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diffuse large B-cell lymphoma (DLBCL)

Appears to include more than one disease entity. Defined as a diffuse proliferation of neoplastic B cells with nuclear size greater than or equal normal macrophage nuclei or twice normal lymphocyte size. Classification: 1) working formulation a) diffuse large cell lymphoma b) large cell immunoblastic lymphoma 2) Kiel classification - centroblastic lymphoma Epidemiology: - 30-40% of non-Hodgkins lymphomas in western countries. Pathology: (microscopic variants) - centroblastic - immunoblastic - T-cell/histiocyte rich - anaplastic - plasmablastic - DLBCL with expression of full length ALK - germinal center B-cell-like with best prognosis Immunophenotype: - CD45 + - sIg +/- (50-75% +) - pan B cell antigens + - CD43 - - CD5 10% + - CD10 25-50% + - cyclin D1 - - CD30 + in most anaplastic DLBCL, occasionally + in other cases - bcl-2 30-50% + - bcl-6 + in high proportion of cases - Ki67 usually high (>40%, can be over 90%) Genetics: - reaarangement of immunoglobulin heavy & light chain genes & somatic mutations in variable regions - IRF4/DUSP22 locus rearrangement [16] - t[14;18] translocation of bcl-2 gene, 20-30% (see below) - t(14;15)(q32;q11-q13) involving BCL8 with IgH - chromosome 3q27 abnormalities, involving bcl-6 region, ~30% - myc rearrangement uncommon - myc rearrangement + bcl-2 &/or bcl-6 aberrations labeled "double hit" & "triple hit" lymphomas [] - 4 predominant genotypes [15] - co-occurrence of MYD88(L265P) & CD79B mutations - BCL6 fusions & NOTCH2 mutations - NOTCH1 mutations - EZH2 mutations & BCL2 translocations - t(2;6)(p12;q25) involving ZC3H12D with IGK may be the cause of the transformation of follicular lymphoma to diffuse large B-cell lymphoma - overexpression of PARP9 in fatal high-risk DLBCL compared to cured low-risk tumors - constitutive activation of NF-kappa B, 50% due to deletions of A20, confer poor prognosis - infection by EBV - other implicated genes TBRG1, PASD1, MCTS1 Gene expression profiling differences [ref. 2]: - germinal center B cell-like (GCB) DLBCL - t[14;18] translocation of bcl-2 gene - amplification of c-rel locus on chromosome 2p - overall 5 year survival 60% - activated B cell-like (ABC) DLBCL - activation of anti-apoptotic NF kappa B pathway - protein kinase C beta 1 more highly expressed in ABC vs GCB DLBCL - cyclic AMP phosphodiesterase 4B more highly expressed in ABC vs GCB DLBCL - overall 5 year survival 35% Clinical manifestations: - most patients present with stage 3 or 4 disease - B symptoms (fever, night sweats, weight loss) - neurolymphomatosis with progressive peripheral neuropathy (sensory & motor) (case report) [13] - rapid progession of disease without therapy [6] Laboratory: - complete blood count - basic metabolic panel - liver panel - serum lactate dehydrogenase (higher levels associated with poorer prognosis) - see ARUP consult [16] Radiology: - interim PET scan predictive of outcome in patients after 1 cycle of chemotherapy [10] - CT scan followup after chemotherapy [6] - residual mass in patient with otherwise good response to chemotherapy may represent scar tissue [6] - serial CT scan to assess stability of solitary mass [6] Management: - R-CHOP regardless of disease stage or prognosis [5,6] (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) - overall response rate 73% - 62% complete response - median overall survival: 29 months - 59% of patients were alive at 2 years, 47% progression free - high-dose intravenous methotrexate added to R-CHOP (case report) [13] - more intensified initial therapy suggested for "double hit" & "triple hit" lymphoma (see genetics section) - R-HyperCVAD/MA (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone/methotrexate, cytarabine) - R-CODOX-M/IVAC (rituximab, cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, etoposide cytarabine) - DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide & doxorubicin with rituximab). - glofitamab (Columvi) improves overall survival over rituximab [18] - high-dose chemotherapy with autologous stem cell transplantation (rescue) for patients who have achieved remission with R-CHOP [6] - apparently indicated only if residual disease [6] - radiation therapy of involved field in addition to R-CHOP is an option in early stage disease [6] - H pylori eradication for diffuse large B-cell lymphoma of the stomach [9] - prognosis - aggressive lymphoma with rapid progression, but greater potential for cure [6] - the revised International Prognostic Index (R-IPI) is a better predictor of outcome than anemia, diabetes mellitus, or presence of B symptoms [6,12]

Interactions

disease interactions

Related

intravascular large B-cell lymphoma

Specific

angioendotheliomatosis primary mediastinal B-cell lymphoma

General

diffuse lymphoma large cell lymphoma peripheral B-cell lymphoid neoplasm

References

  1. WHO Classification Tumours of Haematopoietic and Lymphoid Tissues. IARC Press 2001.
  2. Davis RE & Staudt LM. Molecular diagnosis of lymphoid malignancies by gene expression profiling. Curr Opin Hematol 9:333-338, 2002 PMID: 12042708
  3. Alizadeh AA et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503-11, 2000 PMID: 10676951
  4. Compagno M et al Mutations of multiple genes cause deregulation of NF-B in diffuse large B-cell lymphoma. Nature 2009 May 3; [e-pub ahead of print] PMID: 19412164 http://dx.doi.org/10.1038/nature07968
  5. Peyrade F et al. Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: A multicentre, single-arm, phase 2 trial. Lancet Oncol 2011 May; 12:460 http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70069-9/fulltext
  6. Medical Knowledge Self Assessment Program (MKSAP) 16, 17, 18, 19. American College of Physicians, Philadelphia 2012, 2015, 2018, 2021.
  7. Lenz G, Wright G, Dave SS et al Stromal gene signatures in large-B-cell lymphomas. N Engl J Med. 2008 Nov 27;359(22):2313-23 PMID: 19038878
  8. 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 20;346(25):1937-47. PMID: 12075054
  9. Ferreri AJ, Govi S, Ponzoni M. The role of Helicobacter pylori eradication in the treatment of diffuse large B-cell and marginal zone lymphomas of the stomach. Curr Opin Oncol. 2013 Sep;25(5):470-9 PMID: 23942292
  10. Kostakoglu L, Goldsmith SJ, Leonard JP et al FDG-PET after 1 cycle of therapy predicts outcome in diffuse large cell lymphoma and classic Hodgkin disease. Cancer. 2006 Dec 1;107(11):2678-87 PMID: 17063502
  11. Martelli M, Ferreri AJ, Agostinelli C et al Diffuse large B-cell lymphoma. Crit Rev Oncol Hematol. 2013 Aug;87(2):146-71 PMID: 23375551
  12. Sehn LH, Berry B, Chhanabhai M et al The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007 Mar 1;109(5):1857-61. Epub 2006 Nov 14. PMID: 17105812
  13. Rush RP, Saltman AP, Prica AA, Breiner A, Detsky AS. Connecting the Dots. N Engl J Med. 2017 Sep 7;377(10):978-984. PMID: 28877025 http://www.nejm.org/doi/full/10.1056/NEJMcps1613804
  14. Minerd J. with Expert Critique by Taylor J More-Intensive Induction Therapy for Double-Hit Lymphoma? In the absence of clinical trials, retrospective studies suggest yes. MedPage Today. ASCO Reading Room 03.21.2018 https://www.medpagetoday.com/reading-room/asco/hematologic-malignancies/71894
  15. Schmitz R, Wright GW, Huang DW et al Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. N Engl J Med 2018; 378:1396-1407. April 12, 2018 PMID: 29641966 http://www.nejm.org/doi/full/10.1056/NEJMoa1801445
  16. ARUP Consult: IRF4/DUSP22 Gene Rearrangement by FISH https://arupconsult.com/ati/irf4-dusp22-rearrangements
  17. Sehn LH, Salle G Diffuse Large B-Cell Lymphoma. N Engl J Med 2021; 384:842-858 PMID: 33657296 https://www.nejm.org/doi/full/10.1056/NEJMra2027612
  18. Bassett M Glofitamab Regimen Improves Survival in DLBCL. Granted accelerated approval last year, bispecific antibody passes its confirmatory test. MedPage Today June 20, 2024 https://www.medpagetoday.com/meetingcoverage/eha/110740

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