**3. Etiology and pathogenesis**

*Normal and Malignant B-Cell*

mas and leukemia.

prognosis of various B-cell lymphomas [24–26].

**2. B-cell lymphomas: origin and development**

myeloma, lymphoplasmacytic lymphoma [1, 20, 22–25].

The 2001 and 2008 World Health Organization classification of hematopoietic and lymphoid tumors established guidelines for the diagnosis of malignant lymphomas; however, subsequently, there have been major advances with

significant clinical and biologic implications which necessitated further revisions [22, 23]. Hence further revision was done in 2016 which reflects a consensus among hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities leading to more targeted therapeutic strategies. The current WHO classification uses morphologic, immunophenotypic, genotypic, and clinical features to classify the lymphoid neoplasms into five broad categories as precursor B-cell neoplasms, peripheral B-cell neoplasms, precursor T-cell neoplasms, peripheral T-cell neoplasms and Hodgkin lymphoma. Hodgkin lymphoma though originates from B-cell has distinctive pathologic features and is treated as a separate entity**.** This chapter discusses about the etiology and pathogenesis, clinical features, recent WHO classification of B-cell lymphomas (2017), the highlights of modifications brought in, the morphology, immunophenotype, staging, treatment and

The differentiation of the B-cell lineage starts from stem cells the common lymphoid precursor to plasma cells that occurs successively in the fetal liver, bone marrow, and lymph nodes. The characteristic marker of B cells is the presence of immunoglobulins, which act as the cell surface antigen receptor. The genes that code for antibody are rearranged in the course of differentiation from stem cell to pre-B cell [20]. Understanding the stages of B-cell maturation has facilitated the recognition of the interrelationships between the various types of B-cell lympho-

The WHO classification distinguishes two major categories within B-cell lymphomas: precursor and mature. The precursor B-cell lymphomas comprise those lymphoblastic lymphomas and leukemia that derive from progenitor cells that have not yet been activated by antigen and are still in an undifferentiated stage. All other lymphomas representing different stages of differentiation are included in the category of mature B-cell lymphomas. Naïve B-cell can give rise to mantle cell lymphoma, small lymphocytic lymphoma/ chronic lymphocytic lymphoma. Lymphomas originating in the cells of the germinal centres are follicular lymphomas, Burkitt lymphoma and diffuse large B cell lymphoma. Post germinal center cells can give rise to marginal zone lymphoma, small lymphocytic lymphoma/ chronic lymphocytic lymphoma, diffuse large B cell lymphoma, plasma cell

B-cell lymphomas constitute a broad spectrum, extending from small- to largecell types, and from low to high grades of clinical behavior. The term "grade" is defined by the size and shape of cells and nuclei; density of chromatin; the number of mitoses (proliferation index), which may indicate the aggressiveness of a tumor; and by its clinical behavior. However, aggressiveness and tumor grade cannot be used synonymously because their correlation is not consistent; some lymphomas of highly aggressive behavior, such as mantle cell lymphoma, may exhibit low histo-

Hodgkin lymphoma (HL) encompasses another group of lymphoid neoplasms that are characterized by neoplastic Reed-Sternberg cells derived from the germinal center or post-germinal center B cells and differ from NHL in several respects. Hence it is treated as a separate category though it is derived from B-cells.

**48**

logic grades.

Chromosomal Translocations and Other Acquired Mutations are present in the majority of lymphomas. Many specific rearrangements are associated with particular neoplasms, suggesting a critical role in their genesis. The mutation can produce a "dominant negative" protein that interferes with a normal function (a loss of function) or inappropriate increase in some normal activity (a gain of function). Oncoproteins created by genomic aberrations often block normal maturation, turn on pro-growth signaling pathways that enhance the self-renewal of tumors cells, or protect cells from apoptotic cell death. Pro-growth signaling mutations produce a constitutively active tyrosine kinase; oncogenic tyrosine kinases activate RAS and its two downstream signaling arms, the phosphoinositide-3-kinase/AKT8 virus oncogene cellular homolog (PI3K/AKT) and mitogen-activated protein kinases (MAPK) pathways and thereby drive cell growth. Oncogenic mutations most frequently occur in germinal center B cells during antibody diversification. B cells that enter germinal centres after antigen stimulation upregulate the expression of activation-induced cytosine deaminase (AID), a specialized DNA-modifying enzyme which is essential for immunoglobulin (Ig) gene modifications: (1) class switching, an intragenic recombination event in which the IgM heavy-chain constant gene segment is replaced with a different constant segment leading to a switch in the class (isotype) of antibody produced; and (2) somatic hypermutation, which creates point mutations within Ig genes that may increase antibody affinity for antigen. Certain protooncogenes, such as myelocytomatosis oncogene cellular homolog (MYC), are activated in germinal center B-cell lymphomas by translocations to the transcriptionally active Ig locus. Other proto-oncogenes, such as BCL6, a transcription factor that has an important role in many B cell malignancies, are frequently activated in germinal center B-cell lymphomas by point mutations that also seem to stem from "mistargeted" DNA breaks induced by AID. A different type of regulated genomic instability is unique to precursor B cells, which express a V (D)J recombinase that cuts DNA at specific sites within the Ig [1].

Other factors include immunosuppression; infectious agents like Epstein-Barr virus, Human T-cell lymphotropic virus type 1, *Helicobacter pylori*, Hepatitis C virus, Human herpesvirus 8 (Kaposi sarcoma), Human herpesvirus 6, Human T-cell lymphotropic virus type 2 are known to be associated with lymphomas [27–31]. Male gender, increasing age, family history of non-Hodgkin's lymphoma, prior cancer history, drug history, immunosuppressive agents like phenytoin, methotrexate; occupational history like exposure to herbicides, pesticides, wood dust, epoxy glue, solvents; jobs in farming, forestry, painting, carpentry, tanning, hair dye use, sunlight exposure, nutritional factors, blood transfusion are the other possible etiologic factors [1, 32–37].
