New developments in the pathology of malignant lymphoma. A review of the literature published from September 2015–December 2015

J Hematopathol (2016) 9:19–27 DOI 10.1007/s12308-016-0269-4 REVIEW OF THE LITERATURE New developments in the pathology of malignant lymphoma. A review of the literature published from September 2015–December 2015 J. Han van Krieken 1 Published online: 22 February 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Introduction It remains a challenge to discuss every 3 months the published literature on the pathology of lymphomas. A pleasant challenge, because I need to read many interesting works, but also an impossible one: I cannot read everything. Nevertheless, I hope that also this month, I can provide the readership with an interesting summary of my personal selection. Biology of lymphoma Hodgkin lymphoma CD30 expression is a hallmark of Hodgkin lymphoma (HL), and this is associated with activation of the nuclear factor-κB (NF-κB) pathway. Epstein-Barr virus (EBV) latent membrane protein-1 (LMP-1) and ligand-independent signaling by overexpressed CD30 are both known to cause activation of NF-κB in lymphomas, but in normal cells hyperactivation of NF-κB triggers cellular senescence and apoptosis. Ishikawa et al. [1] show that IκB-ζ, an inducible regulator of NF-κB, is constitutively expressed in Burkitt lymphoma (BL) and HL cell lines. In addition, immunohistochemically nuclear IκB-ζ was positive in BL cells and Hodgkin and Reed-Sternberg * J. Han van Krieken 1 Department of Pathology, Radboud University Medical Centre, P.O. Box 9101, 6500, HB Nijmegen, The Netherlands (HRS) cells. Expression of LMP-1 and CD30 increased IκB-ζ expression at the transcriptional level. IκB-ζ promoter was regulated by activation of the NF-κB-inducing kinase (NIK)/IκB kinase/NF-κB pathway via the carboxyl-terminal tumor necrosis factor (TNF) receptor-associated factor (TRAF)-interacting regions of LMP-1 and CD30. Interestingly, IκB-ζ inhibited NF-κB activation by LMP-1 and CD30. The results suggest that NF-κB-induced IκB-ζ negatively modulates NF-κB hyperactivation, resulting in a fine balance that ultimately endows a net evolutionary benefit to the survival of BL and HL cells. This work shows how complicated checks and balances are in normal and neoplastic cells and how difficult it is to deduct function from mere immunohistochemical analysis of tumors. Another example is provided by Oelmann et al. [2] who studied expression of IL-1beta, IL-1R1, and IL-1R2 in 17 HL by mRNA in situ hybridization (ISH). Signaling through the IL-1-receptor type 1 (IL-1R1), IL-1 is required for initiation and maintenance of diverse activities of the immune system, and a second receptor, IL-1R2, blocks IL-1 signal transduction. IL-1beta expressing cells, morphologically consistent with endothelial cells and fibroblasts, occurred in all HL tissues with elevated transcript levels in areas of active fibrosis. HRS cells of all cases expressed low IL-1R1 transcript levels in some tumor cells and high levels of IL-1R2 in large proportions of HRS cells. Only few bystander cells showed low levels of IL-1R1 and IL-1R2 RNA. HL patient sera carried variably amounts of IL-1R2 protein with significantly increased titers in patients with active disease compared to patients in complete remission and c o n t r o l i n d i v i d u a l s w i t h o u t H L . We s t e r n b l o t s and co-immunoprecipitations showed binding of the IL-1R2 to the intracellular IL-1R-accessory protein (IL-1IRAcP). These data suggest functions of the IL-1R2 as a Bdecoy-receptor^ sequestrating paracrine IL-1 extracellularly and intracellularly by engaging IL-1IRAcP, thus depriving IL1-R1 molecules of 20 their extracellular and intracellular ligands. Expression of IL1R2 by HRS cells seems to contribute to local and systemic modulation of immune function in HL. B cell lymphomas Nowadays, whole genome or exome sequencing (WGS; WES) has become a widely available tool so we can expect rapid increase in the knowledge on genetic changes in many tumors. Peveling-Oberhag et al. [3] investigated splenic marginal zone lymphoma (sMZL) using this technique in two cases. They found 25 different somatic mutations, including known mutations in the NOTCH2 and MYD88 genes, but the other 23 had not been associated with SMZL before. However, in none of 24 additional sMZL, these latter mutations were also found. Therefore, this approach was not very successful in finding recurrent genetic alterations in this study, but further work is needed. The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL), but the biological consequences of these mutations are not known. Two groups of researchers took on the challenge to determine the role of these mutations in lymphoma development and come with similar results. Ortega-Molina et al. [4] show in mouse models that KMT2D affects methylation of histone H3 and expression of a set of genes, including those in the CD40, JAK-STAT, Tolllike receptor, and B cell receptor signaling pathways. Other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3, and TNFRSF14. Furthermore, they show that KMT2D functions as a tumor suppressor and that its loss in B cells results in diminished B cell differentiation and class switch recombination as well as lymphoma development. Zhang et al. [5] show that FL- and DLBCL-associated KMT2D mutations impair KMT2D enzymatic activity, leading to diminished global H3K4 methylation in germinal-center (GC) B cells and DLBCL cells. Conditional deletion of KMT2D early during B cell development, but not after initiation of the GC reaction, results in an increase in GC B cells and enhances B cell proliferation in mice. Moreover, genetic ablation of KMT2D in mice overexpressing Bcl2 increases the incidence of GC-derived lymphomas resembling human tumors. These findings suggest that KMT2D acts as a tumor suppressor gene whose early loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. BL and FL both have features of GC B cells but are biologically and clinically quite distinct. Kretzmer et al. [6] performed whole-genome bisulfite, genome and transcriptome sequencing in 13 immunoglobulin (IG)-MYC translocationpositive BL, 9 BCL2 translocation-positive FL and 4 normal GC B cell samples. There was different methylation of J Hematopathol (2016) 9:19–27 intragenic regions between BL and FL that strongly correlated with expression of associated genes. The results demonstrate a tight connection between somatic mutation, DNA methylation, and transcriptional control in key B cell pathways deregulated differentially in different types of GC B cell lymphomas. Hartmann et al. [7] tried to gain better understanding of the signaling molecules in the microenvironment of B cell samples, which in the end, might lead to new treatment approaches. They analyzed (...truncated)