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Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma

Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma
Literature review current through: Sep 2023.
This topic last updated: Jul 21, 2022.

INTRODUCTION — Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL), accounting for approximately 25 percent of adult NHL cases. (See "Classification of hematopoietic neoplasms".)

The molecular pathogenesis of DLBCL is a complex, multistep process that ultimately results in the transformation and expansion of a malignant clone of germinal or post-germinal B cell origin. While some steps in this pathway have been elucidated, many remain unknown. The best-characterized oncogenic events are acquired genetic lesions (eg, rearrangements of BCL6, BCL2, and MYC), many of which are also seen in other NHL variants. This may reflect in part the not uncommon evolution of low-grade lymphoma into DLBCL. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma" and "Histologic transformation of follicular lymphoma" and "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma".)

The following sections will describe genetic changes, aberrant gene and protein expression, and other alterations that are thought to play a role in the development of DLBCL. It is increasingly appreciated that the diagnostic category of "DLBCL" is heterogeneous in terms of morphology, genetics, and biologic behavior. The 2016 World Health Organization classification of lymphoid neoplasms recommends that immunohistochemistry and/or gene expression profiling be used to subclassify "typical" DLBCL into tumors of germinal center and non-germinal center origin, in recognition that these two classes of tumors have different prognoses with current therapies [1]. Most of the non-germinal center tumors fall into a specific category, the activated B cell (ABC) type, so named based on a resemblance to the gene expression signature of normal activated B cells, whereas others fall into an unclassifiable category. In addition, several clinicopathologic entities are recognized that share some features with "typical" DLBCL yet are sufficiently distinct to be considered separate diagnostic and/or therapeutic categories:

T cell rich large B cell lymphoma. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma" and "Initial treatment of advanced stage diffuse large B cell lymphoma".)

Primary mediastinal large B cell lymphoma. (See "Primary mediastinal large B cell lymphoma".)

Intravascular large B cell lymphoma. (See "Intravascular large cell lymphoma".)

Lymphomatoid granulomatosis, an Epstein-Barr virus (EBV) positive large B cell lymphoma, often occurring at extranodal sites such as the lung, in which the EBV-positive B cells are scarce and the host response in the form of T cells and macrophages makes up the majority of the tumor mass. (See "Pulmonary lymphomatoid granulomatosis".)

EBV-positive DLBCL, which resembles typical DLBCL morphologically (unlike lymphomatoid granulomatosis) but demonstrates latent EBV infection in the tumor cells.

DLBCL associated with IRF4 rearrangements, a subtype that is predominantly seen in children and young adults, frequently involves Waldeyer's ring and the gastrointestinal tract, and has an excellent outcome with chemotherapy.

DLBCL associated with chronic inflammation, a subtype of DLBCL that arises in the context of local chronic inflammation, often present for many years.

This topic will review the pathobiology and genetics of DLBCL and primary mediastinal large B cell lymphoma. General discussions of the pathobiology and specific chromosomal abnormalities seen in NHL subtypes are presented separately. (See "Genetic abnormalities in hematologic and lymphoid malignancies" and "General aspects of cytogenetic analysis in hematologic malignancies" and "Overview of the pathobiology of the non-Hodgkin lymphomas".)

CELL OF ORIGIN — DLBCL is a heterogeneous clinicopathologic entity that includes tumors derived from germinal center B cells or post-germinal center B cells (also called activated B cells). The germinal center or post-germinal center ancestry of these cells is principally supported by the identification of somatic mutations in the variable region of the immunoglobulin genes (IgVH), which serves as a marker of germinal center transit [2]. The majority of cases also demonstrate ongoing somatic mutations, which reflect the pressure of antigen selection associated with post-germinal center lymphocytes (figure 1) [3]. (See "Normal B and T lymphocyte development".)

Additional information regarding the cell of origin is derived from gene expression profile analyses described in more detail below. (See 'Gene expression heterogeneity of DLBCL' below.)

ABERRANT BCL6 EXPRESSION — The majority of DLBCL tumors express the B cell lymphoma 6 (BCL6) gene, which encodes a transcriptional repressor. In normal B cells, BCL6 negatively regulates its own expression by binding to the BCL6 promoter. Persistent expression in DLBCL is the result either of acquired mutations in the BCL6 promoter that prevent BCL6 binding or of translocations that place BCL6 under the control of heterologous transcriptional regulatory elements that are not subject to BCL6 autoregulation [4]. Overexpression of BCL6 in B cell lymphoma cells leads to downregulation of BCL6 target genes, including the TP53 tumor suppressor gene, which may be one way in which BCL6 protects cells from undergoing apoptosis in response to DNA damage (figure 2).

The combined frequency of BCL6 mutations and rearrangements approaches 100 percent in DLBCL cases, suggesting that structural alterations of the 5' noncoding region of the BCL6 gene are necessary for the development of these tumors [5].

BCL6 action — The B cell lymphoma 6 (BCL6) gene, located at band 3q27, encodes a 95 kD nuclear phosphoprotein of the BTB-POZ transcription factor family [6]. BCL6 contains six zinc-finger motifs (which bind to its DNA recognition sequence), a POZ transrepression domain, and a second repression domain [7]. The net effect is that BCL6 is a potent repressor of transcription [8]. In addition to regulation of genes with BCL6 binding sites, BCL6 can also mediate repression of genes that lack BCL6 binding sites by associating with other DNA-binding factors [9].

BCL6 in normal cells — BCL6 is expressed in mature germinal center B cells, but not in their differentiated cell progeny (plasma cells and memory B cells). It acts as a transcription repressor for many genes, including BCL6 itself, through a negative feedback loop involving BCL6 binding sites in the BCL6 promoter.

Overexpression of BCL6 in B cell lymphoma cell lines prevents the cells from undergoing apoptosis in response to DNA damage [9-11]. It is hypothesized that BCL6 expression permits the DNA strand breaks that are required for normal somatic hypermutation and class switching to proceed in the germinal center without triggering apoptosis [12]. BCL6 may do so by suppressing the expression and activity of multiple components of the DNA damage response, including TP53 (an effector of apoptosis in response to DNA damage) and ATR, ATM, and CHK1 (DNA damage checkpoint proteins) [13]. Notably, BCL6 also downregulates the activity of several genes that can contribute to B cell transformation, such as MYC and BCL2 [14]; these anti-oncogenic activities of BCL6 are frequently lost in DLBCL, sometimes through mutations or translocations involving MYC and BCL2 that abrogate their regulation by BCL6. BCL6 expression must subsequently be downregulated for normal germinal center B cells to exit the germinal center and progress to the post-germinal center phase of B development [15-17].

BCL6 knockout mice cannot form germinal centers and have impaired T cell-dependent antibody responses, indicating that BCL6 is required for germinal center formation [18]. Transgenic mice engineered to overexpress BCL6 from the immunoglobulin heavy chain promoter, thereby mimicking the (3;14) translocation seen in human DLBCL show increased germinal center formation and develop a lymphoproliferative disorder that frequently progresses to a DLBCL-like lymphoma [19].

BCL6 dysregulation in DLBCL — As mentioned above, the BCL6 gene is expressed in most cases of DLBCL. In some instances, this may merely reflect the stage of B cell differentiation at which the tumor cells arrest, but in approximately 30 percent of DLBCL it is the consequence of a translocation that places the gene under the control of a new promoter. In an additional subset of cases, BCL6 expression stems from or is enhanced by a mutation in the BCL6 gene promoter that interferes with the BCL6-dependent negative autoregulatory loop for this gene. Persistent expression or overexpression of BCL6 results in several alterations in germinal center (GC) B cells that are believed to contribute to lymphomagenesis [14,20], including:

Inhibition of cell cycle arrest, via repression of factors such as cyclin-dependent kinase inhibitor 1A.

Modulation of apoptosis through effects on BCL2 and caspases.

Dampening the DNA-damage response through downregulation of p53 and DNA damage checkpoint factors.

Promotion of expression of activation-induced cytosine deaminase (AID), an enzyme that contributes to genomic instability by participating directly in somatic hypermutation. BCL6 upregulates AID indirectly by inhibiting the expression of the micro-RNAs miR-155 and miR-361, which suppress AID expression.

Inhibition of egress from germinal centers, by suppressing the expression of PRDM1 (also known as BLIMP-1), a transcription factor that promotes plasma cell differentiation.

This has led to the hypothesis that cells unable to downregulate BCL6 (either due to a mutation or translocation) are unable to exit the germinal center and differentiate; this block in differentiation may promote lymphomagenesis by holding cells in a proliferative, genomically unstable state (due to persistent expression of activation-induced cytosine deaminase [AID], an enzyme that causes somatic hypermutation, and downregulation of p53 and other DNA damage response factors).

Genetic alterations that upregulate BCL6

BCL6 mutations — Approximately 70 percent of DLBCLs have multiple, often biallelic, mutations in the BCL6 gene that cluster in its 5' non-coding region, within 2 kb of the transcription initiation site [5,21]. These mutations occur frequently in systemic nodal DLBCL, primary extranodal DLBCL, CD5(+) DLBCL, CD30(+) DLBCL, and primary splenic DLBCL, but generally not in primary mediastinal large B cell lymphoma [21]. (See 'Mediastinal large B cell lymphoma' below.)

BCL6 mutations also occur in a small proportion of normal germinal center B cells, 30 percent of follicular lymphomas, and varying percentages of chronic lymphocytic leukemia/small lymphocytic lymphoma, Burkitt lymphoma, and MALT lymphoma. Except for a subset of follicular lymphomas, they are generally independent of translocation to immunoglobulin (Ig) loci or other rearrangements of the BCL6 locus. The mutations are often single base substitutions, most commonly transitions, and bear the molecular signature of mutations that are induced by AID as part of the normal process of somatic hypermutation [10,11]. In tumors with BCL6 translocation, they occur more commonly on the der(14q32) translocated allele [22].

The genomic sequences most frequently involved in these mutations are adjacent to the BCL6 promoter and overlap with the major cluster of chromosomal breakpoints, suggesting that mutations and rearrangements may both be selected for their ability to alter that region, which appears to be important for the negative autoregulation of BCL6 [5,10,11].

Translocations involving the BCL6 gene — Approximately 30 percent of DLBCLs in immunocompetent hosts and 20 percent of AIDS-related cases display rearrangement of the BCL6 gene on chromosome 3q27 [6,23-25]. Reciprocal translocations juxtapose 3q27 to one of several chromosomal sites, including 14q32 (IgH), 2p11 (Ig kappa), 22q11 (Ig lambda), as well as more than 10 other chromosomal sites unrelated to antigen receptor loci. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Genetic features'.)

The chromosomal translocation breakpoints lying within the 5' region flanking BCL6 usually fall within the noncoding first exon or first intron [6,26]. In a minority of cases, the chromosomal breakpoint is not located in the immediate proximity of the BCL6 gene, suggesting that more distant breakpoint clusters exist. In all cases displaying direct involvement of BCL6, the coding region is left intact, whereas the 5' regulatory region, containing the promoter sequences, is either completely removed (in case of breaks within the first exon or intron) or truncated [26]. As a result, all of the coding exons of BCL6 are linked to sequences from heterologous genes, placing BCL6 under the control of constitutively active regulatory sequences that drive BCL6 overexpression. Most commonly, these alterations result in the juxtaposition of heterologous promoters to the BCL6 coding domain, leading to increased BCL6 expression by a mechanism called promoter substitution [26,27]. Dysregulated expression of the translocation partner gene, now regulated by the BCL6 promoter, may also occur [27].

Other alterations that upregulate BCL6 — Other reported indirect mechanisms leading to hyperactivity of BCL6 in DLBCL include gain-of-function mutations in MEF2B, which encodes a transcription factor that upregulates BCL6 expression [28]; and loss-of-function mutations in factors that regulate BCL6 through post-translational modifications, such as FBXO11 (which promotes BCL6 ubiquitylation and degradation) [29]; and CREBBP and EP300, which acetylate and thereby inactivate BCL6 [30,31].

TP53 DOWNREGULATION — Up to 20 percent of DLBCL demonstrate mutations or deletions of the TP53 tumor suppressor gene (the gene that encodes p53) [32,33]. In addition, TP53 transcription is at least partially controlled by the BCL6 protein, which is often overexpressed in DLBCL. The normal ("wild type") TP53 gene, located at 17p13.1, produces a DNA-binding protein, p53, that induces a variety of growth-limiting responses, including cell cycle arrest (in order to facilitate DNA repair), apoptosis, senescence, and differentiation. Downregulation of TP53 expression or expression of mutant p53 protein results in a loss of the normal growth-limiting activities of this gene.

Effect of BCL6 on TP53 — As mentioned above, the B cell leukemia 6 (BCL6) protein is a transcription repressor that decreases the expression of many genes, including itself and the tumor suppressor gene TP53. Mutations in the TP53 gene of DLBCL are seen almost exclusively in cases without BCL6 translocations, suggesting that the aberrant expression of BCL6 circumvents the selective pressure for TP53 mutations [12]. (See 'BCL6 dysregulation in DLBCL' above.)

TP53 mutations — Approximately 20 percent of patients with DLBCL exhibit TP53 mutations [32-34]. Mutations are seen in sequences of the TP53 gene that encode the non-DNA binding domain regions or different DNA-binding domain regions including Loop-L3, Loop-Sheet-Helix, and Loop-L2 [34]. The region involved may have prognostic implications [32,33].

As an example, a multicenter study demonstrated TP53 mutations in 102 of 477 (21 percent) cases of DLBCL [34]. The presence of a TP53 mutation was associated with worse overall survival. Furthermore, the location of the mutation within the p53 protein appeared to be important, with DNA binding domain mutations associated with the worst outcome, followed by mutations of the Loop-Sheet-Helix and Loop-L3. Mutations in Loop-L2 did not affect survival. The presence of a DNA binding domain mutation in TP53 was an independent predictor of survival, suggesting that these mutations are important either in DLBCL pathogenesis or in DLBCL susceptibility to chemotherapy.

The p53 protein activates the expression of the CDKN1A gene, which encodes the p21 cyclin dependent kinase inhibitor (CIP1/WAF1). Expression of p21 appears to be an independent predictor of failure-free and overall survival in DLBCL treated with R-CHOP. As an example, a prospective intergroup trial demonstrated that the addition of rituximab to standard chemotherapy had no effect on the clinical outcomes of patients with p21 negative tumors, but significantly improved the failure-free survival of patients with p21 positive tumors [35].

OTHER MECHANISMS

Aberrant somatic hypermutation — Somatic hypermutation is the introduction of point mutations and small deletions or insertions, usually affecting the variable regions of immunoglobulin heavy chain genes of germinal center B cells. Somatic hypermutation is a key component of affinity maturation during humoral immune responses. In normal germinal center cells, somatic hypermutation also targets the 5' regions of some non-immunoglobulin genes, including BCL6 [11,36,37]. Approximately half of DLBCL cases demonstrate aberrant somatic hypermutation targeting proto-oncogenes involved in cell proliferation, differentiation, and signal transduction. (See "Overview of the pathobiology of the non-Hodgkin lymphomas", section on 'B cell germinal center reaction'.)

In one study, aberrant somatic hypermutation was found to target multiple loci, including proto-oncogenes in more than 50 percent of cases of DLBCL, suggesting a malfunction of somatic hypermutation [38].

Another study reported that approximately 25 percent of DLBCLs demonstrate somatic hypermutation resulting in the inactivation of SOCS1 (an inhibitor of JAK/STAT signaling), resulting in deregulated STAT activity [39].

The importance of aberrant somatic hypermutation is also supported by studies of lymphomagenesis in mice engineered to overexpress BCL6 in germinal center B cells. In these animals, inactivation of somatic hypermutation through knockout of the activation-induced cytosine deaminase (AID) gene markedly suppresses the appearance of DLBCL [40].

Of further interest, some of the hypermutable genes are also susceptible to chromosomal translocations in the same regions, consistent with a role for hypermutation in generating DNA double-strand breaks that may lead to rearrangements such as translocations. By mutating multiple genes, and possibly by favoring chromosomal translocations, aberrant hypermutation may be a major contributor to lymphomagenesis.

BCL2 overexpression — B cell leukemia/lymphoma 2 (BCL2) is an oncogene that blocks programmed cell death (apoptosis), leading to prolonged cell survival. BCL2 overexpression is often the result of a (14;18) translocation that places BCL2 under the control of immunoglobulin regulatory elements. This translocation is common in follicular lymphoma, but is also seen in up to 30 percent of DLBCL, especially germinal center-like DLBCL. (See 'Gene expression heterogeneity of DLBCL' below and "Pathobiology of follicular lymphoma", section on 'Translocations involving BCL-2'.)

MYC overexpression — MYC gene rearrangements occur in 5 to 15 percent of DLBCL [41]. This translocation has the same molecular consequence as those seen in Burkitt lymphoma, namely overexpression of MYC protein. Approximately 80 percent of these rearrangements involve the IGH locus, while the other 20 percent involve the Ig light chain loci or non-immunoglobulin genes, such as BCL6, ZCCHC7, and RFTN1 [42]. DLBCLs with MYC rearrangements appear to have a particularly poor prognosis [41,43]. Amplification and/or overexpression of the MYC gene without gene rearrangement has also been described in DLBCL and is also associated with poor prognosis [41,44-46]. As an example, one study reported that 38 percent of DLBCL tumors demonstrated an increase in the MYC gene copy number, which was also associated with increased MYC mRNA levels [46]. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma", section on 'Translocations involving the MYC oncogene'.)

Immune evasion — Evasion of host immunity is considered a hallmark of cancer, and insight into how tumors evade host immunity has led to successful immunotargeting of many tumors with agents that negate tumor cell evasion mechanisms. Several mechanisms of immunoevasion have been described in DLBCL. Approximately 60 percent of DLBCL cases fail to express class I MHC complexes that are needed for immunosurveillance by cytotoxic T cells. Mechanisms include loss-of-function mutations in beta-2 microglobulin (B2M), HLA-A, HLA-B, and HLA-C, and defective transport of B2M or HLA-I molecules [47,48]. Similarly, loss of HLA class I expression is often accompanied by loss of expression of CD58, which is needed for immune surveillance by natural killer (NK) cells [47]. A comprehensive genomic analysis of 304 DLBCLs reported that 74 percent exhibited genetic alterations that are predicted to enhance immunoevasion [49].

Abnormal lymphocyte trafficking — Normal lymphocytes migrate through the body in response to complex microenvironmental cues. Abnormal trafficking may impact lymphocyte development and play a role in the pathogenesis of DLBCL. As an example, local gradients of the lipid metabolite sphingosine-1-phosphate (S1P) help to coordinate migration necessary for affinity maturation and class switch recombination. In one hypothesis, the population of maturing B cells is kept in check by the S1P receptor (S1PR2), which inhibits migration, trapping the vast majority of cells in the germinal center and limiting survival.  

Reports have demonstrated abnormalities in S1PR2 in DLBCL. S1PR2 deficiency due to mutations in the S1PR2 promoter is common in germinal center B cell type DLBCL [50-52]. In contrast, S1PR2 promoter mutations are not seen in activated B cell (ABC) type DLBCL. Instead, S1PR2 appears to be silenced in ABC DLBCL by the transcriptional regulator FOXP1 [53]. An additional 15 to 20 percent of germinal center B cell type DLBCLs is associated with mutations in GNA13, a gene encoding a small G protein that regulates B cell motility [52]. These observations support the role of acquired alterations that affect motility and trafficking as common feature of DLBCL.

Another example of genetic lesions that affect the trafficking of DLBCL cells are mutations in P2RY8, a gene encoding a G-protein coupled receptor that inhibits the migration of germinal center B cells. Loss-of-function mutations in P2RY8 may allow malignant germinal center B cells to "escape" from the germinal center microenvironment, possibly enhancing their spread to other sites within lymph nodes and other tissues [54]. Mutations in GNA13, which encodes the G-protein that is associated with P2RY8 in germinal center B cells, also are found in DLBCL, further linking signals involving P2RY8 to DLBCL migration.

HETEROGENEITY OF DLBCL — As described above, the diagnostic category of "diffuse large B cell lymphoma" is heterogeneous in terms of morphology, genetics, and biologic behavior. While a number of clinicopathologic entities that are sufficiently distinct to be considered separate diagnostic categories (eg, intravascular lymphoma) are now recognized, it is difficult to reliably subclassify DLBCL into morphologic variants (ie, centroblastic lymphoma and immunoblastic lymphoma) [55]. By contrast, molecular subtyping appears to identify subtypes with different prognoses. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Morphology' and "Prognosis of diffuse large B cell lymphoma", section on 'Gene expression profiling'.)

Molecular heterogeneity of DLBCL — The biologic diversity of DLBCL has been validated by the identification of multiple genetic subtypes. Early molecular subclassifications were based on the presence of BCL2 or BC6 gene rearrangements to create three distinct subtypes, which may have different prognoses [56]:

BCL6-positive DLBCL (40 percent): Rearrangements of BCL6 in the absence of other known genetic lesions. BCL6-positive DLBCL are de novo lymphomas, presenting without a previous history of follicular lymphoma (FL). (See 'Aberrant BCL6 expression' above.)

BCL2-positive DLBCL: B cell leukemia/lymphoma 2 (BCL2) can be activated either alone or in combination with TP53 mutations. BCL2-positive DLBCL carrying TP53 mutations derive from the histologic transformation of a previous FL, whereas the histogenesis of BCL2-positive/TP53-negative DLBCL is controversial. (See 'BCL2 overexpression' above.)

Cases with germline BCL2 and BCL6 genes.

In one study, cases associated with BCL6 rearrangements displayed the most favorable prognosis, whereas cases carrying BCL2 translocations had the poorest outcome [56]. The third group (ie, cases without rearrangements of BCL6 and BCL2) displayed an intermediate prognosis. Of interest, grade IIIB follicular lymphoma, which has an aggressive clinical course similar to DLBCL, demonstrated a pattern of cytogenetic changes similar to DLBCL, suggesting a close relationship between these two tumor subtypes [57]. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Tumor grade'.)

Gene expression heterogeneity of DLBCL — Gene expression has been extensively studied in DLBCL using microarray technology. One line of investigation that has come to dominate the field uses supervised clustering to sort DLBCLs based on likely cell of origin. This work has characterized three types of DLBCL: germinal center B cell-like (GCB), activated B cell-like (ABC), and a not-otherwise-specified type 3 (figure 1) [58-61]. The optimal combination of immunohistochemical markers that can reliably separate GCB from ABC type DLBCL is controversial and remains in flux [62]. (See "Prognosis of diffuse large B cell lymphoma", section on 'Overview'.)

Germinal center B cell-like – The germinal center B cell-like (GCB) DLBCL has a gene expression profile characteristic of normal germinal center B cells. The immunoglobulin gene demonstrates intraclonal heterogeneity and ongoing somatic hypermutation [63]. This subtype is often associated with the (14;18) translocation (IgH/BCL2 fusion gene) typical of follicular lymphoma and amplifications of the locus on chromosome 2 which codes for the REL oncogene. GCB has also been associated with gains of chromosome 12q12 [64]. (See 'BCL2 overexpression' above.)

Activated B cell-like – The activated B cell-like (ABC) DLBCL demonstrates a gene expression profile similar to that of post-germinal center activated B cells. The immunoglobulin gene demonstrates intraclonal homogeneity [63]. The ABC subtype is associated with loss of 6q21, trisomy 3, and gains of 3q and 18q21-22 [64,65]. The commonly deleted locus on 6q includes the gene for the tumor suppressor PRDM1 (BLIMP-1), a master regulator of the differentiation of mature B lymphocytes into plasma cells [66]. Loss of PRDM1 may lead to inhibition of terminal differentiation, one possible pathogenetic pathway in DLBCL. ABC DLBCLs also have high expression of PDE4B, which prevents cAMP from triggering apoptosis [67].

In addition, ABC DLBCLs have high expression and constitutive activity of the nuclear factor kappa B (NF-KB) complex involved in the B cell receptor (BCR) signaling pathway [4,59,68]. ABC DLBCLs carry somatic mutations in multiple genes that are positive regulators of NF-kappaB, including CARD11, TRAF2, and TRAF5 [69]. The survival of ABC DLBCLs without CARD11 mutations appears to be dependent upon the expression of another BCR signaling component known as Bruton tyrosine kinase (BTK) [4]. (See "Toll-like receptors: Roles in disease and therapy".)

Type III – Type III DLBCL is a heterogeneous group of tumors that have gene expression profiles that differ from germinal center and post-germinal center B cells. Its pathobiology is unknown.

An alternative molecular classification scheme generated by the unsupervised clustering of gene expression profiles divides DLBCL into three groups characterized by the expression of genes involved in B cell signaling (BCR), oxidative phosphorylation, or the host immune response [70]. Of note, the tyrosine kinase SYK, which participates in BCR signaling and is selectively active in BCR-type, is a proposed therapeutic target in DLBCL and certain other B cell neoplasms [71,72]. Supervised analysis of DLBCL expression profiles from the same group identified expression of PKC-beta as a marker of poor outcome [73], a finding also noted by others [74]. This association has led to trials of PKC-beta inhibitors (eg, enzastaurin) in DLBCL.

The use of gene expression profiling in the diagnosis of DLBCL and the determination of prognosis has been limited to date by the need for fresh tissue for profiling on gene arrays. New approaches that allow subtyping of DLBCL using RNA isolated from formalin-fixed paraffin-embedded tissues have emerged and are being used clinically at some centers [75]. (See "Prognosis of diffuse large B cell lymphoma", section on 'Cell of origin studies'.)

INSIGHTS FROM DEEP SEQUENCING OF DLBCL GENOMES — Deep sequencing of DNA is providing new insights into the pathobiology of DLBCL, which may lead to new therapies and/or establish new genetic classification systems for DLBCL.

More than 150 recurrent mutations have been identified in DLBCL [49,76,77]. Some of the most frequent mutations involve genes that regulate histone modifications, such as MLL2, MEF2B, EZH2, and CREBBP [30,78]. This suggests that epigenetic alterations play an important role in the pathobiology of DLBCL and may provide new treatments because many epigenetic regulators are enzymes that can be targeted with drugs.

These studies may lead to a new genetic classification system for DLBCL. Various classification systems have been proposed, but there is not yet consensus regarding a preferred model nor clear evidence of advantages over current methods for categorizing DLBCL.

Examples of proposed models include:

In one study of 574 DLBCL samples, four subtypes were identified that differed by gene-expression signature, phenotype, and response to immunochemotherapy [77]. The four major subtypes were described as MCD (mutations of MYD88L265P and CD79B), BN2 (BCL6 fusions and NOTCH2 mutations), N1 (NOTCH1 mutations), and EZB (EZH2 mutations and BCL2 translocations).

A study of 304 DLBCL specimens identified five genetic subtypes that were associated with distinct outcomes and appeared to convey prognostic information independent of the International Prognostic Index [49]. The categories were identified as: low-risk activated B cell (ABC) of extrafollicular/marginal zone origin; two distinct subsets of germinal center B cell (GCB) with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability.

A population-based study of 928 patients with DLBCL resolved five distinct molecular subtypes by sequencing 293 genes associated with hematologic malignancies [79]. The MYD88 category was associated with a poor prognosis and was strongly associated with the ABC cell-of-origin (COO) category. The BCL2 category was strongly associated with the GCB category and a generally good prognosis; this category included most cases of transformed follicular lymphoma or concurrent follicular lymphoma. The SOCS1/SGK1 category had the most favorable prognosis and shared molecular features with primary mediastinal B cell lymphoma, while the remaining categories had less distinctive prognostic and subtype associations.

A study of 1,001 specimens identified 150 genetic driver mutations, and a prognostic model was developed that outperformed current methods based on COO, International Prognostic Index, and dual MYC and BCL2 expression [76].

The pattern of somatic mutations in DLBCL varies according to the COO (GCB versus ABC types) [80]. Both classes of DLBCL are equally likely to have mutations involving BCL6, TP53, genes that encode immunosurveillance factors, and genes that are involved in regulation of the epigenome. However, GCB tumors are more likely to have mutations in the epigenetic regulator EZH2, GNA13 (a putative regulator of cell motility), and BCL2 translocations, whereas ABC-type DLBCLs are more often associated with mutations in genes that increase B cell receptor signaling and activation of the pro-survival transcription factor NF-kB, such as MYD88, CD79A, CARD11, and TNFAIP3 (also known as A20). Whole genome sequencing has also demonstrated widespread genomic rearrangements and evidence of chromothripsis (ie, local chromosome shattering) [50]. Based on the analysis of subclonal variants within the same tumor, it appears that tumors continue to acquire mutations throughout their initial outgrowth. Mutations in genes such as EZH2, MYD88, CARD11, and CD79A previously thought to initiate tumorigenesis are among the events that are sometimes present only in subclones, indicating that these mutations may also occur after tumor initiation.

MEDIASTINAL LARGE B CELL LYMPHOMA — Primary large B cell lymphoma of the mediastinum (PMBL) is a variant of DLBCL arising in the mediastinum from the thymic (medullary) B cell. As long-suspected on clinical grounds, biological data suggest that PMBL should be separated from DLBCL [81]. Specifically, the gene expression profile of PMBL is more similar to that of classic Hodgkin lymphoma (cHL) than that of DLBCL [29,82], and the genetic drivers in PMBL are somewhat distinct from those found in DLBCL.

Molecular changes that are closely associated with PMBL include:

Signaling abnormalities – Constitutive activation of the JAK-STAT and NF-kB signaling pathways are hallmarks of PMBL [83]. As an example, whole exome sequencing of 95 PMBL tumors identified recurrent mutations in JAK-STAT, NF-kB, and interferon response factor (IRF) signaling pathways [84].

Immune evasion – PMBL is associated with genomic abnormalities that enable immune evasion. Numerical and structural genomic changes of chromosome 9p24.1 (which includes loci that encode PD-L1 and PD-L2) and alterations to CIITA (the master transcriptional regulator of major histocompatibility complex class [MHC] II gene expression) are thought to contribute to PMBL pathogenesis by fostering immune evasion [81,84-87].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Diffuse large B cell lymphoma in adults (Beyond the Basics)")

SUMMARY

Description – Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma. The molecular pathogenesis of DLBCL is a complex, multistep process leading to the outgrowth of a malignant clone of germinal or post-germinal B cell origin.

Heterogeneity of DLBCL – DLBCL is a heterogeneous clinicopathologic entity that includes tumors derived from germinal center B cells or post-germinal center B cells (also called activated B cells) (figure 1). (See 'Cell of Origin' above and 'Heterogeneity of DLBCL' above.)

BCL6 mutations in DLBCL – The majority of DLBCL tumors demonstrates translocations or mutations that result in the increased expression of the B cell lymphoma 6 (BCL6) gene. Overexpression of BCL6 leads to downregulation of target genes, including the TP53 tumor suppressor gene, which prevents the cells from undergoing apoptosis in response to DNA damage (figure 2). (See 'Aberrant BCL6 expression' above.)

TP53 (p53) mutations – Up to 20 percent of DLBCL demonstrate mutations or deletions of the TP53 tumor suppressor gene. In addition, TP53 transcription is at least partially controlled by BCL6, which encodes a transcriptional repressor. Downregulation of TP53 expression or expression of mutant p53 products results in a loss of the normal growth-limiting activities of this gene. (See 'TP53 downregulation' above.)

Other contributors to pathogenesis of DLBCL – Other mechanisms important in the pathogenesis of subsets of DLBCL include aberrant somatic hypermutation, BCL2 overexpression, MYC overexpression, evasion of host immunity, and altered tumor cell motility/trafficking. (See 'Other mechanisms' above.)

Primary large B cell lymphoma of the mediastinum (PMBL) – PMBL is a variant of DLBCL that arises in the mediastinum from the thymic (medullary) B cell. The pathogenesis of PMBL appears to be closer to that of classical Hodgkin lymphoma than that of DLBCL, and involves activation of JAK-STAT and NF-KB signaling and acquisition of genetic lesions that allow the tumor cells to escape from immune surveillance. (See 'Mediastinal large B cell lymphoma' above.)

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Topic 4722 Version 21.0

References

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