Disease |
Double-hit lymphoma (DHL), triple-hit lymphoma (THL), diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma (HGBL) with MYC, BCL2 and/or BCL6 rearrangements |
Epidemiology | The DH lymphoma most commonly affects elderly patients with a median age of 62-74 years (range 18-96 years), and both sexes are affected with a slight male predominance. The incidence of DH genotype has been difficult to assess because fluorescence in situ hybridization (FISH) studies have not been used widely on unselected series, and the published data may be biased toward a specific type of lymphoma. Nevertheless, DH lymphoma has been reported in 5-15% of patients with DLBCL and aggressive B-cell lymphoma. Comprehensive analysis of Mitelman Database of Chromosome Aberrations in Cancer (Aukema et al, 2011, Oliveira et al 2017), DH lymphomas with breaks at MYC, BCL2 and/or BCL6 regions were identified in 14% of DLBCL cases; 62% of those involved MYC and BCL2 sites, 18% involved MYC and BCL6 while the remaining cases had triple translocations. Using FISH, Barrans et al (2010) identified DH and TH genotypes in 12% cases with de novo DLBCL; the majority of these cases had BCL2 and MYC translocations (66%), BCL6 and MYC breaks in 10% and breaks in all three sites in 24% of cases. MYC and BCL2 translocations are also found in a small proportion of follicular lymphoma. We identified MYC breaks in 7% of t(14;18)-bearing follicular lymphoma cases; all described to have a high grade morphology with Burkitt-like or blastic morphology replacing residual follicles (Mohamed et al, 2001). Pedersen et al have reported that in transformed lymphoma, DH genotype was very frequent found in 21% of cases; all had follicular lymphomas (Pedersen et al 2012). |
Clinics | Patients with DH lymphomas commonly have an aggressive clinical course, characterized by advanced stage disease, extranodal involvement, and high serum lactate dehydrogenase levels. The extranodal sites include the bone marrow, central nervous system, gastrointestinal tract, liver, spleen, lung, pleural fluid, testis, ovaries, skin, and thyroid gland. Bone marrow is involved in about 50% of patients and many have a leukemic disease. The International Prognostic Index score (IPI score) is often intermediate-high or high (Barrans et al 2010, Petrich et al 2014). Most patients have a de novo disease while a minority (10%) present with a history of a low-grade follicular lymphoma or other B-cell lymphoma, then develop DHL presumably by the acquisition of MYC rearrangement. Double Expresser lymphoma Immunohistochemistry (IHC) has identified a fraction of DLBCL cases with high expression of MYC and BCL2 proteins (Perry et al 2014, Mahmoud et al 2015). These double expresser lymphomas (DE) are lacking MYC and BCL2 translocations and are usually of non-GC types. DE lymphomas are much more common than DH lymphomas, with approximately 30% of DLBCL being reported as DE lymphomas. Most studies use a cutoff of 40% for MYC IHC and a cutoff of 70% for BCL2 to define DE lymphoma (Green et al 2012 A). Clinically, the DE lymphomas have more aggressive clinical course than those lacking MYC and BCL2 protein expression. |
Pathology | Because DHL is genotypically defined; it is not restricted to a specific histology subtype. Most tumors are medium to large in size, with atypical morphology and very high proliferation rate. Previously, DH lymphomas were diagnosed as diffuse large B-cell lymphoma (DLBCL), aggressive B-cell lymphoma not otherwise specified (NOS) or Burkitt-like lymphoma. Rare cases were classified as lymphoblastic lymphoma. The increase recognition of these lymphomas led the 2008 WHO classification of hematopoietic and lymphoid neoplasms to introduce a provisional category of "B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL", (BCLU) to recognize a subset of very aggressive lymphoma in which the distinction between DLBCL and BL is difficult (Campo et al 2011, Swerdlow et al 2014). The 2008 WHO criteria were somewhat subjective and vaguely defined; as a result, recent studies have not been consistent with survival and disease outcome. Therefore, separation of these cases has become necessary to better define these clinically aggressive tumors. In the revised 2016 WHO classification of lymphoid neoplasms, all LBCL with "double hit" and "triple hit" genotype are included in a single category of "high-grade B-cell lymphomas (HGBL) with MYC and BCL2 and/or BCL6 rearrangements" (Swerdlow et al, 2016). Immunophenotype Most double hit lymphomas have a germinal center (GC) phenotype with expression of CD10 and BCL6 and lack of MUM1/IRF4. Expression of BCL2 protein is detected in almost 95% of cases supporting the observation that the BCL2 translocation is mainly found in GC type of DLBCL, and also MYC translocations are associated with a GC molecular profile in DLBCL. The proliferation index as measured by Ki67 immunohistochemical staining is often high (>90%). Therefore, although not very specific, co-expression of CD10, BCL6, BCL2, and a high Ki67 may predict double hit genotype in tumors morphologically diagnosed as DLBCL (Aukema et al 2011, Swerdlow et al 2014). |
Treatment | Standard therapies such as R-CHOP developed for patients with DLBCL are less effective in DHL, with a median overall survival of 12 months or less, as the majority of patients experience disease progression. Currently, more, intensive chemotherapy such as dose adjusted R-EPOCH therapy, is being evaluated which appears to be effective in many DH lymphoma patients. Consideration for frontline stem cell transplant in responding patients are also suggested (Oki et al 2014, Petrich et al 2014, Dunleavy 2015). |
Prognosis | Patients with classic, FISH-defined DH lymphomas have a very poor prognosis, usually present with high clinical risk factors, such as high IPI scores and bone marrow involvement. The outcome is dismal with rare long term survival after standard therapy (Perry et al 2014, Petrich et al 2014, Oki et al 2014). Several recent studies have indicated that the outcome of DE lymphomas, as defined by IHC is inferior to that of DLBCL but better than that of DH lymphomas. Therefore, the co-expression of MYC and BCL2 proteins in DLBCL is considered a prognostic biomarker of an inferior outcome (Green et al, 2012 B). |
Double-hit B-cell lymphomas |
Aukema SM, Siebert R, Schuuring E, van Imhoff GW, Kluin-Nelemans HC, Boerma EJ, Kluin PM |
Blood 2011 Feb 24;117(8):2319-31 |
PMID 21119107 |
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Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab |
Barrans S, Crouch S, Smith A, Turner K, Owen R, Patmore R, Roman E, Jack A |
J Clin Oncol 2010 Jul 10;28(20):3360-5 |
PMID 20498406 |
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The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications |
Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES |
Blood 2011 May 12;117(19):5019-32 |
PMID 21300984 |
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Dave SS, Fu K, Wright GW, Lam LT, Kluin P, Boerma EJ, Greiner TC, Weisenburger DD, Rosenwald A, Ott G, Müller-Hermelink HK, Gascoyne RD, Delabie J, Rimsza LM, Braziel RM, Grogan TM, Campo E, Jaffe ES, Dave BJ, Sanger W, Bast M, Vose JM, Armitage JO, Connors JM, Smeland EB, Kvaloy S, Holte H, Fisher RI, Miller TP, Montserrat E, Wilson WH, Bahl M, Zhao H, Yang L, Powell J, Simon R, Chan WC, Staudt LM; Lymphoma/Leukemia Molecular Profiling Project |
Molecular diagnosis of Burkitt's lymphoma N Engl J Med |
PMID 16760443 |
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Aggressive B cell Lymphoma: Optimal Therapy for MYC-positive, Double-Hit, and Triple-Hit DLBCL |
Dunleavy K |
Curr Treat Options Oncol 2015 Dec;16(12):58 |
PMID 26634708 |
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High levels of nuclear MYC protein predict the presence of MYC rearrangement in diffuse large B-cell lymphoma |
Green TM, Nielsen O, de Stricker K, Xu-Monette ZY, Young KH, Møller MB |
Am J Surg Pathol 2012 Apr;36(4):612-9 |
PMID 22314191 |
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Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone |
Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, Nielsen O, Gadeberg OV, Mourits-Andersen T, Frederiksen M, Pedersen LM, Møller MB |
J Clin Oncol 2012 Oct 1;30(28):3460-7 |
PMID 22665537 |
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Apoptotic signaling by c-MYC |
Hoffman B, Liebermann DA |
Oncogene 2008 Oct 27;27(50):6462-72 |
PMID 18955973 |
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Scoring of MYC protein expression in diffuse large B-cell lymphomas: concordance rate among hematopathologists |
Mahmoud AZ, George TI, Czuchlewski DR, Zhang QY, Wilson CS, Sever CE, Bakhirev AG, Zhang D, Steidler NL, Reichard KK, Kang H, Foucar K, Vasef MA |
Mod Pathol 2015 Apr;28(4):545-51 |
PMID 25431238 |
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Chromosomal analyses of 52 cases of follicular lymphoma with t(14;18), including blastic/blastoid variant |
Mohamed AN, Palutke M, Eisenberg L, Al-Katib A |
Cancer Genet Cytogenet 2001 Apr 1;126(1):45-51 |
PMID 11343778 |
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Double hit lymphoma: the MD Anderson Cancer Center clinical experience |
Oki Y, Noorani M, Lin P, Davis RE, Neelapu SS, Ma L, Ahmed M, Rodriguez MA, Hagemeister FB, Fowler N, Wang M, Fanale MA, Nastoupil L, Samaniego F, Lee HJ, Dabaja BS, Pinnix CC, Medeiros LJ, Nieto Y, Khouri I, Kwak LW, Turturro F, Romaguera JE, Fayad LE, Westin JR |
Br J Haematol 2014 Sep;166(6):891-901 |
PMID 24943107 |
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Double-hit lymphomas: clinical, morphological, immunohistochemical and cytogenetic study in a series of Brazilian patients with high-grade non-Hodgkin lymphoma |
Oliveira CC, Maciel-Guerra H, Kucko L, Hirama EJ, Brilhante AD, Quevedo FC, da Cunha IW, Soares FA, Niero-Melo L, Dos Reis PP, Domingues MA |
Diagn Pathol 2017 Jan 7;12(1):3 |
PMID 28061782 |
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Double-hit BCL2/MYC translocations in a consecutive cohort of patients with large B-cell lymphoma - a single centre's experience |
Pedersen MØ, Gang AO, Poulsen TS, Knudsen H, Lauritzen AF, Nielsen SL, Gang UO, Nørgaard P |
Eur J Haematol 2012 Jul;89(1):63-71 |
PMID 22510149 |
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MYC and BCL2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with rituximab |
Perry AM, Alvarado-Bernal Y, Laurini JA, Smith LM, Slack GW, Tan KL, Sehn LH, Fu K, Aoun P, Greiner TC, Chan WC, Bierman PJ, Bociek RG, Armitage JO, Vose JM, Gascoyne RD, Weisenburger DD |
Br J Haematol 2014 May;165(3):382-91 |
PMID 24506200 |
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MYC-associated and double-hit lymphomas: a review of pathobiology, prognosis, and therapeutic approaches |
Petrich AM, Nabhan C, Smith SM |
Cancer 2014 Dec 15;120(24):3884-95 |
PMID 25060588 |
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Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements |
Sesques P, Johnson NA |
Blood 2017 Jan 19;129(3):280-288 |
PMID 27821509 |
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Diagnosis of 'double hit' diffuse large B-cell lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma: when and how, FISH versus IHC |
Swerdlow SH |
Hematology Am Soc Hematol Educ Program 2014 Dec 5;2014(1):90-9 |
PMID 25696840 |
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The 2016 revision of the World Health Organization classification of lymphoid neoplasms |
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES |
Blood 2016 May 19;127(20):2375-90 |
PMID 26980727 |
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