The Histological and Biological Spectrum of Diffuse Large B-Cell Lymphoma in the World Health Organization Classification

Abstract

Diffuse large B cell lymphomas (DLBCL) are aggressive B-cell lymphomas that are clinically, pathologically and genetically diverse, in part reflecting the functional diversity of the B-cell system. The focus in recent years has been towards incorporation of clinical features, morphology, immunohistochemistry and ever evolving genetic data into the classification scheme. The 2008 WHO classification reflects this complexity with the addition of several new entities and variants. The discovery of distinct subtypes by gene expression profiling (GEP) heralded a new era with a focus on pathways of transformation as well as a promise of more targeted therapies, directed at specific pathways. Some DLBCLs exhibit unique clinical characteristics with a predilection for specific anatomic sites; the anatomic site often reflects underlying biological distinctions. Recently, the spectrum of EBV-driven B-cell proliferations in patients without iatrogenic or congenital immunosuppression has been better characterized; most of these occur in patients of advanced age, and include EBV-positive large B-cell lymphoma of the elderly. HHV-8 is involved in the pathogenesis of primary effusion lymphoma, which can present as a “solid variant.” Two borderline categories were created; one deals with tumors at the interface between classical Hodgkin lymphoma (cHL) and DLBCL. The second confronts the interface between Burkitt Lymphoma (BL) and DLBCL, so called “B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma” in the 2008 classification. Most cases harbor both MYC and BCL2 translocations, and are highly aggressive. Another interesting entity is ALK+ DLBCL, which renders itself potentially targetable by ALK inhibitors. Ongoing investigations at the genomic level, with both exome and whole genome sequencing, are sure to reveal new pathways of transformation in the future.

The Role of EBV in the Pathogenesis of Diffuse Large B Cell Lymphoma

“…The general organizing principles of DLBCL as it understood today were initially presented in the REAL classification of 1994, and were subsequently incorporated into the WHO classification (Menon et al 2012) standard. While these evolving classifications have provided a clearer categorization of these tumors, the diagnosis does not capture all the observed clinicopathologic heterogeneity that is commonly observed in the disease.…”

“…Among these neoplasms, B cell lymphoproliferative disorders (LPDs) are the most frequent and strongly associated. Diffuse large B cell lymphoma is the most common lymphoid malignancy in adults, accounting for nearly a third of nonHodgkin's lymphoma cases (NHL) globally (Fisher and Fisher 2004;Menon et al 2012;Jemal et al 2011).…”

Diagnosis of ‘double hit’ diffuse large B-cell lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma: when and how, FISH versus IHC

“…Consistent with the premise that BCLU is not used uniformly, the proportion of BCLU with MYC rearrangements varies widely in the literature from 33% to 91% (or "most"), with 78% reported in one study to be DHL. 4,24,38,39 Compared with DLBCL, BCLU has more MYC-R, but fewer BCL6-R, and, compared with BL, fewer MYC-R and more BCL6-R and BCL2-R. Consistent with this finding, the intermediate group of lymphomas between BL and DLBCL identified by GEP is reported to have Identify blastoid and pleomorphic mantle cell lymphomas Identify CD5ϩ DLBCL, a recognized immunophenotypic variant Aid in distinction from Burkitt lymphoma, exclude plasmablastic lymphoma, assist in distinction of other types of large B-cell lymphomas In situ hybridization for Epstein-Barr virus at least in cases that have some polymorphism and patient is Ͼ 50 years old (rule out EBVϩ DLBCL of the elderly) In the absence of classical cytogenetic studies, cytogenetic FISH studies to identify MYC, BCL2 and BCL6 rearrangements at least in a subset of cases more likely to have a positive yield † such as: All DLBCL with a GC phenotype plus cases of BCLU and/or a combination of the following with any positive finding being followed up with FISH studies (the more parameters selected the more cases tested and the fewer cases missed, none are 100% sensitive) MYC Ͼ40% (some recommend Ͼ20%) Ki-67 Ͼ80% (a poor criterion used in isolation) BCL2 strongly positive (will miss most BCL6 DHL, may require use of Ͼ1 BCL2 antibody) MYCϾ40% and BCL2 Ͼ50% ("DE" cases, see comments re MYC and BCL2 above) Histopathology suggests BCLU If MYC rearrangement is identified, demonstration of translocation partner has been shown to be of importance in limited studies (IGH// versus non-immunoglobulin partner) but would be considered more optional at the current time.…”

“…MYC-R are reported in ϳ6%-14% of DLBCL and in 33%-91% of BCLU. [5][6][7]16,[18][19][20][21][22]24,25,38,39 The majority are found in the setting of a DHL; however, 17%-75% are SHL, with the majority of studies reporting between 30% and Ͻ50%. [5][6][7][8]16,[19][20][21][22][23][24][25]27,37,40 SHLs have been reported to be as aggressive as DHL or at least an adverse prognostic indicator, 8,15,16,20,21,24,27 but others report that DHL lymphomas are more aggressive.…”

A population-based study of cellular markers in R-CHOP treated diffuse large B-cell lymphoma patients

“…Diffuse large B-cell lymphomas (DLBCL) constitute a heterogeneous group of aggressive B-cell lymphomas that are clinically, pathologically and genetically diverse [1]. Treatment with the current standard immunochemotherapy regime comprising rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin and prednisolone (R-CHOP) is curative for greater than 60-70% of patients, however, almost one third of patients remain refractory to initial therapy or ultimately relapse [2].…”