diffuse large B-cell lymphoma

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

2 main types :
 Germinal Center B-Cell like DLBCL / GCB-DLBCL
 Activated B-cell like DLBCL / ABC-DLBCL

The greatest difference resided between distinct populations of germinal centre (GC) cell tumours; the first being CD10-, Bcl-6+, MUM-1- and the second CD10+ Bcl-6+ MUM-1+. The former group displayed median survival time of 143 months, the latter only 11 months (19787248).

Images

 Axillary lymph node: diffuse large cell lymphoma, immunoblastic type DLBCL

• https://twitter.com/BellaMicheleang/status/857251922742566920

 82 yo woman - lymph node - SLL transformed in DLBCL

• https://twitter.com/vcockenpot/status/747531161501569024

Digital slides

 HPC:297 : Gastric diffuse large B-cell lymphoma (mucosal biopsies)
 HPC:302 : Mediastinal-pulmonary diffuse large B-cell lymphoma (DLBCL), EBV-associated
 HPC:305 : Diffuse large B-cell lymphoma of the tonsil (DLBCL of the tonsil)
 HPC:307 : Parotidal diffuse large B cell lymphoma (Parotidal DLBCL) and MALT lymphoma
 HPC:314 : Mammary diffuse large B cell lymphoma (Mammary DLBCL)
 HPC:321 : Diffuse large B-cell lymphoma of the tonsil (DLBCL of the tonsil) (Mucosal biopsy)
 HPC:329 : Duodenal diffuse large B-cell lymphoma (mucosal biopsies)
 HPC:340 : T-cell rich diffuse large B cell lymphoma (T-cell rich DLBCL)
 HPC:349 : Mediastinal sclerosing diffuse large B-cell lymphoma
 JRC:1609 : Primary diffuse large B-cell lymphoma of lung

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.

Diffuse large B-cell lymphoma (DLBCL) is disproportionately common relative to other types of lymphoma in patients with congenital, iatrogenic, or acquired immune defi ciency states.

Patients with B-cell diffuse large cell lymphoma may present with steadily enlarging peripheral lymphadenopathy or extranodal disease (soft tissue, bone, oropharynx).

Although rare, a primary mediastinal B-cell diffuse large cell lymphoma has also been described in children.

Variants

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease with considerable heterogeneity reflected in the 2008 World Health Organization classification.

In recent years, genome-wide assessment of genetic and epigenetic alterations has shed light upon distinct molecular subsets linked to dysregulation of specific genes or pathways.

Besides fostering our knowledge regarding the molecular complexity of DLBCL types, these studies have unraveled previously unappreciated genetic lesions, which may be exploited for prognostic and therapeutic purposes.

Following the last World Health Organization classification, it has been witnessed the emergence of new variants of specific DLBCL entities, such as :
 CD30+ DLBCL, human immunodeficiency virus–related
 age-related variants of plasmablastic lymphoma,
 EBV+ DLBCL arising in young patients.

Some entities present a diagnostic challenge, such as:
 T-cell/histiocyte-rich large B-cell lmphoma
 unclassifiable large B-cell lymphomas .

Microscopy

DLBCL has a diffuse growth pattern and may have intermixed fibrosis (particularly in the mediastinum).

Cytoplasm is abundant and may be either amphophilic or densely eosinophilic.

The cytology of the tumor cells ranges from that of reactive immunoblasts (round nucleus, thick nuclear membrane, single large eosinophilic nucleolus, abundant cytoplasm), to polylobate and even frankly ana-plastic multilobate cells.

Immunochemistry

Immunophenotypically, tumor cells mark with pan B-cell markers (CD19, CD20, CD79A, CD22) and are surface Ig+ (except in mediastinal large B-cell lymphoma). CD10 is positive in a minority.

 pan B-cell markers (CD19+, CD20+, CD79a+, CD22+)
 CD10-/+
 sIg+ or mIg+ (50-75%)
 CD30+/- (CD30+ in anaplastic variant)
 CD5 +/- (10%)
 CD10 +/- (30-60%)
 BCL6 +/- (60-90%)
 IRF4/MUM1 +/- (35-65%)
 Ki67 (>40%)
 p53 +/- (20-60%)

DLBCL variants (WHO,2008) (see joint document)

 diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS)

• common morphologic variants
  • centroblastic DLBCL
  • immunoblastic DLBCL
  • anaplastic DLBCL (pleomorphic DLBCL )
  • plasmablastic DLBCL

 rare morphologic variants
 molecular subgroups

• germinal center B-cell-like DLBCL (GCB-DLBCL)
• activated B-cell-like DLBCL (ABC-DLBCL)

 molecular subgroups

• CD5-positive DLBCL
• germinal center B-cell-like DLBCL (GCB-DLBCL)
• non-germinal center B-cell-like DLBCL (non-GCB-DLBCL)

 diffuse large B-cell lymphoma subtypes

• T-cell/histiocyte-rich large B-cell lymphoma (T-cell/histiocyte-rich DLBCL)
• primary DLBCL of the CNS
• primary cutaneous DLBCL, leg type
• EBV positive DLBCL of the elderly

 other lymphomas of the large B cells

• primary mediastinal (thymic) large B-cell lymphoma
• intravascular large B-cell lymphoma
• DLBCL associated with chronic inflammation
• lymphomatoid granulomatosis
• ALK-positive large B-cell lymphoma
• plasmablastic lymphoma (plasmablastic DLBCL, diffuse large B-cell lymphoma of plasmablastic type)
• large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease
• primary effusion lymphoma

 borderline cases

• B-cell lymphoma, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma
• B-cell lymphoma, with features intermediate between diffuse large B-cell lymphoma and Hodgkin lymphoma (DLBCL with Hodgkin features) (15982329)

Molecular variants

 MYC-associated DLBCL (22314191)

Localization

 nodal diffuse large B-cell lymphoma (nodal DLBCL)

• mediastinal diffuse large B-cell lymphoma

 extra-nodal diffuse large B-cell lymphoma

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

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

Gene mutations

 Mutations of the PIK3CA gene (18382359)

• The PI3K/AKT pathway might be involved in the development of some certain diffuse large B-cell lymphoma (DLBCL) by as-yet unclear mechanisms.
• PIK3CA mutations in exons 9 and 20
• The PI3K/AKT pathway is activated in DLBCL.
• PIK3CA is rarely mutated in DLBCL, indicating there could be some other PI3K-pathway activation mechanisms operative in DLBCL. (18382359)

Evolution

 pre-B acute lymphoblastic leukemia

Transcriptional profiling

 Three discrete subsets of DLBCLs (15550490)

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

Case studies

 Case UPMC #600

References

 Nodal Diffuse Large B-cell Lymphomas in Children and Adolescents: Immunohistochemical Expression Patterns and c-MYC Translocation in Relation to Clinical Outcome. Gualco G, Weiss LM, Harrington WJ Jr, Bacchi CE. Am J Surg Pathol. 2009 Oct 7. PMID: 19816150

 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