**2. Classification and pathogenesis of DLBCL**

Non-Hodgkin's lymphoma (NHL) classification is based on pathohistological findings. The history of classification of lymphoid neoplasms begins in the 1940s. Based on the advancement in knowledge, the work classification and Kiel have replaced the revised European-American Classification of Lymphomas, and it is a step ahead of the classification given by the WHO [8].

Classifications are an essential part of modern medicine, offering a consensus on the terminology and disease definitions to be used interdisciplinary both in research and clinical practice. Evolution of lymphoma classification includes numerous attempts from descriptive schemes, relying on morphology to strictly clinically oriented stratifications proposed by hematologists, usually without significant international acceptance. The classification of the WHO (Swerdlow et al. 2008) differs from the previous classifications in defining the real entities of the disease through multiple divisions. The new entities defined in this release include extended immunophenotypes and some gene information relevant to the classification. Panel antibody was selected based on morphological differential diagnosis and tumor location. DLBCL is a diffuse proliferation of large neoplastic B lymphoid cells of the same size or up to two times than the normal lymphocyte or extremely large as in macrophages. The origin of these cells are B cells of the germinating center and postgerminant cells [8]. DLBCL can occur in the form of nodal and extranodal diseases. Approximately 40% of patients are present with extranodal disease. Any tissue organ can be the primary site of DLBCL, but the gastrointestinal tract is the most common site [33].

Tumor cells are B large transformed lymphocytes, but the morphological picture of DLBCL is varied, and the predominant morphological cell type can distinguish six subtypes of DLBCL: centroblastic, immunoblastic, T lymphocyte/histiocyte rich, anaplastic, plasmablastic, and DLBCL with cells similar to Reed-Sternberg cells and expression of anaplastic lymphoma kinase (ALK) protein. Tumor cells are positive, as defined by the disease, on pan-B markers CD19, CD20, CD22, and CD79a, and the positivity of intracytoplasmic or surface immunoglobulin (Ig) markers is distinctly expressed as CD5, CD10, CD30, and CD45 markers. Numerous chromosomal abnormalities have been detected with DLBCL, but no specific diagnostic changes have been isolated. The most frequent changes are breaks of regions 14q32, 3p21, 3q27, 22q12, 1q25, and 18q21 and additional chromosomes 7,9,12 and 4q31-35,13p13-14 and 17p11-13,8,9. In 11–23% of cases, DLBCL with advanced clinical stage of the disease revealed nine regions of chromosomal amplification and isolated amplified genes with a potential role in the formation of lymphoma. The clinical significance of each individual change has not been established, but some changes are associated with advanced clinical stage or poorer response to therapy. The abovementioned chromosomal abnormalities are generally not found as individual changes. The accumulation of a greater number of abnormalities indicates the progression of genetic changes, which play an important role in the pathogenesis of DLBCL [8, 33].

**83**

*B Cell Lymphomagenesis*

*DOI: http://dx.doi.org/10.5772/intechopen.87241*

T-cell/histiocyte-rich large B-cell lymphoma Primary DLBCL of the central nervous system

DLBCL associated with chronic inflammation

Primary mediastinal (thymic) large B-cell lymphoma

Germinal center B cell-like (GCB) Activated B-cell-like (ACB)

Primary cutaneous DLBCL, leg type

EBV mucocutataneous ulcer

Lymphomatoid granulomatosis

Burkitt lymphoma

Hodgkin lymphoma

**Table 1.**

Intravascular large B-cell lymphoma ALK+ large B-cell lymphoma Plasmablastic lymphoma Primary effusion lymphoma

Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS)

Epstein–Barr virus (EBV) positive DLBCL, not otherwise specified (NOS)

Human herpesvirus 8 (HHV8)+ DLBCL, not otherwise specified (NOS)

High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 translocations

*The 2016 update of WHO classification of DLBCL: subtypes and related entities [8].*

B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical

**4. Prognostic markers in DLBCL**

Burkitt-like lymphoma with 11q aberration

High-grade B-cell lymphoma, NOS

**4.1 Gene expression profile (GEP)**

clinical course is completely different [50–52].

Clinical and morphological differences in DLBCL suggest the biological significance of subtypes, which may help in adapting the therapy to be defined. The development of DNA microarray techniques provided the ability to identify gene expression of the tumor with a new molecular entity and a molecular predictor essential for survival. DNA microarray can analyze thousands of sites of previously identified genes. DLBCL has been identified by several tumor markers associated with unfavorable outcome after therapy and which can be linked to tumor cells and normal B lymphocytes. Phenotypic cells resemble normal B lymphocytes, but the

Gene expression profile has shown that DLBCL can be divided into two molecular entities that differ in the gene expression profile. Hans et al. have identified two subgroups of DLBCL [34, 52]. One subgroup was called germinal center B-cell-like (GCB) and has a characteristic gene expression of normal GC B cells, in about 50% of cases, and the second group was called activated B-cell-like (ABC). Type-3 group is defined as nonclassified cases. According to the GEP classification, the observed prognosis distinguishes two major subtypes after the chemotherapy. Patients with GCB lymphoma have a more favorable outcome in 5-year survival than patients in the ABC group (68% vs. 24%) [52]. The distinction between GCB and ABC

#### **3. The WHO classification which was revised in 2016**

See **Table 1**.

*Normal and Malignant B-Cell*

**2. Classification and pathogenesis of DLBCL**

step ahead of the classification given by the WHO [8].

each type of lymphoma. *BCL1* translocation results in disturbed cell cycle regulation. *BCL2* and API2-MALT1 have an antiapoptotic function [49]. API2-apoptosis inhibitor 2-MALT1 (mucosa-associated lymphoid tissue lymphoma translocation gene 1)-induced NF-kappaB activation may contribute to antiapoptotic action probably through NF-kappaB-mediated upregulation of apoptotic inhibitor genes [49].

Non-Hodgkin's lymphoma (NHL) classification is based on pathohistological findings. The history of classification of lymphoid neoplasms begins in the 1940s. Based on the advancement in knowledge, the work classification and Kiel have replaced the revised European-American Classification of Lymphomas, and it is a

Classifications are an essential part of modern medicine, offering a consensus on the terminology and disease definitions to be used interdisciplinary both in research and clinical practice. Evolution of lymphoma classification includes numerous attempts from descriptive schemes, relying on morphology to strictly clinically oriented stratifications proposed by hematologists, usually without significant international acceptance. The classification of the WHO (Swerdlow et al. 2008) differs from the previous classifications in defining the real entities of the disease through multiple divisions. The new entities defined in this release include extended immunophenotypes and some gene information relevant to the classification. Panel antibody was selected based on morphological differential diagnosis and tumor location. DLBCL is a diffuse proliferation of large neoplastic B lymphoid cells of the same size or up to two times than the normal lymphocyte or extremely large as in macrophages. The origin of these cells are B cells of the germinating center and postgerminant cells [8]. DLBCL can occur in the form of nodal and extranodal diseases. Approximately 40% of patients are present with extranodal disease. Any tissue organ can be the primary

site of DLBCL, but the gastrointestinal tract is the most common site [33].

**3. The WHO classification which was revised in 2016**

Tumor cells are B large transformed lymphocytes, but the morphological picture of DLBCL is varied, and the predominant morphological cell type can distinguish six subtypes of DLBCL: centroblastic, immunoblastic, T lymphocyte/histiocyte rich, anaplastic, plasmablastic, and DLBCL with cells similar to Reed-Sternberg cells and expression of anaplastic lymphoma kinase (ALK) protein. Tumor cells are positive, as defined by the disease, on pan-B markers CD19, CD20, CD22, and CD79a, and the positivity of intracytoplasmic or surface immunoglobulin (Ig) markers is distinctly expressed as CD5, CD10, CD30, and CD45 markers. Numerous chromosomal abnormalities have been detected with DLBCL, but no specific diagnostic changes have been isolated. The most frequent changes are breaks of regions 14q32, 3p21, 3q27, 22q12, 1q25, and 18q21 and additional chromosomes 7,9,12 and 4q31-35,13p13-14 and 17p11-13,8,9. In 11–23% of cases, DLBCL with advanced clinical stage of the disease revealed nine regions of chromosomal amplification and isolated amplified genes with a potential role in the formation of lymphoma. The clinical significance of each individual change has not been established, but some changes are associated with advanced clinical stage or poorer response to therapy. The abovementioned chromosomal abnormalities are generally not found as individual changes. The accumulation of a greater number of abnormalities indicates the progression of genetic changes, which play an important role in the pathogenesis of DLBCL [8, 33].

**82**

See **Table 1**.


**Table 1.**

*The 2016 update of WHO classification of DLBCL: subtypes and related entities [8].*
