Overview of the pathobiology of the non-Hodgkin lymphomas

INTRODUCTION — Non-Hodgkin lymphoma (NHL) consists of a diverse group of malignant tumors of the lymphoid tissues variously derived from the clonal expansion of B cells, T cells, natural killer (NK) cells or precursors of these cells. This topic will review the most common mechanisms underlying the pathobiology of the NHLs.

Specifics regarding the pathobiology of the more common lymphoma subtypes are discussed separately:

●Diffuse large B cell lymphoma (see "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma")

●Mantle cell lymphoma (see "Pathobiology of mantle cell lymphoma")

●Burkitt lymphoma (see "Pathobiology of Burkitt lymphoma")

●Small lymphocytic lymphoma/chronic lymphocytic leukemia (see "Pathobiology of chronic lymphocytic leukemia")

●Follicular lymphoma (see "Pathobiology of follicular lymphoma" and "Pathobiology of follicular lymphoma", section on 'Introduction')

●Lymphoplasmacytic lymphoma (see "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma", section on 'Pathogenesis')

●Extranodal marginal zone lymphoma (see "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)", section on 'Pathogenesis')

●Splenic marginal zone lymphoma (see "Splenic marginal zone lymphoma", section on 'Pathogenesis')

CELL OF ORIGIN — Lymphomas are derived from B and T lymphocytes or natural killer (NK) cells at varying stages of maturation, and many of the biologic features of these malignant cells reflect their normal counterparts. A cell of origin has been proposed for each type of NHL based on morphologic, immunophenotypic, and genetic features of the malignant cells. However, in many cases this is not clear cut. Some NHLs classified as the same NHL subtype may be derived from cells at different stages of maturation (eg, germinal center B cell like diffuse large B cell lymphoma versus activated B cell like diffuse large B cell lymphoma). Other NHL subtypes do not have an easily identified cell of origin (eg, hairy cell leukemia, chronic lymphocytic leukemia). (See "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma", section on 'Gene expression heterogeneity of DLBCL' and "Clinical features and diagnosis of hairy cell leukemia", section on 'Pathogenesis'.)

NK cells share immunophenotypic and functional features with gamma/delta T lymphocytes making the distinction between tumors derived from NK and gamma/delta T cells difficult. For cases in which this distinction is unclear, the term "NK/T cell" NHL is used (eg, extranodal NK/T cell lymphoma, nasal type).

B cell lymphoma — B cell lymphomas can arise at any stage of normal B cell development, but most are derived from cells that have been exposed to the germinal center reaction [1]. Normal B cell development can be divided into three main stages (see "Normal B and T lymphocyte development", section on 'B cell development'):

●Pre-germinal center – Normal early B cell development takes place in the bone marrow and results in the transformation of a B progenitor cell (pre-pro B cell) into a mature B cell. Mature B cells have undergone immunoglobulin VDJ gene rearrangement and express a complete IgM antibody molecule on the cell surface. After release from the bone marrow, antigen-naïve mature B cells are exposed to antigen in the interfollicular area of the secondary lymphoid tissues (eg, lymph nodes, spleen). After this exposure, the majority migrate into the germinal center. A small population of antigen-naïve mature B cells circulates in the peripheral blood or resides in primary lymphoid follicles and follicle mantle zones. These cells provide the initial IgM antibody response (figure 1).

•Naïve mature B cells in the mantle zone are thought to give rise to mantle cell lymphoma. (See "Pathobiology of mantle cell lymphoma", section on 'Cell of origin'.)

●Germinal center – Mature, antigen-exposed B cells proliferate in the center of a primary follicle among follicular dendritic cells to form a germinal center. These centroblasts mature into centrocytes as they transition into the light zone of the germinal center. In the germinal center, B cells undergo class-switch recombination (from IgM to IgG or IgA) and somatic hypermutation (to increase antibody affinity for antigen). In addition, the immunoglobulin heavy and light chain variable region genes and other genes that are off-targets for somatic hypermutation (eg, BCL-6) undergo mutation in the germinal center and act as markers of germinal center transit.

•Centroblasts are thought to give rise to Burkitt lymphoma/leukemia and germinal center B cell (GCB) diffuse large B cell lymphoma. (See "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma", section on 'Cell of Origin' and "Pathobiology of Burkitt lymphoma", section on 'Cell of origin'.)

•Centrocytes are thought to give rise to follicular lymphoma.

•Marginal zone B cells are thought to give rise to marginal zone lymphoma.

●Post-germinal center – After transit through the germinal center, B cells can become memory B cells or plasmablasts, which undergo further development to become plasma cells.

•Plasmablasts are thought to give rise to activated B cell like (ABC) diffuse large B cell lymphoma. (See "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma", section on 'Cell of Origin'.)

•Plasma cells are thought to give rise to multiple myeloma. (See "Multiple myeloma: Pathobiology", section on 'Cell of origin'.)

T cell or NK cell lymphoma — T and NK cell lymphomas can arise at any stage of normal T or NK cell development. As described above, NK cells share phenotypic and functional features with gamma/delta T lymphocytes making the distinction between tumors derived from these cells difficult. For cases in which this distinction is unclear, the term "NK/T cell" NHL is used.

Normally, prothymocytes reside in the bone marrow and produce lymphoid progenitors that travel to the thymus and undergo positive and negative selection resulting in mature, antigen-naïve T cells. The T cell receptor (TCR) genes are rearranged during this process resulting in a heterodimeric receptor made of either alpha and beta (also called TCR2) or gamma and delta (also called TCR1) chains. Alpha/beta T cells are released from the thymus as CD4 positive or CD8 positive naïve T cells. Antigen exposure stimulates their transformation into T lymphoblasts which then become effector cells, memory cells, or follicular helper T cells of germinal centers. In contrast, gamma/delta T cells undergo little cellular expansion within the thymus but may expand considerably in the periphery. NK cells develop in the bone marrow and travel to the spleen, mucosa, and peripheral blood without maturing in the thymus. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation'.)

●Thymic T cells are thought to give rise to lymphoblastic T cell NHL.

●Post-thymic T cells and NK cells are thought to give rise to the other peripheral T cell NHLs.

PATHOGENETIC MECHANISMS — As with other malignancies, the pathogenesis of lymphomas is a complex process involving progressive accumulation of genetic lesions that affect oncogenes and tumor suppressor genes. In some cases, there is a genetic predisposition for the development of certain NHL subtypes (eg, familial chronic lymphocytic leukemia/small lymphocytic lymphoma [CLL/SLL]). In addition, the lymph node microenvironment, which includes stromal cells, macrophages, regulatory T cells, and the lymph node vasculature, has been implicated in the promotion of lymphomagenesis [2].

Important mechanisms that contribute to lymphomagenesis include:

●Balanced chromosomal translocations – The genome of most types of lymphoma is characterized by balanced chromosomal translocations that are often strongly associated with a disease subtype. As an example, t(11;14), which is frequently found in mantle cell lymphoma is associated with overexpression of cyclin D1 [3]. (See 'Balanced translocations' below.)

●Unbalanced chromosomal alterations – Unbalanced chromosomal alterations are often recognized by genomic sequencing; such alterations are often associated with tumor progression and adverse outcomes. CLL/SLL, in particular, is typically associated with unbalanced genetic abnormalities [4]. (See 'Unbalanced chromosomal abnormalities' below.)

●Somatic mutations – Some somatic mutations are present in all cells of the lymphoma (suggesting that they are early pathogenic events); those considered important contributors to lymphomagenesis are often referred to as "driver mutations." Other mutations are found in only a subset of the lymphoma cells, suggesting that they may be acquired as a later step in pathogenesis or as a progression event [5-7]. Examples of characteristic mutations associated with NHL are described below. (See 'Somatic mutations' below.)

●Epigenetic modifications – Mutations often affect genes that regulate histone modifications, including MLL2, MEF2B, EZH2, and CREBBP in DLBCL [8,9], and CREBBP, EP300, and MLL2 in follicular lymphoma [5,10]. Mutations in CREBBP for example are loss-of-function events that lead to depletion of H3K27 acetylation and silencing of genes involved in B cell signaling and immune response [11].

Some features of lymphomagenesis differ from mechanisms associated with solid tumors:

●The lymphoma genome is relatively stable during most stages of NHL development, whereas many solid tumors (especially epithelial tumors) are associated with apparently random genomic instability.

●Microsatellite instability (a hallmark of defects in DNA mismatch repair genes) has been described in only a small percentage of lymphomas (especially those arising in the context of immunodeficiency [12]), whereas it is more commonly associated with sporadic solid tumors and especially some hereditary syndromes that predispose to developing cancer [13].

CHROMOSOMAL TRANSLOCATIONS

Balanced translocations — Chromosomal translocations represent the genetic hallmark of lymphoid malignancies. Most NHL-associated translocations represent reciprocal and balanced recombination between two specific chromosomes, which are recurrently associated with a given tumor type and are clonally represented in each affected patient. (See "Chromosomal translocations, deletions, and inversions".)

The most frequent cytogenetic abnormalities have been characterized at the molecular level, leading to the identification of genes that are altered in B cells or T cells, and can cause tumors in transgenic animal models. Most of these genetic lesions selectively associate with specific NHL subtypes, thus representing markers of potential diagnostic significance [14,15]. (See "Genetic abnormalities in hematologic and lymphoid malignancies" and "General aspects of cytogenetic analysis in hematologic malignancies".)

The common feature of all chromosomal translocations associated with NHL is the presence of proto-oncogenes in proximity to the chromosomal recombination sites. In most cases, the structure of the proto-oncogene, and in particular its coding domain, is not affected by the translocation. However, the pattern of expression of the gene is altered by juxtaposition of heterologous regulatory sequences derived from the partner chromosome (proto-oncogene deregulation). Two distinct types of proto-oncogene deregulation may occur:

●Homotopic deregulation occurs when the chromosomal translocation alters the pattern of a proto-oncogene normally expressed in lymphocytes.

●Heterotopic deregulation occurs when a proto-oncogene normally not expressed in lymphoid cells is ectopically expressed in the lymphoma.

In most types of NHL-associated translocations, the heterologous regulatory regions responsible for proto-oncogene deregulation are derived from antigen receptor loci, which are expressed at high levels in the target tissue.

An alternative mechanism of oncogene activation by chromosomal translocation is the juxtaposition of two genes to form a chimeric gene coding for a novel chimeric protein. This mechanism, which is common in chromosomal translocations associated with acute myeloid leukemia and chronic myeloid leukemia, is not associated with NHL, with the exception of t(2;5)(p23;q35) as found in the NHL variant, anaplastic lymphoma, and t(11;18) as found in extranodal marginal zone lymphoma [16]. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)", section on 'Pathogenesis' and "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

Molecular cloning of the loci involved in the translocations most frequently associated with NHL has led to the identification of a number of proto-oncogenes involved in lymphomagenesis. The structural and functional consequences of each chromosomal translocation associated with NHL are described separately in the context of the molecular pathogenesis of the various NHL subtypes.

Unbalanced chromosomal abnormalities — The current model of lymphoma pathogenesis suggests that balanced translocations are the initiating events, while unbalanced chromosomal gains and losses are likely to be associated with clonal evolution that occurs with disease progression. Studies in follicular lymphoma have found an average of four to eight additional chromosomal abnormalities in addition to the characteristic t(14;18) [17,18]. Many of these occur at specific reproducible chromosomal locations and, in the case of amplifications, have been associated with increased expression of genes in that region [19]. Loss of 6q has been found in multivariate analysis to predict poor survival in follicular lymphoma [20], but as with most of the unbalanced chromosomal abnormalities, the gene involved is as yet unknown. (See "Pathobiology of follicular lymphoma", section on 'Other genetic lesions'.)

Recurrent and subtype-specific NHL variants associated with specific chromosomal deletions suggest that loss of currently unidentified tumor suppressor genes contribute to lymphomagenesis [17]. The most frequent of these deletions involves the long arm of chromosome 6 (6q) [21]. In some cases, 6q deletion is the sole cytogenetic abnormality and is often associated with poor prognosis [3]. Deletions of chromosome 13q14 represent the most frequent lesion in CLL/SLL, occurring in more than half of cases [22]. Mapping studies have determined that the minimal region of deletion does not include the retinoblastoma tumor suppressor gene, which is also located on chromosome 13q14, but rather is focused on MIR15-16 [22]. These micro-RNA genes, such as miR-15a or miR-16-1, may also act as tumor suppressors [23,24]. MicroRNAs are small conserved noncoding RNAs that downregulate their target genes by specifically decreasing their mRNA levels [25]. The B cell leukemia/lymphoma 2 (Bcl-2) gene is thought to be a target of miR-15a/miR16-1. (See "Staging and prognosis of chronic lymphocytic leukemia", section on 'Complex karyotype'.)

SOMATIC MUTATIONS — The timing of acquisition of somatic mutations in lymphomas and how they may interact with chromosomal translocations or unbalanced chromosomal abnormalities are still being elucidated for each subtype of lymphoma. In general, some somatic mutations are clonal, ie, present in all cells of the lymphoma, suggesting that they are early pathogenic events. However, many somatic mutations in genes considered to be "drivers," meaning that they are expected to be important to the pathogenesis of the lymphoma, are found in only a subset of the lymphoma cells, suggesting that they may be acquired as a later step in pathogenesis or as a progression event [5-7].

Mutations that activate the B cell receptor and NFKB pathways in diffuse large B cell lymphoma (DLBCL) are common in NHLs [26-28]. Less commonly, mutations affect RNA splicing (eg, chronic lymphocytic leukemia/small lymphocytic leukemia [CLL/SLL] [29,30]), the NOTCH pathway (eg, CLL/SLL [30,31] and marginal zone lymphomas [32]), and immune surveillance (eg, inactivating mutations or deletions of beta-2 microglobulin in DLBCL and Hodgkin lymphoma [HL] [33], and copy number variations or structural aberrations leading to upregulation of PD-L1, most notably in HL [34]). Deletions and mutations of the TP53 tumor suppressor gene, are strongly associated with certain types of NHL (eg, late stages of follicular lymphoma, CLL/SLL, mantle cell NHL, Burkitt lymphoma and other aggressive B cell NHL) and adverse prognosis [35-38]. Inactivation of p53 is often due to point mutation of one allele and/or chromosomal deletion of the second allele, and/or mutation of other pathway members [35].

GENOME DAMAGE — The precise mechanism(s) leading to chromosomal translocations in NHL are unknown, although specific translocations might be determined, in part, by the spatial organization of the respective chromosomes within the nucleus of lymphoid cells that are undergoing physiologic changes to their antigen receptor genes [14]. These aberrations might also represent mistakes within the mechanisms involved in antigen receptor gene rearrangements in lymphoid cells. This hypothesis is supported by the observation that most translocations in NHL involve chromosomal breakpoints within immunoglobulin (Ig) loci in B cell NHL and within T cell receptor (TCR) loci in T cell NHL. In B cell NHL, breakpoints within the Ig loci are often located precisely within joining (J) and switch (S) sequences, which normally mediate Ig gene rearrangements during B cell development. Thus, translocations resulting from errors of the enzymatic machinery mediating Ig or TCR recombinations pathologically join sequences from different chromosomes instead of sequences within the same antigen receptor locus. These errors become apparent only when the consequences of the abnormal recombination provide a selective growth advantage to the cell. In addition, the genome in certain lymphoma subtypes has been altered by the introduction of exogenous genes via a number of oncogenic viruses.

The following sections will review the mechanisms by which antigen receptor gene rearrangements and viral infections may increase the risk of lymphoma development.

B cell germinal center reaction — The vast majority of B cell lymphomas are derived from germinal center or post-germinal center B cells. During the normal germinal center reaction, there are two major genetic modifications, each of which are required for normal immune development, but also place the cell at risk of acquiring additional mutations that may be oncogenic:

●Class-switch recombination changes the immunoglobulin heavy-chain from IgM to IgG, IgA, or IgE. (See "Immunoglobulin genetics", section on 'Class-switching'.)

●Somatic hypermutation is the introduction of point mutations and small deletions or insertions, usually affecting the variable regions of immunoglobulin heavy chain genes of germinal center B cells. Somatic hypermutation is a key component to the affinity maturation of the humoral immune response. (See "Immunoglobulin genetics", section on 'Somatic hypermutation'.)

Under normal circumstances, the variable region of immunoglobulin heavy chain genes (IgV) of germinal center B cells undergoes somatic hypermutation (SHM), introducing point mutations and small deletions or insertions that allow affinity maturation of the humoral immune response [39]. This process requires activation-induced cytidine deaminase (AID), a mutation-generating enzyme [40]. The genomic instability created by this somatic hypermutation process may also be responsible for the generation of chromosomal translocations between oncogenes and the immunoglobulin loci in human B cell lymphomas (see 'Chromosomal translocations' above) [41].

BCL6 is thought to be the critical mediator that allows germinal center B cells to tolerate the DNA strand breaks required for SHM and class switching without triggering apoptosis [42]. The normal SHM process in germinal center B cells can also, to a lesser extent, involve BCL6 itself, as well as other genes [43,44]. Mutations in BCL-6 or chromosomal rearrangements involving BCL-6, perhaps triggered by SHM, appear to contribute to lymphomagenesis in general [45], particularly to the aggressive and highly aggressive lymphomas. (See "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma".)

Aberrant SHM of BCL6 and other proto-oncogenes, including PIM1, MYC, PAX5, and RhoH (TFF), often involves the coding region of these genes, and has also been detected in a large number of lymphomas, including:

●Diffuse large B cell lymphoma (DLBCL) (see "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma", section on 'Aberrant somatic hypermutation')

●Primary central nervous system diffuse large B cell lymphoma [46]

●AIDS-associated lymphomas, including Burkitt lymphoma and DLBCL, but also seen in primary effusion lymphomas [47] (see "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology", section on 'BCL6 expression')

●Monoclonal post-transplant lymphoproliferative disorders, including DLBCL and BL [48]

●The cutaneous B cell lymphomas, including primary cutaneous follicle center lymphoma and primary cutaneous large B cell lymphoma, leg type [49]

●Transformation of follicular lymphoma (more commonly) and chronic lymphocytic leukemia (less commonly) to DLBCL [50]

●Extranodal marginal zone lymphoma (EMZL) of mucosa associated lymphoid tissues (MALT) and EMZL in transformation to DLBCL [51]

●Hodgkin lymphoma, including nodular lymphocyte-predominant and classical variants [52]

●Chronic lymphocytic leukemia [53]

These observations confirm that the phenomenon of aberrant somatic hypermutation is more commonly associated with aggressive or transformed NHL variants, but that this mechanism is also seen in Hodgkin lymphoma and some lower grade lymphomas, suggesting a more general mechanism of lymphomagenesis. Some of the hypermutable genes are also susceptible to chromosomal translocations in the same regions, consistent with a role for hypermutation in generating translocations by DNA double-strand breaks. By mutating multiple genes, and possibly by favoring chromosomal translocations, aberrant hypermutation may be a major contributor to lymphomagenesis.

T cell receptor gene rearrangement — The majority of T cell lymphomas are derived from post-thymic T cells. During development, T cells undergo gene rearrangement of their T cell receptor (TCR). Gene rearrangement of these antigen-specific receptors is essential for the development of a highly diverse repertoire of TCRs required for an effective immune system, but also places the cell at risk for acquiring potentially oncogenic chromosomal translocations.

As with Ig molecules, TCR proteins contain variable, diverse, joining, and constant regions. TCR genes rearrange via the same mechanisms and according to the same rules as immunoglobulin (Ig) genes in B cells. However, unlike B cell Ig genes, TCR genes do not undergo somatic hypermutation following initial rearrangement. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation'.)

T cell lymphomas demonstrate characteristic TCR gene recombination patterns and translocations between TCR loci and proto-oncogenes. This is perhaps best demonstrated in cases of precursor T cell acute lymphoblastic leukemia/lymphoma where about one-third of cases demonstrate chromosomal translocations involving the TCR alpha and delta loci at chromosome 14q11 and beta and gamma loci at 7q34 [54,55]. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma", section on 'Genetic features'.)

VIRUSES — Oncogenic viruses introduce foreign genes into their target cells. Three distinct viruses are associated with the pathogenesis of specific NHL subtypes [56]:

●Epstein-Barr virus (EBV)

●Human T cell lymphotropic virus I (HTLV-I)

●Human herpesvirus 8 (HHV-8)

In contrast, HIV infection increases the risk of lymphoma largely related to its immunosuppressive effects rather than through the introduction of oncogenic genes. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology", section on 'HIV infection'.)

Epstein-Barr virus — EBV has been associated with the development of endemic, sporadic, including AIDS-associated Burkitt lymphoma, EBV-positive diffuse large B cell lymphoma, and EBV-positive mucocutaneous ulcer [57,58]. EBV is also implicated in the pathobiology of lymphoma in the setting of immunosuppressive therapy, including after organ transplantation or in the setting of chronic low-dose methotrexate therapy [14,59-63]. (See "Pathobiology of Burkitt lymphoma", section on 'Epstein-Barr virus (EBV) infection' and "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology", section on 'EBV co-infection' and "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders".)

Upon infection of a B lymphocyte, the EBV genome is transported into the nucleus, where it exists predominantly as an extrachromosomal circular molecule (episome). This process is mediated by the cohesive terminal repeats, which are represented by a variable number of tandem repeat (VNTR) sequences [64]. Because of this heterogeneity, the number of VNTR sequences enclosed in newly formed episomes may differ considerably, representing a constant clonal marker of the episome and, consequently, of a single infected cell [64].

Evidence for a pathogenetic role of the virus in NHL infected by EBV is circumstantial, but strong:

●EBV can significantly alter the growth of B cells.

●EBV-infected lymphomas usually display a single form of fused EBV termini, suggesting that the entire population represents the clonally-expanded progeny of a single infected cell [64,65].

●Lymphomas that arise after organ transplantation or during chronic methotrexate therapy will sometimes at least transiently regress following either withdrawal of the immunosuppression that presumably allowed EBV reactivation or use of a variety of anti-viral measures [66]. (See "Treatment and prevention of post-transplant lymphoproliferative disorders", section on 'Treatment'.)

EBV lymphoproliferations, particularly in the setting of immunodeficiency, can have a heterogeneous polymorphic or monomorphic appearance and may or may not meet the criteria for a lymphoma. EBV-positive polymorphic B-cell LPD, NOS is the term used for such proliferations that cannot be more definitively categorized, while EBV-positive DLBCL, NOS has been defined as an aggressive lymphoma that, by definition, shows >80 percent of the malignant cells expressing EBER.

HTLV-I virus — Infection with human T-lymphotropic virus, type I (HTLV-I) has been implicated in adult T cell leukemia-lymphoma (ATL) seen in the Caribbean and Japan. ATL is associated with HTLV-I infection of the tumor clone in 100 percent of the cases [67]. HTLV-I induced T cell transformation does not occur through transduction of a viral oncogene or activation of a human proto-oncogene adjacent to the HTLV-I integration site in the T cell genome. Rather, the pathogenetic effect of HTLV-I in ATL seems to be due to the viral production of a transregulatory protein (HTLV-I Tax) that markedly increases expression of all viral genes and transcriptionally activates the expression of certain host genes.

This is described in more detail separately. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma", section on 'Pathogenesis'.)

HHV-8 virus — Human herpesvirus 8 (HHV-8) is a novel member of the gamma-Herpesviridae family, closely related to Herpesvirus saimiri and was originally detected in biopsies of AIDS-related Kaposi sarcoma [68]. Among lymphomas, HHV-8 infection is selectively restricted to body-cavity-based lymphomas (eg, or primary effusion lymphoma), where the viral genome is found within the tumor cells in virtually 100 percent of cases [69,70].

The mechanism of viral carcinogenesis is not fully elucidated, but may involve viral proteins that are homologous to D-type cyclins and/or interleukin-6 [71,72]. This is discussed in more detail separately. (See "Primary effusion lymphoma", section on 'Pathogenesis' and "Human herpesvirus-8 infection".)

HIV — Although HIV infection is a risk factor for the development of NHL, HIV itself does not infect the neoplastic cells of AIDS-related lymphomas. The pathogenesis of NHL in the setting of HIV infection is poorly understood, but immune deregulation leading to loss of control of viruses, such as EBV, is thought to play an important role. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology", section on 'Pathobiology'.)

Simian virus 40 — Although simian virus 40 (SV-40) is a polyoma virus with oncogenic potential in humans and animals, it likely does not play a role in the pathobiology of NHL. SV-40 nucleic acids have been identified in a large proportion of patients with mesothelioma and some brain cancers. Its actions are thought to result from inactivation of tumor suppressors, including p53 and members of the retinoblastoma family by a peptide known as the SV-40 large T-antigen. (See "Epidemiology of malignant pleural mesothelioma", section on 'Viral oncogenes' and "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections".)

Concerns over the potential association between SV-40 and NHL were initially raised because of SV-40 contamination of poliovirus vaccines used in the United States from 1955 to 1963 [73]. However, two epidemiologic studies have cast doubt on the significance of potential exposure to SV-40:

●In one study, childhood exposure to SV-40 through receipt of contaminated poliovirus vaccine was not associated with increased risk for AIDS-associated NHL [74].

●In a population-based case-control study, there was no evidence that SV-40 seropositive individuals were at increased risk for NHL [75].

SUMMARY

●Description – Non-Hodgkin lymphoma (NHL) comprises a diverse group of malignant tumors of lymphoid tissues variously derived from the clonal expansion of B cells, T cells, natural killer (NK) cells, or lymphoid precursors. The pathogenesis of lymphomas involves accumulation of multiple genetic lesions affecting proto-oncogenes and tumor suppressor genes.

●Cell of origin – A cell of origin has been proposed for each type of NHL based on morphologic, immunophenotypic, and genetic features of the malignant cells, but many cases are not clear cut. (See 'Cell of origin' above.)

•B cell lymphomas – The vast majority are derived from germinal center or post-germinal center B cells. Major genetic modifications occur during the normal germinal center reaction of B cells. These changes (class-switch recombination and somatic hypermutation) are required for normal immune development, but also place the cell at risk of acquiring additional mutations that may be oncogenic. (See 'B cell germinal center reaction' above.)

•T cell lymphomas – Most are derived from post-thymic T cells. Gene rearrangement of T cell receptors (TCR) is essential for the development of a highly diverse repertoire of TCRs required for an effective immune system, but also places the cell at risk for acquiring potentially oncogenic chromosomal translocations. (See 'T cell receptor gene rearrangement' above.)

●Pathogenetic mechanisms – Lymphomagenesis is linked to chromosomal rearrangements, acquired somatic mutations, genome damage, and escape from immune surveillance. Lymphomas generally have less genome instability than solid tumors. (See 'Pathogenetic mechanisms' above.)

●Chromosomal translocations

•Balanced chromosomal translocations – Characteristic balanced chromosomal translocations are associated with certain types of lymphoma; many are thought to be initiating events in lymphomagenesis. (See 'Balanced translocations' above.)

•Unbalanced chromosomal translocations – Unbalanced chromosomal gains and losses contribute to development of certain lymphomas and contribute to clonal evolution and disease progression in many lymphomas. (See 'Unbalanced chromosomal abnormalities' above.)

●Somatic mutations – Progressive accumulation of mutations that affect oncogenes and tumor suppressor genes are important contributors to lymphomagenesis. Critical "driver mutations" are present in the entire lymphoma clone, while other mutations that contribute to tumor progression may be present in subclones of the lymphoma. Mutations that activate the B cell receptor and NF-kB pathways are common, but other pathways (eg, NOTCH, RNA splicing, p53, epigenetic maintenance, immune surveillance) are also affected. (See 'Somatic mutations' above.)

●Genome damage – Rearrangement of antigen receptor genes is critical to maturation of B lymphocytes (ie, B cell receptor) and T lymphocytes (ie, T cell receptor). Genome damage associated with aberrant rearrangements and/or DNA repair contributes to lymphomagenesis. (See 'Genome damage' above.)

●Viruses – Three distinct viruses are associated with pathogenesis of specific NHL subtypes:

•Epstein-Barr virus (EBV) – Associated with the development of Burkitt lymphoma, some DLBCLs and lymphoma in the setting of immunosuppressive therapy. (See 'Epstein-Barr virus' above.)

•Human T cell lymphotropic virus I (HTLV-I) – Implicated in adult T cell leukemia-lymphoma (ATL). (See 'HTLV-I virus' above.)

•Human herpesvirus 8 (HHV-8) – Involved in development of body cavity-based lymphomas (eg, primary effusion lymphoma). (See 'HHV-8 virus' above.)