Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with recognized variability in clinical outcome, genetic features, and cells of origin.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults, accounting for approximately 30 000 new cases each year and nearly 40% of all non-Hodgkin lymphomas (NHLs).

Although the cause of most DLBCLs remains unknown, predisposing factors include congenital and acquired immunodeficiency states that are often associated with dysregulated apoptosis or defective DNA repair.

Variants

 anaplastic DLCL (pleomorphic DLBCL)
 plasmablastic DLCL (diffuse large B-cell lymphoma of plasmablastic type)
 large B-cell lymphoma with Hodgkin features (15982329)

Localization

 nodal diffuse large B-cell lymphoma
 extra-nodal diffuse large B-cell lymphoma

• cutaneous diffuse large B-cell lymphoma
• digestive diffuse large B-cell lymphoma

Immunophenotype

 CD19+
 CD22+
 CD10-/+
 sIg+

Putative cell of origin: Large transformed B-cells harbouring somatic hypermutation of the Ig genes (ongoing mutations in some cases)

Cytogenetics

 t(14;18)(q32;q21) (IGH/MALT1 fusion protein) (14652825)
 t(11;18)(q21;q21) (14502259)
 t(9;14)(p13;q32) (12885465)à
 t(2;5) (ALK/NPM fusion gene) (14576483)
 t(2;17) (ALK/CLTC fusion gene) (12920229)
 t(3;V)(q27;V) with BCL6 rearrangements at 3q27 (6-30% of cases)
 MYC rearrangements (7-10% of cases)

Molecular biology

 In immunocompetent hosts, approximately 50% DLBCL carry one of two primary molecular lesions defining two distinct genotypic subgroups, characterized by activation of either the BCL-6 or the BCL-2 proto-oncogene. (14972786)

 The remaining 50% of DLBCL in immunocompetent hosts display one of several molecular lesions, each associated with a small subset of cases and including activation of the proto-oncogenes REL, MUC-1, BCL-8 and c-MYC. (14972786)

 The molecular pathogenesis of immunodeficiency-associated DLBCL differs substantially from that of DLBCL in immunocompetent hosts. (14972786)

 EBV infection is present in a large fraction of immunodeficiency-associated DLBCL, whereas it is consistently negative in DLBCL of immunocompetent hosts, probably reflecting the critical role of disruption of the immune system in this disease. (14972786)

 DNA microarray technology in DLBCL led to the distinction of two disease variants: a germinal center like DLBCL and an activated peripheral B-cell like DLBCL. Overall the molecular features of DLBCL may identify prognostic categories of the disease and may represent a powerful tool for therapeutic stratification. (14972786)

 gene rearrangements by translocation

• BCL6 at 3q27 (35-40%)
• BCL2 at 18q21 (13%)
• MYC at 8q24 (15%)
• TNFRSF6 at 10q24 (FAS or CD95) (20%)

 aberrant somatic hypermutation (aberrant SHM) (45%)
 tumor suppressor genes inactivations

• p53 mutations or deletions (20% of the cases) (% variations depending on detection methods: molecular genetics and FISH more sensitive that conventional cytogenetics))

Chromosomal imbalances (CGH data)

Anomalies

3p gains

1q

5

7q

14

Xq

7q

12p

6q

Allelic imbalances

 2p16
 3q26-27
 6p23
 6q23-25
 7q31
 11q23-24
 12p12-13
 18q21

LOH

 5q21: APC
 9p21: (INK4A/ARF)
 13q14: RB
 17p13: TP53

Evolution

 pre-B acute lymphoblastic leukemia

Transcriptional profiling

 Three discrete subsets of DLBCLs (15550490)

• Oxidative Phosphorylation
• B-cell Receptor/Proliferation
• Host Response

References

 Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M, Wu B, Pasqualucci L, Neuberg D, Aguiar RC, Dal Cin P, Ladd C, Pinkus GS, Salles G, Harris NL, Dalla-Favera R, Habermann TM, Aster JC, Golub TR, Shipp MA. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood. 2005 Mar 1;105(5):1851-61. PMID: 15550490

 Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M, Wu B, Pasqualucci L, Neuberg D, Aguiar RC, Dal Cin P, Ladd C, Pinkus GS, Salles G, Harris NL, Dalla-Favera R, Habermann TM, Aster JC, Golub TR, Shipp MA. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood. 2004 Nov 18; PMID: 15550490