Review

Leukemia (2007) 21, 37–43. doi:10.1038/sj.leu.2404449; published online 12 October 2006

Diffuse large B-cell lymphoma: a heterogeneous group of non-Hodgkin lymphomas comprising several distinct clinicopathological entities

P De Paepe1 and C De Wolf-Peeters2

  1. 1Department of Pathology, AZ St-Jan AV, Brugge, Belgium
  2. 2Department of Pathology, Division of Morphology and Molecular Pathology, Catholic University Leuven, Leuven, Belgium

Correspondence: Dr P De Paepe, Department of Pathology, AZ St-Jan AV, Brugge, Ruddershove 10, B-8000 Brugge, Belgium. E-mail: pascale.depaepe@azbrugge.be

Received 4 August 2006; Revised 13 September 2006; Accepted 20 September 2006; Published online 12 October 2006.

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Abstract

Diffuse large B-cell lymphoma (DLBCL) as defined by the World Health Organization (WHO) classification is clinically, morphologically and genetically a heterogeneous group of malignant proliferations of large lymphoid B cells. Over the last 6 years, several studies have been published improving our understanding of these lymphomas. These studies analyzed DLBCL by their gene expression profile, provided further information on some of the variants of DLBCL listed in the WHO classification and stressed the impact of the site of origin of these tumors. This review summarizes these recent data and explores their impact on the recognition of new clinicopathological lymphoma entities.

Keywords:

DLBCL, classification, morphology, microarray, immunohistochemistry

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Introduction

Diffuse large B-cell lymphoma (DLBCL) account for approximately 40% of adult non-Hodgkin lymphomas. It is clinically, morphologically and genetically a heterogeneous group of tumors composed of large B cells.

The Kiel classification1 subdivided large B-cell lymphomas by pure morphology into centroblastic and immunoblastic lymphomas. The Working Formulation2 on the other hand subdivided large B-cell lymphomas according to their biological behavior into an intermediate-grade (large cleaved and large non-cleaved) and a high-grade (immunoblastic) category. In 1994 the International Lymphoma Study Group (ILSG), an international group of hematopathologists from Europe, the United States and Asia, introduced a new approach to lymphoma classification. Lymphoma entities were defined based on the presence of a constellation of distinct morphological, immunophenotypic, genetic and clinical features and for each lymphoma entity a putative cell of origin was postulated. The ILSG consensus list of real lymphoma entities was called the 'Revised European-American Lymphoma' (REAL) classification3, 4, 5 which has been largely adopted by the World Health Organization (WHO) classification in 2000. One of the listed entities in the REAL classification was DLBCL, though known to represent a heterogeneous group of tumors. Several clinicopathological entities with characteristic morphological, immunophenotypic, cytogenetic and clinical features have been recognized since within this group of lymphomas. These were listed as separate entities in the WHO classification as primary mediastinal large B-cell lymphoma (PMBCL), intravascular large B-cell lymphoma and primary effusion lymphoma (PEL). All other large B-cell lymphomas, not fitting into one of these three entities, remained lumped under the term of 'DLBCL' with the understanding that several subtypes were likely to exist but clear criteria to differentiate them from each other were lacking. Nevertheless, several morphological variants of DLBCL (centroblastic, immunoblastic, anaplastic, plasmablastic, T-cell/histiocyte rich and anaplastic lymphoma kinase (ALK)-positive DLBCL), not yet considered to represent specific clinicopathological entities, are described in the WHO classification.6 With the development of novel techniques, in particular the microarray technology, allowing gene expression analysis of the tumor cells and their stromal background, a large amount of new information was obtained, leading to a better understanding of the lymphomas composed of large B cells. Moreover, since the publication of the WHO in 2000, additional information has become available on some of the variants of DLBCL, supporting their recognition as distinct lymphoma entities according to the REAL principles. Finally, several studies have drawn the attention to the impact of the anatomical site of involvement by DLBCL.

In this review, we will mainly concentrate on these recently published data and explore their impact on the recognition of new clinicopathological entities, fulfilling the 'REAL' principles, within the group of DLBCL.

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New insights into large B-cell lymphomas based on microarray analysis and immunohistochemical studies

GCB-like, ABC-like and type III DLBCL

Several microarray studies7, 8 performed on untreated, de novo DLBCL, identified two main, prognostically different subgroups. Both were characterized by a distinct gene expression profile either characteristic of normal germinal center B-cells or of activated blood memory B-cells. The germinal center B-cell-like (GCB-like) subgroup was correlated with a significantly better prognosis in comparison to the activated B-cell-like (ABC-like) subgroup. This prognostic significance was independent of the international prognostic index.7, 8, 9, 10, 11 No correlation was found between these subgroups of DLBCL and the different morphological variants listed in the WHO.7

A third (type 3) subgroup comprised cases that did not express genes characteristic of the GCB-like nor of the ABC-like subgroup. This subgroup had a poor outcome similar to that of the ABC-like subgroup and is until present, and in contrast to the GBC-like and the ABC-like subgroup, not further studied.

ABC-like and GCB-like DLBCL are associated with different underlying oncogenic mechanisms

A difference in the incidence of BCL2 gene rearrangement was shown within the two subgroups as t(14;18)(q32;q21) was found to occur almost exclusively in the GCB-like subgroup.7, 12, 13 These BCL2 gene rearranged cases furthermore shared a striking similar gene expression profile, suggesting that they represent a unique subset within the group of GCB-like DLBCL.12

In the ABC-like subgroup on the contrary, activation of the nuclear factor kappa B (NF-kappaB) pathway was found. Indeed, these lymphomas express NF-kappaB target genes resulting from a constitutive activity of inhibitor kappa B (IkappaB) kinase. This enzyme phosphorylates IkappaB, the inhibitor of NF-kappaB, resulting in its proteasomal degradation. Administration of MLX105, an IkappaB kinase inhibitor of the beta-carbolene class, to ABC-like (but not GCB-like) DLBCL cell lines induces apoptosis (Staudt LM. Ann Oncol 2005;16 (Suppl 5): v36; abstract).

ABC-like and GCB-like DLBCL are characterized by distinct patterns of chromosomal imbalances

The subgrouping of DLBCL by microarray data is supported by comparative genomic hybridization studies and distinct patterns of chromosomal imbalances were reported for both subgroups. ABC-like tumors frequently displayed trisomy 3, gains of 3q and 18q21–q22 and losses of 6q21–q22 whereas GCB-like tumors frequently showed gains of 12q12.14, 15

Some of the potentially important genes harbored by these chromosomal regions have been identified.

The PRDM1/BLIMP1 gene, a transcriptional repressor expressed in a subset of GCB cells and in plasma cells and required for terminal B-cell differentiation, lies on chromosome 6q21–q22.2. It was shown that most of non-GCB DLBCL cases lack PRDM1/BLIMP1 protein expression, despite the presence of PRDM1/BLIMP1 messenger RNA. Mutational analysis of PRDM1/BLIMP1 indicates a tumor-suppressor role for this gene and inactivation of PRDM1/BLIMP1 may contribute to lymphomagenesis by blocking terminal B-cell differentiation into plasma cells.16, 17

Amplification of 18q21, which contains the BCL2 gene, was more frequent in ABC tumors (18%) than in GCB tumors (5%). The majority of the cases of GCB-DLBCL with amplification of 18q21 also had the translocation t(14;18).

As GCB-like and ABC-like tumors arise from B cells at different stages of differentiation (germinal center cells versus post-germinal center cells), apparently utilize different oncogenic pathways (t(14;18)(q32;q21) translocation in GCB-like tumors versus activation of the NF-kappaB pathway in ABC-like tumors) and have distinct survival rates, it can be assumed that both molecularly defined subgroups represent different disease entities.

Of interest, in children, a striking predominance of GCB-like DLBCL is found which might explain the difference in clinical outcome observed in children versus adults. However, in contrast to adult GCB-like DLBCL, no association with the t(14;18) translocation was found which may suggest that other biological mechanisms might underlie pediatric DLBCL.18

The most important characteristics of ABC-like and GCB-like tumors are summarized in Table 1.


Does immunohistochemistry allow the identification of GCB-like and ABC-like DLBCL?

Microarray analysis in daily diagnostic work is not yet feasible. For that reason the usefulness of immunohistochemistry in the identification of GCB-like and ABC subgroups of DLBCL has been investigated by several groups.19, 20, 21 Most of these studies use CD10 and bcl-6 as GCB B-cell markers and MUM1/interferon regulatory factor (IRF)4 as an activated or non-GCB B-cell marker.

CD10 is a proteolytic enzyme expressed on the surface of GCB cells and on a variety of other cells, including lymphoid precursor cells and some epithelial cells. Its precise function remains unknown but CD10 expression is a characteristic finding in lymphoblastic, Burkitt's and follicular lymphoma. CD10 expression in DLBCL is found in approximately 30 to 40% of cases.22, 23 It is generally considered a marker for follicle center cell origin and is thus used as an indicator of GCB-like DLBCL. Several reports found CD10 expression a favorable prognostic factor for disease-free survival (DFS) and achievement of complete remission.12, 19, 23

The BCL6 gene is believed to play a central role in the germinal center formation and is expressed upon initiation of the GC reaction and is downregulated upon selection for apoptosis or differentiation. Bcl-6 protein expression is strictly confined to the nucleus, sparing the nucleolus. Expression is found in normal GCB cells (centroblasts as well as centrocytes) and in 50–70% of DLBCL tumor cells. The prognostic significance of bcl-6 protein expression is yet unclear. Of interest, Bcl-6 protein expression does not correlate with the presence or absence of the BCL6 gene rearrangement.24, 25

MUM1/IRF4 (multiple myeloma oncogene 1) protein is a member of the (IRF) family of transcription factors. They play an important role in the regulation of gene expression in response to signaling by interferons and other cytokines. MUM1/IRF4 is only expressed in lymphocytes and probably plays a critical role in plasma cell development. MUM1 monoclonal antibodies show nuclear staining in plasma cells and a small percentage of GCB cells displaying some degree of plasmacytic differentiation. Most GCB and mantle cells are MUM1 negative. MUM1 expression can be detected in 40–50% of DLBCL cases.20, 21, 26 Unlike normal GCB cells in which BCL6 and MUM1 expression is mutually exclusive, tumor cells of DLBCL can co-express both proteins.27

The usefulness of immunohistochemistry to identify the GBC-like and ABC-like subgroups is still debated. Although several studies demonstrated that immunohistochemistry performed on formalin- fixed and paraffin-embedded tissue allows reliable identification of these subgroups using only three markers (CD10, bcl-6 and MUM-1)20, 21 applying the algorithm proposed by Hans et al.20 (see Figure 1a), other studies failed to demonstrate the prognostic significance of subgroups identified by this algorithm.26, 28 Bcl-2 protein, an antiapoptotic protein, is expressed in up to 80% of DLBCL. Although there are no clear differences in bcl-2 expression in ABC-like and GCB-like DLBCL, the mechanisms of bcl-2 expression in both subgroups are distinct. GCB-like DLBCL are frequently associated with the t(14;18)(q32;q21) that places the BCL2 gene under the control of the immunoglobulin heavy chain gene (IgH) enhancers, leading to bcl-2 overexpression. High bcl-2 expression might also result from amplification of the BCL2 gene, a phenomenon which was reported in up to 30% of DLBCL,29 generally belonging to the ABC-like subgroup. The prognostic value of bcl-2 protein expression in DLBCL has been extensively studied. Several studies demonstrated that a high bcl-2 expression represents a bad prognostic factor30, 31 in the ABC-like32 and GCB-like DLBCL.28 Of interest, by adding the expression of bcl-2 to the GCB/ABC related proteins CD10 and MUM1 (see Figure 1b), a new algorithm to identify prognostic subgroups in DLBCL was proposed.33 It was demonstrated to have a stronger prognostic power than the algorithm of Hans et al.20

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

(a) Immunohistochemical algorithm of Hans et al. for subdividing DLBCL into prognostic subgroups. (b) Alternative immunohistochemical algorithm for subdividing DLBCL into a favorable (group 1) and unfavorable (group 2) group (Muris et al.).

Full figure and legend (18K)

Can we recognize ABC-like and GCB-like DLBCL by morphology?

Although the initial gene expression study of DLBCL failed to demonstrate any statistical significant correlation between molecular defined ABC-like and GCB-like DLBCL and the morphological variants defined by the WHO classification, certain 'trends' were observed. In the GCB-like group, centroblastic monomorphic DLBCL was most commonly observed, whereas the ABC-like group comprised most of the immunoblastic and centroblastic polymorphic DLBCL cases.7 Similarly an association between the CD10+ GCB-like immunophenotypic profile and centroblastic morphology on the one hand and an ABC-like immunophenotypic profile and immunoblastic morphology on the other hand was found.26

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What are the entities yet evolving within the DLBCL resulting from these studies?

Large cleaved DLBCL

This lymphoma is composed of large, often spindle-shaped lymphoid cells with indented and twisted nuclei, lacking prominent nucleoli and embedded in delicate fibrous septa. Follicular dendritic networks or remnants thereof are absent. A significant correlation was found between this morphology, a GCB-like immunophenotypic profile, expression of CD10 and BCL2 gene rearrangement. Clinically, these cases show a slight female predominance and present at a younger age in comparison with the other DLBCL. No differences in terms of DFS and overall survival (OS) from the other DLBCL have been demonstrated.28

Spindle cell DLBCL

This is another entity recognized within the GCB-like subgroup. In contrast to the large cleaved DLBCL, these lymphomas are consistently CD10 and MUM1 negative but bcl-6 positive. Moreover, they do not show any evidence of BCL2 gene rearrangement whereas BCL6 gene mutations are demonstrated in all cases. These tumors present as primary extranodal lymphomas, predominantly affecting women.34

Immunoblastic DLBCL

This lymphoma is composed almost exclusively of immunoblasts. It is found within the ABC-like subgroup and is characterized by consistent MUM1 expression and infrequent bcl-6 expression. It mostly affects male patients presenting with nodal disease at an advanced stage. Of interest, immunoblastic morphology is a significant adverse predictor of DFS in univariate and multivariate analyses.28

FOXP1-positive DLBCL

Gene expression profiling and immunophenotypic studies showed that FOXP1 (FORKHEAD BOX P1), a transcription factor containing a DNA-binding domain called either the winged-helix or fork head domain35 and located on chromosome 3, is expressed in normal activated B cells and overexpressed in a subset of DLBCL with a predominantly ABC-like phenotype.20, 36, 37, 38 The significance of FOXP1 overexpression in lymphomas is debated. Recent reports suggest that it carries an independent prognostic significance and correlates with poor survival in DLBCL patients.37, 38 Interestingly, FOXP1 expression is also observed in marginal zone B-cell lymphomas (MZL). The molecular mechanisms underlying FOXP1 expression in both DLBCL and MZL were investigated and it was shown that expression of FOXP1 may rarely (in 1% of cases) result from a translocation t(3;14)(p13;q32). Surprisingly, 60% of FOXP1-positive DLBCL harbors trisomy 3 (with in 70% of these cases association with trisomy 18). Similarly, 45% of FOXP1-positive extranodal MZL is associated with trisomy 3.39 Of interest, FOXP1 represents also a significant predictor of unfavorable DFS in FOXP1-positive MZL in particular in those MZL with a polymorph histology (defined as a mixed population of centrocytes-like cells, small lymphocytes and a variable number of activated B cells) and carrying trisomy 3 and 18. This particular subgroup of MZL is at risk of transforming into DLBCL. The morphology of these secondary DLBCL is very similar to that of de novo FOXP1-positive DLBCL with trisomy 3 and 18. Based on these findings it has been speculated that 'de novo FOXP1-positive DLBCL' with +3 and +18 are marginal zone related lymphomas40 and may represent a large cell variant of MZL (similar to the large cell variant of mantle cell lymphoma).

PMBCL

This lymphoma was listed as a provisional entity in the REAL classification and was retained as a distinct clinicopathological entity in the WHO classification. Of interest, gene expression studies support this view as they demonstrate that PMBCL carry a distinct expression profile, which is related to that of classical Hodgkin's lymphoma.

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Additional information on DLBCL-variants supporting their recognition as lymphoma entities

ALK+DLBCL

This lymphoma is listed as a rare morphological variant of DLBCL in the WHO classification. Up to now, 15 cases of ALK+ DLBCL have been reported in literature.41, 42, 43, 44, 45, 46, 47 These cases are characterized by a distinct morphology and phenotype. The tumor is composed of a diffuse, rather monotonous proliferation of large immunoblast- or plasmablast-like cells with a plasma cell phenotype (CD20-/CD79aplusminus/CD138+) and a strong submembranous granular cytoplasmic staining for ALK. ALK is a member of the tyrosine kinase receptor family and full-length ALK is thought to play a major role in embryonic neural development. Aberrant ALK expression has been described in anaplastic large-cell lymphomas and inflammatory myofibroblastic tumors and results from genomic rearrangements of the ALK gene with various partner genes.48, 49, 50, 51 ALK expression in DLBCL is not the result of full-length ALK expression as originally reported52 but is due, in most of the cases, to a recurrent translocation t(2;17)(p23;q23) resulting in the CLTC-ALK fusion protein.43, 44 In a few cases ALK expression in these tumors can also result from the t(2;5)(p23;q35) translocation leading to the NPM (NUCLEOPHOSMIN)-ALK fusion protein.46

This lymphoma occurs in children and adults (age ranging from 10 to 59 years) and shows a male predominance (male to female ratio of 12:3). Although the tumor is associated with poor survival in adults, the biological behavior in children is unknown owing to the low number of cases reported at present.

T-cell-rich/histiocyte-rich lymphomas (THRBCL)

This lymphoma is mentioned as a variant of DLBCL in the WHO classification and is defined, in its broadest sense, as a tumor of large B-cells accompanied by numerous T-cells and histiocytes. This lymphoma should not be confused with B-cell lymphomas rich in stromal T cells thereby mimicking peripheral T-cell lymphomas and described in the past as T-cell-rich B-cell lymphomas.53 THRBCL was recognized first by Delabie et al.54 as a lymphoma composed of a small number of large scattered neoplastic B cells (representing less than 10% of the total cell population) embedded in an abundant stromal reaction comprising small T cells and an abundant amount of histiocytes. These tumors mimic nodular lymphocyte predominant Hodgkin lymphoma (NLPHL).55 In contrast to the indolent NLPHL, THRBCL presents mostly at an advanced clinical stage and carries a very aggressive behavior.54 Moreover, patients with THRBCL are at high risk of treatment failure.56, 57

THRBCL displays a particular gene expression profile as shown by gene expression profiling using microenvironment and host inflammatory response as defining features in DLBCL.58 In that study, three biologically robust clusters of DLBCL were identified characterized either by an 'oxidative phosphorylation', a 'B-cell receptor/proliferation' or 'host response (HR)' profile. These clusters were unrelated to the previously recognized molecular subgroups (GCB-like, ABC-like and type III). Of interest the HR cluster harbored THRBCL and had a robust NF-kappaB target gene signature. These findings further support the view that THRBCL is a distinct lymphoma entity.

DLBCL with plasmablastic morphology

The plasmablastic variant of DLBCL, originally mentioned as a morphological variant in the WHO, is now regarded as a heterogeneous group of tumors probably representing different entities. These are rare tumors, occurring in the setting of human immunodeficiency virus infection (PEL and plasmablastic lymphoma of the oral cavity) and in immunocompetent patients (ALK-positive DLBCL and pyothorax-associated lymphomas59, 60). Recent reviews on B-cell lymphomas with plasmablastic differentiation and acquired immunodeficiency syndrome-related lymphomas have been written and can be recommended.61, 62, 63

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DLBCL arising in special anatomic sites

In contrast to T-cell lymphoma classification, the anatomic location was not one of the major features for defining B-cell lymphoma entities in the REAL and WHO classification. Recently the location of large B-cell lymphomas has obtained growing interest, as clinical behavior may be largely dependant on the site of presentation. Therefore, site-specific lymphoma classification systems were developed.

It is well known that primary cutaneous B-cell lymphomas follow a much more indolent clinical course than their nodal and extracutaneous extranodal counterparts. Recently, the EORTC-WHO consensus classification of cutaneous lymphomas64 was introduced. In this classification system, two major subtypes of DLBCL were recognized and classified as two distinct lymphoma entities. 'Primary cutaneous follicle center lymphoma' (PCFCL) is characterized by a diffuse, diffuse and follicular or rarely pure follicular proliferation of small and large cleaved cells admixed with centroblasts. These tumors are preferentially located on the head and trunk and are associated with an indolent clinical behavior. The second type is the 'primary cutaneous DLBCL, leg type' (PCBCL, leg type). These tumors predominantly affect elderly patients, particularly females. They were first described on the leg but subsequently reported in other locations, like head or trunk. These tumors often show an immunoblastic morphology and behave aggressively, frequently disseminating to extracutaneous sites. Distinction between these two primary cutaneous DLBCL lymphomas has been confirmed by a microarray study where PCFCL and PCBCL, leg type were shown to have expression profiles similar to that of GCB-like DLBCL on the one hand and ABC-like extracutaneous DLBCL on the other.65 Both primary cutaneous DLBCL entities are further characterized by a distinct phenotype: PCFCL displays a CD10plusminus/bcl-6+/MUM1-/bcl-2plusminus (or GCB-like) phenotype whereas PCBCL, leg type, typically displays a CD10-/BCL-6plusminus/MUM-1+/bcl-2+ (ABC-like phenotype) phenotype. Although these two cutaneous lymphoma entities show many similarities with their non-primary cutaneous lymphoma counterparts there are however some cytogenetic differences. PCFCL is, in contrast to its nodal and extracutaneous extranodal counterpart, not associated with t(14;18)(q32;q21).

Likewise, 'primary central nervous system DLBCL' (PCNSL) was shown to be associated with a predominantly ABC-like immunophenotype.66 The clinical behavior and prognosis of these lymphomas is not only influenced by the anatomic location but apparently also by biological factors (ABC-like versus GCB-like tumors with different underlying oncogenic mechanisms). Immunohistochemical expression of bcl-6 in PCNSL is found to be associated with a longer OS.67

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Conclusion

Classification of lymphomas is a continuous process, driven by growing insights and knowledge on the biology of these tumors, often acquired through recently developed techniques. Microarray studies have clearly illustrated the heterogeneity within the group of DLBCL and have identified two prognostically different subgroups. These studies further provided a tremendous amount of additional information on DLBCL resulting in the discovery of several genes contributing in lymphomagenesis, the identification of new oncogenic pathways and the recognition of several new prognostic markers. Hematopathologists will now have the task to translate these data in morphological characteristics useful in daily diagnostic practice and use this information to identify further clinicopathological entities within the large group of DLBCL.

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