EBV-positive diffuse large B-cell lymphoma of the elderly

Abstract

Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (DLBCL) of the elderly, initially described in 2003, is a provisional entity in the 2008 World Health Organization classification system and is defined as an EBV-positive monoclonal large B-cell proliferation that occurs in patients >50 years of age and in whom there is no known immunodeficiency or history of lymphoma. These tumors are more common in Asia but also occur in North America and Europe at a low frequency. These neoplasms exhibit a morphologic continuum, from polymorphous to monomorphous, but morphologic features do not correlate with prognosis as all patients have a clinically aggressive course. Most EBV-positive DLBCL of the elderly patients have an activated B-cell immunophenotype and are characterized by prominent nuclear factor-κB activation. Cytogenetic complexity is usually low. In this review, we comprehensively delineate the data emerging from analyses of EBV latency program, microRNA-mediated EBV viral oncogenesis, functional genomics of EBV and its biology, and differential diagnosis challenge for EBV-positive DLBCL of the elderly. It is hoped that the improved understanding of these tumors will lead to the development of novel therapeutic approaches, enhance the effectiveness of clinical trials, and improve prognosis.

Figure 1

Schematic diagram of linear EBV genome (∼172 kb). (A) In proportion to their size, largely unique (U1-U5), internal repeat (IR1-IR4), and terminal repeat (TR) sequence domains are demonstrated. Ori P (indicated in red), the origin for latent infection EBV episome replication, has plasmid maintenance and DNA replication activity. Location of exons for latent EBV-induced membrane proteins and nuclear proteins and the size of each gene are shown. Of note, LMP1 transcription has an opposite direction to the other gene transcripts. LMP2 can only be transcribed when EBV exists as episome because the gene spans across the TR. LMP2A is transcribed from exon 1, whereas LMP2B is transcribed from exon 2. EBNAs are transcribed from differently spliced primary EBNA transcript. In latency III, EBNA1 transcription begins from Cp or Wp, whereas it starts from Qp in latency I or II. EBNA-LP has variable sizes due to variable numbers of repetitive exons. (B) Schematic diagram of circular EBV genome. The U1-U5, IR1-IR4, TR, and Ori P sequence domains are indicated. Open reading frames for latent proteins are shown. Of note, the size of each open reading frame does not illustrate the size of each latent protein. (C) Amino acid sequences of CTAR1 and CTAR2. TRAF-binding motif in CTAR1 and TRADD-binding motif are indicated with an underbar. Numbers on the right denote the order of the amino acid sequence. Cp, C promoter; EBNA-LP, EBNA leader protein; LMP, latent membrane protein; TRAF, tumor necrosis factor receptor-associated factor; TRADD, tumor necrosis factor receptor type 1–associated DEATH domain; Qp, Q promoter; Wp, W promoter.

Figure 2

Schematic diagram of EBV-mediated oncogenic signaling pathway activation in EBV-positive diffuse large B-cell lymphoma of the elderly. LMP1 has a 6-transmembrane domain with a long cytoplasmic C-terminal chain. It can self-aggregate to activate itself constitutively and provide a platform to interact with downstream molecules. LMP1 provides a proliferation signal via activating NF-κB, PI3K/Akt, MEK-ERK, and JNK–AP-1 MAPK pathways. It also gives signal for cell cycle progression by enhancing cyclin-dependent kinase 2 and phosphorylation of Rb protein and by inhibiting p16 and p27. LMP1 can also activate bcl-2 to provide an antiapoptotic signal. CTAR1 can directly interact with TRAF1, 2, 3, and 5 to activate NF-κB, PI3K/Akt, MEK-ERK, and JNK–AP-1 MAPK pathways. CTAR2 needs TRADD to interact with TRAF2 to activate NF-κB. Both canonical and noncanonical pathways of NF-κB are activated to give proliferation signal to the nucleus. There are 3 putative JAK3-binding motifs between CTAR1 and CTAR2. However, this finding was not reproduced by others.^- AP-1, activator protein 1; ERK, extracellular signal-regulated kinases; JAK3, Janus kinase 3; JNK, Jun amino-terminal kinases; MEK, MAPK/ERK kinase; PI3K, phosphatidylinositol 3-kinase; TRADD, tumor necrosis factor receptor type 1–associated DEATH domain; TRAF, tumor necrosis factor receptor–associated factor.

Figure 3

Geographical variations of overall survival and progression-free survival in EBV-positive diffuse large B-cell lymphoma of the elderly. (A-B) EBV-positive DLBCLs of the elderly showed worse overall survival and progression-free survival in Korean patients. (C-D) EBV positive DLBCLs of the elderly were more aggressive compared with >60-year-old patients with ABC subtype and GCB subtype in European patients. (E-F) In North America, EBV-positive DLBCLs of the elderly showed no difference in overall survival and progression-free survival in comparison with EBV-negative DLBCL patients. (G-H) In North America, EBV⁺CD30⁺ DLBCL of the elderly showed significant difference in overall survival and progression-free survival in comparison with either EBV⁺CD30⁻ or EBV⁻D30⁺ DLBCL patients.

Figure 4

Morphologic variants and immunophenotypic profiling in EBV-positive diffuse large B-cell lymphomas of the elderly. (A,E,I,M,Q,U) The monomorphic subtype is characterized by monotonous sheets of large transformed B cells. (B,F,J,N,R,V) Polymorphic DLBCL-like subtype shows canonical large B-cell neoplasm morphology, characterized by a high density of large neoplastic cells and scattered cells with Reed-Sternberg (RS)-like and Hodgkin-like features. (C,G,K,O,S,W) The polymorphic HL-like subtype shows a lower density of neoplastic cells with RS-like and Hodgkin-like features. (D,H,L,P,T,X) The polymorphic PLPD-like subtype is DLBCL with polymorphic LPD-like features. It is characterized by a low density of neoplastic cells without HL-like features. EBV-positive DLBCL of the elderly is predominantly the ABC subtype. (A,E,I,M,Q,U) Interestingly, the monomorphic case presented in this figure shows the GCB subtype. All polymorphic subtypes show the ABC-DLBCL molecular phenotype.

Figure 5

Gene expression profiling in the DLBCL ABC subtype was performed according to EBV status. The EBV-positive case shows a distinct gene expression pattern compared with cases with EBV negativity, with overexpression of multiple components of the NF-κB pathway.

Figure 6

Therapeutic modulation of EBV infection and associated signaling pathways. Strategies to inactivate EBV infection or EBV-associated oncogenic pathways have been explored in lymphoma cells. Many therapeutic targets have been identified. (1) Conventional chemotherapeutic agents or radiation target DNA. (2) Different strategies disrupting miRNAs can be offered. (3) EBV-specific cytotoxic T cells are engineered and reinfused to patients as immunoregulatory therapy approach. (4) Lytic cycle of EBV is induced by a couple of agents, and antiherpetic agents targeting virus in lytic cycle are added. Agents targeting the (5) NF-κB pathway, (6), PI3K/Akt pathway, (7) PKC pathway, or (8) MAPK pathway can be tried. Monoclonal antibodies, Brentuximab vedotin and Rituximab, are available targeting for (9) CD30 and (10) CD20, respectively.