DLBCL patients with MYC rearrangement to an IG partner have a shorter overall survival than patients without MYC rearrangement and in one large study patients with double or triple hit lymphoma with MYC translocation to a non-IG partner did not show any significant difference in outcomes to patients with DLBCL without MYC rearrangement. This reinforces the need for identification of the MYC translocation partner via appropriate FISH probe selection.
Further investigation of HGBL DH/TH via gene expression profiling in newer studies has reinforced that heterogeneity in outcomes exists amongst these patients, and that further sub classification via gene expression profiling and/or mutation analysis may be necessary to provide accurate prognostication.
Song et al in a study of 87 cases of de novo DLBCL of germinal centre type treated with R-CHOP defined a subset of cases as “double-hit” on the basis of gene expression profiling (DHsig+), with most but not all cases showing double- or triple-hits on FISH. In this cohort, patients with DHsig+ and TP53 mutation had the worst overall and progression free survival, with good overall survival in DHsig+ patients without TP53 abnormalities. These mutations have been postulated to lead to a highly aggressive phenotype through evasion of apoptosis driven by BCL2 in the absence of TP53 mediation.
First-line treatment for HGBL is rituximab in combination with intensive chemotherapy, most commonly CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) with or without CNS prophylaxis. Some studies have shown intensive induction regimens such as R-EPOCH to be associated with an improved response rate and progression free survival. In vitro studies of novel targeted agents such as BET inhibitors both alone and in combination with BCL-2 and MDM2-p53 inhibitors have shown promising results and further investigation of targeted therapies are needed to improve the otherwise dismal overall prognosis of these tumours.
There is currently no known familial association.
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