1. General information

#### 1.1. Epidemiology

Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL). It constitutes for approximately 25% of patients with NHL [1].

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The incidence of NHL is 19.5 per 100,000 men and women per year. Approximately 2.1% of men and women will be diagnosed with NHL at some point based on 2012–2014 SEER database [2] (SEER data). The incidence of DLBCL is approximately 7 cases per 100,000 persons per year. Males have a higher incidence with (M/F) incidence ratio of 1.5–1.6. Incidence is higher among whites than blacks or Asians and increases steeply with age. The overall incidence of DLBCL has declined 0.5% per year during 1992–2001 [2]. This decline was observed predominantly in men aged 25–54, on contrary in the elderly, the incidence of DLBCL increased 1.4% per year during the same time-period.

2.2. Cell of origin

The cell of origin classification (COO) has been the most significant development in the understanding of DLBCL biology. The gold standard test to identify COO is Gene expression profiling (GEP). GEP divides DLBCL into germinal center B cell (GCB), activated B cell (ABC) or unclassifiable (Type 3) types. GCB DLBCL is derived from normal GC centroblasts. Various mechanisms have been elucidated that drives pathogenesis of these subclasses based on COO [5]. GCB like tumors contain the (14;18) translocation (IgH/BCL-2 fusion gene) typical of follicular lymphoma and amplifications of the locus on chromosome 2 which codes for the c-Rel oncogene. BCL2 is dysregulated by t (14;18), PTEN deletions and amplification of miR-17-92 leading to deregulation of PI3K/mTOR pathway which are activated further promoting cell survival, proliferation and growth. GCB is further characterized by gain or amplification of MDM2, a negative regulator of the tumor suppressor p53 as well as deletions of the known tumor suppressor genes TP73 and ING1 that lead to genomic stability. The GEP of ABC DLBCL suggests that it is derived from B cells that are in the process of differentiating into plasma cells. Most of the genes expressed by normal GCB cells are down regulated in ABC DLBCL. There is upregulation of many genes normally expressed by plasma cells including XBP-1, amplification of BCL2, CD79A/CD79B ITAM mutation/deletion leading to chronic active BCR signaling, CARD11/A20 mutation, MYD88 mutation, STAT3 activation which lead to NFkB activation, FOXP1 activation. ABC-like DLBCL is associated with loss of 6q21, trisomy 3, and gains of 3q and 18q21–22. This locus on 6q encodes suppressor gene PRDM1 (Blimp-1) which is a master regulator in the differentiation of mature B lymphocytes to plasma cells, loss of which may lead to inhibition of terminal differentiation. ABC DLBCL has high expression and constitutive activity of the nuclear factor kappa B (NF-ĸB) complex involved in the B cell receptor signaling pathway. This classification not only defined subgroups with distinct biology and pathogenesis but also identified groups of patients with different outcomes after treatment [4]. In a study done at British Columbia looking at outcomes in patients treated with R-CHOP, there were 56% patients with GCB subtype and 32% with ABC subtype. The ABC group experienced significantly inferior outcomes as compared to the GCB group [6]. A third type, type III DLBCL (Unclassifiable as per GEP profiling) is also identified in which tumor cells have gene expression

Recent Advances in Diffuse Large B Cell Lymphoma http://dx.doi.org/10.5772/intechopen.74263 41

profiles that do not resemble either germinal center or post germinal center B cells [4, 7].

DLBCL with MYC gene rearrangement in addition to BCL2 and/or BCL6 gene rearrangements by Fluorescent in Situ Hybridization (FISH) or standard cytogenetics are known as double-hit lymphomas. MYC is rearranged in 5–15% of DLBCL and is frequently associated with BCL2 or to a lesser extent, BCL6 translocation. They are more aggressive and have a much poorer prognosis. Double-hit lymphomas are now recognized as a distinct entity in the 2016 WHO classification [8]. MYC and BCL2 are the key regulators of cellular proliferation and apoptosis, respectively. Dysregulation of MYC and BCL2 can cause chromosomal translocation or gene amplification but it may also occur by transcriptional upregulation downstream of NFkB pathway signaling [9]. This leads to a highly aggressive clinical behavior with very high Ki67 and overlapping pathologic features with Burkitt's lymphoma. These patients have an inferior

2.3. Double-hit lymphomas/double expressor

#### 1.2. Etiology and risk factors

DLBCL is a mature B cell neoplasm arising from germinal center and post germinal center B cells. Etiology of DLBCL is complex and multifactorial. DLBCL can arise de-novo or from transformation of indolent diseases like chronic lymphocytic lymphoma/small lymphocytic lymphoma (so-called Richter's transformation), follicular lymphoma, and marginal zone lymphoma. Those that originate from previous hematological malignancies are generally more aggressive and carry a poor prognosis. Chemical substances such as pesticides, herbicides, alkylating agents, ionizing radiation have been implicated as risk factors. An association has been found between inherited immune deficiency disorders such as ataxia-telangiectasia, Wiskott-Aldrich syndrome, common variable immunodeficiency, severe combined immunodeficiency, X-linked lymphoproliferative disorder [3]. Patients with acquired immunodeficiency states such as AIDS, organ or stem cell transplantation, autoimmune or rheumatologic diseases also have a higher incidence of DLBCL [4].
