{"entity":{"id":"high-grade-b-cell-lymphoma-myc-bcl2","kind":"cancer","name":"High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma)","aka":["Double-hit lymphoma","DHL","HGBL-MYC/BCL2","HGBCL-DH-BCL2","Diffuse large B-cell lymphoma/high grade B-cell lymphoma with MYC and BCL2 rearrangements","High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements","Double-hit B-cell lymphoma","Triple-hit lymphoma"],"tldr":"An aggressive B-cell lymphoma defined not by how it looks but by two genetic faults in the same cell: a rearrangement of MYC, which drives growth, and one of BCL2, which blocks the cell from dying. It behaves worse than ordinary diffuse large B-cell lymphoma, so finding the rearrangements changes the treatment.","summary":"What it is. Two genes have to be broken for this diagnosis. MYC is a master switch for cell growth; BCL2 is the brake on programmed cell death. A cell that is told to grow and is also prevented from dying becomes a lymphoma that behaves worse than either fault alone would predict. The rearrangements are found by fluorescence in situ hybridisation, a test done on the biopsy, and they are the diagnosis. Nothing about the way the cells look under a microscope reliably identifies them, which is why every aggressive B-cell lymphoma is now tested.\n\nHow it differs from its family. It is a separate entity from diffuse large B-cell lymphoma, although it was carved out of it. WHO-HAEM5 named it diffuse large B-cell lymphoma / high-grade B-cell lymphoma with MYC and BCL2 rearrangements, so that a tumour made of large cells and one made of smaller blastoid cells can carry the same name once the genetics are known; the two books describe it as a homogeneous group with a germinal-centre gene expression profile and a close relationship to follicular lymphoma. Its gene expression overlaps that of Burkitt lymphoma, which is the other aggressive germinal-centre disease driven by MYC.\n\nWhere the two classifications disagree, and why it matters to a reader. Until 2022, cases with MYC and BCL6 rearrangements were counted in the same category. Both books removed them, because their gene expression and mutations are varied and differ from the MYC and BCL2 group. WHO-HAEM5 sends them back to diffuse large B-cell lymphoma or to high-grade B-cell lymphoma not otherwise specified, chosen on how the cells look. The International Consensus Classification created a new provisional entity for them instead, called high-grade B-cell lymphoma with MYC and BCL6 rearrangements. So a person with MYC and BCL6 rearrangements may be told they have a double-hit lymphoma by one pathologist and diffuse large B-cell lymphoma by another, and both are following a 2022 classification.\n\nWhat the signature adds. The gene expression signature that characterises this entity can be present without the rearrangements. In the study that defined it, the signature was found in 27 per cent of germinal-centre diffuse large B-cell lymphomas, only half of which had the double rearrangement, and the people who carried the signature had worse outcomes after standard immunochemotherapy whether or not the rearrangements were there: a five-year time to progression of 57 per cent against 81 per cent. A commercial assay (the DLBCL90 NanoString panel) reproduced that result. The clinical implication is uncomfortable and honest: the test in daily use identifies some but not all of the biologically distinct group.\n\nHow it is treated. More intensively than diffuse large B-cell lymphoma, with prophylaxis against spread to the brain and spinal cord, which is more likely here. The regimens and the evidence for them, which is observational rather than randomised, are written on the diffuse large B-cell lymphoma page and in the treatment layer of this family.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Diffuse_large_B-cell_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"Double-hit gene expression signature defines a distinct subgroup of germinal centre B-cell-like diffuse large B-cell lymphoma (Ennishi and Rosenwald, J Clin Oncol 2019)","url":"https://doi.org/10.1200/JCO.18.01583"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}],"tags":["heme","lymphoma","subtype-page"],"related":["dlbcl","burkitt-lymphoma","follicular-lymphoma","non-hodgkin-lymphoma","primary-mediastinal-b-cell-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","fdg-pet"],"targets":["myc","bcl2"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["double-hit-lymphoma","lymphoma-classification-2022","lymphoma-indolent-versus-aggressive","ipi-score","lymphoma-tx-cns-prophylaxis"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"No United Kingdom population figure exists under the name the 2022 classifications gave this entity, and the corpus does not invent one. What can be said is how often the genetics are found when they are looked for: in the gene-expression study that defined the double-hit signature, 25 of 157 germinal-centre diffuse large B-cell lymphomas carried rearrangements of both MYC and BCL2, and 27 per cent of the whole series carried the signature even though only half of those had the rearrangements. That cohort was assembled to contain the cases, so it is not a population frequency.","subtypes":["Large-cell morphology, which looks like diffuse large B-cell lymphoma down the microscope","High-grade or blastoid morphology, made of medium-sized cells","With an additional BCL6 rearrangement, historically called triple-hit"],"biomarkers":["MYC rearrangement and BCL2 rearrangement, both by fluorescence in situ hybridisation; the diagnosis cannot be made without them","BCL6 rearrangement, reported separately because the 2022 classifications moved MYC with BCL6 out of this entity","Germinal-centre B-cell phenotype: CD10 positive, BCL6 positive, MUM1 usually negative","The double-hit gene expression signature (DHITsig or MHG), measurable on a NanoString panel, which marks a larger group than the rearrangements do","Dual expression of MYC and BCL2 protein by immunohistochemistry, which is a different and much commoner finding and is not this entity"],"standardOfCare":[{"setting":"Making the diagnosis","approach":"Every aggressive B-cell lymphoma biopsy is tested by fluorescence in situ hybridisation for MYC, and if MYC is rearranged, for BCL2 and BCL6. A lymphoma cannot be identified as double-hit by appearance, by immunohistochemistry for MYC and BCL2 protein, or by the cell-of-origin assay; dual protein expression is a separate and much commoner finding with its own, lesser, prognostic weight. Follicular lymphoma is excluded from the entity by both classifications even when it carries both rearrangements.","refs":["histopathology-ihc","myc","bcl2","double-hit-lymphoma","lymphoma-classification-2022"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"Treatment, and what is known about it","approach":"Treated more intensively than diffuse large B-cell lymphoma, and with prophylaxis against disease in the brain and spinal cord, which is more frequent here. There has never been a randomised trial confined to this entity: the intensified regimens in use were adopted from retrospective comparisons after the group was shown to do less well with standard immunochemotherapy. The regimens, the doses and the evidence behind each are on the diffuse large B-cell lymphoma page and in the treatment layer of this family.","refs":["dlbcl","rituximab","lymphoma-tx-cns-prophylaxis","lymphoma-tx-regimen-alphabet","r-chop"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":[],"history":[{"year":2016,"title":"Carved out of diffuse large B-cell lymphoma","note":"The revised fourth edition of the WHO classification created high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements as a category of its own, which made testing for the rearrangements routine.","refs":["dlbcl"]},{"year":2019,"title":"A gene expression signature wider than the rearrangements","note":"An analysis of 157 germinal-centre diffuse large B-cell lymphomas defined a 104-gene double-hit signature present in 27 per cent of them, only half of which carried the rearrangements; those with the signature had a five-year time to progression of 57 per cent against 81 per cent.","refs":["myc","bcl2"]},{"year":2022,"title":"The two classifications split over MYC and BCL6","note":"Both removed cases with MYC and BCL6 rearrangements from the double-hit entity. WHO-HAEM5 reassigns them by appearance; the International Consensus Classification made them a provisional entity of their own.","refs":["lymphoma-classification-2022"]}],"pipeline":[],"openProblems":["No randomised trial has ever been run in this entity. The intensified regimens used for it were adopted from retrospective comparisons, and whether they are better than standard immunochemotherapy for an individual patient is not known.","The test used to make the diagnosis identifies a narrower group than the biology does: the double-hit gene expression signature marks about twice as many patients as the rearrangements do, and those extra patients have the same outcome and are treated as ordinary diffuse large B-cell lymphoma.","The two 2022 classifications handle MYC with BCL6 differently, so the same biopsy can yield two different diagnoses and two different trial eligibilities."],"parent":"non-hodgkin-lymphoma"},"route":"/cancers/high-grade-b-cell-lymphoma-myc-bcl2/","neighbours":{"cancer":[{"id":"burkitt-lymphoma","kind":"cancer","name":"Burkitt lymphoma","route":"/cancers/burkitt-lymphoma/"},{"id":"dlbcl","kind":"cancer","name":"Diffuse large B-cell lymphoma","route":"/cancers/dlbcl/"},{"id":"follicular-lymphoma","kind":"cancer","name":"Follicular lymphoma","route":"/cancers/follicular-lymphoma/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"},{"id":"primary-mediastinal-b-cell-lymphoma","kind":"cancer","name":"Primary mediastinal (thymic) large B-cell lymphoma","route":"/cancers/primary-mediastinal-b-cell-lymphoma/"}],"technology":[{"id":"fdg-pet","kind":"technology","name":"FDG PET","route":"/technologies/fdg-pet/"},{"id":"histopathology-ihc","kind":"technology","name":"Histopathology & immunohistochemistry","route":"/technologies/histopathology-ihc/"}],"pathway":[{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"}],"target":[{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"}],"term":[{"id":"lymphoma-tx-cns-prophylaxis","kind":"term","name":"CNS prophylaxis in aggressive B-cell lymphoma, and the evidence against it","route":"/terms/lymphoma-tx-cns-prophylaxis/"},{"id":"double-hit-lymphoma","kind":"term","name":"Double-hit / high-grade B-cell lymphoma","route":"/terms/double-hit-lymphoma/"},{"id":"lymphoma-indolent-versus-aggressive","kind":"term","name":"Indolent and aggressive lymphoma","route":"/terms/lymphoma-indolent-versus-aggressive/"},{"id":"ipi-score","kind":"term","name":"International Prognostic Index (IPI)","route":"/terms/ipi-score/"},{"id":"r-chop","kind":"term","name":"R-CHOP (lymphoma chemoimmunotherapy)","route":"/terms/r-chop/"},{"id":"lymphoma-tx-regimen-alphabet","kind":"term","name":"The lymphoma regimen alphabet: R-CHOP, pola-R-CHP, DA-EPOCH-R, ABVD, BEACOPP and the rest","route":"/terms/lymphoma-tx-regimen-alphabet/"},{"id":"lymphoma-classification-2022","kind":"term","name":"The two lymphoma classifications of 2022 (WHO-HAEM5 and ICC)","route":"/terms/lymphoma-classification-2022/"}],"drug":[{"id":"rituximab","kind":"drug","name":"Rituximab","route":"/drugs/rituximab/"}]}}