diffuse large B-cell lymphoma (DLBCL)
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Introduction
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
- working formulation
- diffuse large cell lymphoma
- large cell immunoblastic lymphoma
- Kiel classification
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]
- 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).
- 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]
More general terms
More specific terms
References
- ↑ WHO Classification Tumours of Haematopoietic and Lymphoid Tissues. IARC Press 2001.
- ↑ Davis RE & Staudt LM. Molecular diagnosis of lymphoid malignancies by gene expression profiling. Curr Opin Hematol 9:333-338, 2002 PMID: https://www.ncbi.nlm.nih.gov/pubmed/12042708
- ↑ Alizadeh AA et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503-11, 2000 PMID: https://www.ncbi.nlm.nih.gov/pubmed/10676951
- ↑ 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] <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/19412164 <Internet> http://dx.doi.org/10.1038/nature07968
- ↑ 5.0 5.1 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
- ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 Medical Knowledge Self Assessment Program (MKSAP) 16, 17, 18, 19. American College of Physicians, Philadelphia 2012, 2015, 2018, 2021.
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/19038878
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/12075054
- ↑ 9.0 9.1 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: https://www.ncbi.nlm.nih.gov/pubmed/23942292
- ↑ 10.0 10.1 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: https://www.ncbi.nlm.nih.gov/pubmed/17063502
- ↑ Martelli M, Ferreri AJ, Agostinelli C et al Diffuse large B-cell lymphoma. Crit Rev Oncol Hematol. 2013 Aug;87(2):146-71 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23375551
- ↑ 12.0 12.1 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: https://www.ncbi.nlm.nih.gov/pubmed/17105812
- ↑ 13.0 13.1 13.2 Rush RP, Saltman AP, Prica AA, Breiner A, Detsky AS. Connecting the Dots. N Engl J Med. 2017 Sep 7;377(10):978-984. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28877025 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMcps1613804
- ↑ 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
- ↑ 15.0 15.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29641966 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1801445
- ↑ 16.0 16.1 16.2 ARUP Consult: IRF4/DUSP22 Gene Rearrangement by FISH https://arupconsult.com/ati/irf4-dusp22-rearrangements
- ↑ Sehn LH, Salle G Diffuse Large B-Cell Lymphoma. N Engl J Med 2021; 384:842-858 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33657296 https://www.nejm.org/doi/full/10.1056/NEJMra2027612