The histological and biological spectrum of diffuse large B-cell lymphoma in the World Health Organization classification

Abstract

Diffuse large B-cell lymphomas (DLBCLs) 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 toward incorporation of clinical features, morphology, immunohistochemistry, and ever evolving genetic data into the classification scheme. The 2008 World Health Organization classification reflects this complexity with the addition of several new entities and variants. The discovery of distinct subtypes by gene expression profiling 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 Epstein-Barr virus (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 Epstein-Barr virus (EBV)-positive large B-cell lymphoma of the elderly. Human herpesvirus 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 classic Hodgkin lymphoma and DLBCL. The second confronts the interface between Burkitt lymphoma and DLBCL, so-called "B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma" in the 2008 classification. Most cases harbor both MYC and BCL2 translocations and are highly aggressive. Another interesting entity is anaplastic lymphoma kinase-positive DLBCL, which renders itself potentially targetable by anaplastic lymphoma kinase 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.

Figure 1

Immunohistochemistry algorithms for determining molecular subtype. All algorithms use a positivity cut-off in tumor cells of ≥ 30% for immunohistochemical markers unless otherwise indicated in the figure. (GCB-Germinal center B-cells)

Figure 2

DLBCL subtypes. A) DLBCL GCB type which is enriched in centroblasts B) DLBCL ABC type with an immunoblastic morphology C) EBV positive DLBCL of elderly with a polymorphous background and presence of Reed-Sternberg like cells D) PMBL with cytokeratin immunostain highlighting thymic Hassall’s corpuscle E) ALK positive DLBCL demonstrating immunoblastic and plasmablastic features F) Plasmablastic lymphoma in a HIV positive patient demonstrating diffuse sheets of plasmablastic and immunoblastic cells with frequent mitoses, tingible body macrophages and apoptosis G) Double Hit DLBCL containing sheets of monomorphic medium to large cells without a starry sky pattern H) Burkitt lymphoma with sheets of medium sized cells with frequent mitoses and tingible-body macrophages imparting a starry sky pattern.

Figure 3

(Adapted from Jaffe et al. ) Burkitt lymphoma, B-UNC/BL/DLBCL, and DLBCL of the GCB type. B-UNC/BL/DLBCL are generally associated with a complex karyotype with both MYC and BCL2 translocations. BCL2 translocations are found in approximately 30% of the GCB type of DLBCL, but MYC translocation should be absent, and if a dual translocation is found, the case should be classified as B-UNC/BL/DLBCL. Morphologically BL is composed of medium sized cells, with minimal nuclear variation. Cell size is largest in DLBCL, and B-UNC/BL/DLBCL is generally composed of cells of intermediate to large size, with greater variability than Burkitt lymphoma.