New developments in the pathology of malignant lymphoma: a review of the literature published from January to April 2017

J Hematopathol DOI 10.1007/s12308-017-0295-x REVIEW OF THE LITERATURE New developments in the pathology of malignant lymphoma: a review of the literature published from January to April 2017 J. Han van Krieken 1 # The Author(s) 2017. This article is an open access publication Introduction This issue’s review contains, like always, a nice series of new data that hopefully satisfies the interest of the reader. No real theme, but a host of different developments. Biology of lymphoma As is well known, the process of antigen receptor rearrangements can lead to mistakes resulting in oncogenic chromosomal translocations. The enzyme activation-induced cytidine deaminase (AID) plays a role in the initiation of class switching in B-lymphocytes, and therefore, its expression is tightly controlled by the phosphatidylinositol 3-kinase δ (PI3Kδ) pathway. Compagno et al. [1] show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhances the expression of AID resulting in increased frequency of somatic hypermutation and chromosomal translocation, not only of the IgH locus but also to several other sites in the genome. Furthermore, in mice, PI3Kδ inhibitors or ibrutinib increases the formation of AID-dependent tumors. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IGH and other sites in human chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cell lines, and, finally, in patients treated with idelalisib, but not ibrutinib, there is increased somatic hypermutation in the genome. This * J. Han van Krieken 1 Department of Pathology, Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands worrisome effect should be carefully monitored in patients treated with these agents, especially since patients are often treated for a long time and the effects maybe be seen only after quite some time. Classification (and understanding!) of tumors is based on the cell of origin concept. Very distinct malignancies like classical Hodgkin lymphoma (cHL), CLL, and multiple myeloma (MM) arise from B lymphocytes, but have various stages of differentiation. Law et al. [2] performed a large-scale genome-wide association study in many patients (CLL: n = 1842; HL: n = 1465; MM: n = 3790) to see whether there might be a common predisposition for B cell lineage-derived neoplasia. They identified a risk locus at 3q22.2 with opposing effects between CLL and cHL. Eight established non-HLA risk loci showed also pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 was associated with increased CLL and cHL risk and reduced MM risk, and Gly70 in HLADQB1 showed opposing effects between CLL and cHL. These data identify shared biological pathways influencing the development of CLL, HL, and MM but with opposing risks and thus maybe are active at various stages of B cell development. Hodgkin lymphoma HL remains an enigmatic disease with so many different aberrant processes involved. Zahn et al. [3] add a new mechanism, namely the presence of a truncated form of PTPN1 in cHL cells (both in cell lines and in tissues), which upregulates Janus kinase/signal transducer and activator of transcription (JAK/STAT) activity, a common feature of B cell lymphomas. Functional characterization of this variant further indicated that it leads to proliferation and reduced sensitivity to chemotherapy. This latter finding is a bit surprising, cHL being one of the earliest and well-known diseases curable by chemotherapy. Another new mechanism in HL is described by J Hematopathol Agostinelli et al. [4]. They analyzed the functional status of glycogen synthase kinase-3 beta (GSK-3β) in cHL using antibodies raised against fixation-resistant epitopes of phospho Y216 GSK-3β (active form), phospho S9 GSK-3β (inactive form), and β-catenin protein. GSK-3β is a serine/threonine kinase involved in glycogen metabolism, cell cycle progression, differentiation, embryogenesis, migration, metabolism, survival, and cellular senescence. Its main biological function is to inhibit β-catenin by sequestration, and promotion of its proteasomal degradation in the Wnt canonical pathway. The active form of the enzyme was detected in 100 of 100 (100%) of the cases, and in line with that, the β-catenin protein was expressed in only 12 of 100 (12%) of the samples. These findings imply that activation of GSK-3β in cHL results in inhibition of the Wnt/β-catenin signal cascade and the aberrant accumulation of its activated form in nuclei of ReedSternberg and Hodgkin cells. A third new mechanism is described by Etzel et al. [5]. Because it is known that survival and proliferation of Hodgkin and Reed-Sternberg (HRS) cells are dependent on constitutive activation of nuclear factor κB (NF-κB) they looked for mutations in TNF alpha-induced protein 3 (TNFAIP3), one of the inhibitors of NF-κB. In addition, they evaluated protein expression by immunohistochemistry. Of the 37 investigated cHL cases, 8 (22%) had a mutation and these tended to be negative by immunohistochemistry. All these cases were negative for EBV which suggests complementing functions of TNFAIP3 inactivation and EBV infection in cHL pathogenesis. The same gene was studied by Jung et al. [6] in ocular marginal zone lymphoma (oMZL). They analyzed 10 cases using whole-genome and RNA sequencing and an additional 38 cases with targeted sequencing. Major genetic alterations affecting genes involved in NF-κB pathway activation (60%), chromatin modification and transcriptional regulation (44%), and B cell differentiation (23%) were identified. In wholegenome sequencing, the 6q23.3 region containing TNFAIP3 was deleted in five samples (50%). In addition, five structural variation breakpoints in the first intron of IL20RA located in the 6q23.3 region were found in three samples (30%). In targeted sequencing, a disruptive mutation of TNFAIP3 was the most common alteration (54%), followed by mutations of TBL1XR1 (18%), CREBBP (17%), and KMT2D (6%). All TBL1XR1 mutations were located within the WD40 domain, and TBL1XR1 mutants transfected into 293 T cells increased TBL1XR1 binding with nuclear receptor corepressor (NCoR), leading to increased degradation of NCoR and the activation of NF-κB and JUN target genes. This study confirms that genes involved in the activation of the NF-κB signaling pathway are the major driver in the oncogenesis of ocular MZL, which is inline findings in MZL at other sites, especially nodal based ones [7], which are, as earlier described in this Journal, difficult to separate from follicular lymphoma (FL) [8]. B cell lymphomas Although the primary genetic alteration in FL, the t(14;18), is among the earliest detected tumor-associated translocations, the full pathogenesis is not clear. Especially, the importance of the tumor stroma is recognized but not understood. Pandey et al. [9] demonstrate that FL stromal cells overexpress CXCL12. (...truncated)