Etiology and Risk factors
Chromosomal translocations and molecular rearrangements
Nonrandom chromosomal and molecular rearrangements play an important role in the pathogenesis of many lymphomas and correlate with histology and immunophenotype (Table 1). The most commonly associated chromosomal abnormality in NHL is the t(14;18)(q32;q21) translocation, which is found in 85% of follicular lymphomas and 25% to 30% of higher-grade B-cell NHLs. This translocation results in the juxtaposition of the bcl-2 apoptotic inhibitor "oncogene" at chromosome band 18q21 to the heavy-chain region of the immunoglobulin locus within chromosome band 14q32.
The t(11;14)(q13;q32) translocation results in overexpression of bcl-1 (cyclin D1/PRAD 1), a cell-cycle–control gene on chromosome 11q13, and is characteristically associated with mantle cell lymphoma (MCL). The t(3;16)(q27;p11) translocation makes the gene for the interleukin-2 (IL-2) receptor a partner of bcl-6, which is expressed in DLBCL.
Chromosomal translocations involving 8q24 lead to c-myc deregulation, which is seen in nearly all cases of Burkitt lymphoma including those associated with HIV infection.
Environmental factors also may play a role in the development of NHL. Chemicals that have been linked to the development of NHL include a variety of pesticides and herbicides (2,4-D-organophosphates, chlorophenols), solvents and organic chemicals (benzene, carbon tetra-chloride), and wood preservatives. There is some evidence that the association between pesticides and NHL risk was limited to t(14;18)-positive NHL cases.
Several viruses have been implicated in the pathogenesis of NHL, including EBV, HTLV-1, Kaposi sarcoma–associated herpesvirus (KSHV, also known as human herpesvirus 8, or HHV-8), and hepatitis C virus (HCV). Meta-analyses have shown a 13% to 15% HCV seroprevalence in certain geographic regions among persons with B-cell NHL, especially marginal zone NHL.
EBV is a DNA virus that has been associated with Burkitt lymphoma (particularly in endemic areas of Africa), Hodgkin lymphoma, lymphomas in immunocompromised patients (ie, organ transplantation and HIV infection), sinonasal lymphoma (Asia and South America), and sporadically in other B- and T-cell lymphomas. In contrast to studies performed in European patients, Mexican patients with intestinal lymphomas show a high frequency of EBV positivity; this finding is not limited to T-cell NHLs but rather includes a significant portion of B-cell NHLs. EBV can transform lymphocytes in culture. B lymphocytes from normal EBV-positive subjects have been shown to grow as tumors in mice with severe combined immunodeficiency.
HTLV-1 is a human retrovirus that establishes a latent infection via reverse transcription in activated T-helper cells. A minority (3% to 5%) of carriers develop ATLL. An HTLV-1–like provirus has been detected in some patients with mycosis fungoides, although conflicting findings have been reported.
KSHV-like DNA sequences are frequently detected in primary effusion lymphomas, in patients with Kaposi sarcoma, and in those with multicentric (plasma cell variant) Castleman disease.
HCV infection is associated with the development of clonal B-cell expansions and certain subtypes of NHL, particularly in the setting of essential (type II) mixed cryoglobulinemia. HCV may predispose B cells to malignant transformation by enhancing signal transduction upon binding to the CD81 (TAPA-1) molecule.
Infection with Borrelia burgdorferi, the etiologic agent in Lyme disease, has been detected in about 35% of patients with peripheral cutaneous B-cell lymphoma (PCBCL) in Scotland. A near-complete clinical and histologic remission of a primary marginal zone B-cell lymphoma was observed after eradication of B burgdorferi with antibiotic treatment. Gastric MALT lymphoma is seen most frequently, but not exclusively, in association with Helicobacter pylori infection. Studies indicate that Campylobacter jejuni and immunoproliferative small intestinal disease (α-heavy chain disease) are related.
Some reports noted an association between infection with Chlamydia psittaci and ocular adnexal lymphoma. The infection was found to be highly specific and does not reflect a subclinical infection widespread among the general population. Responses to antibiotics have been reported. Attempts to confirm this association in the Western hemisphere have been unsuccessful.
Congenital and acquired states of immunosuppression that are at increased risk include ataxia-telangiectasia, Wiskott-Aldrich syndrome, common variable hypogamma-globulinemia, X-linked lymphoproliferative syndrome, and severe combined immunodeficiency.
Acquired immunodeficiency states such as HIV infection are associated with relative increased risk of NHL of 75 to 100 compared with the general population, although recent data in the post-HAART (highly active antiretroviral therapy) era suggest it has decreased. These NHLs are usually high grade and often present with extranodal disease. Furthermore, iatrogenic immunosuppression (eg, solid organ transplantation [SOT] or hematopoietic stem cell transplantation recipients) have a significantly increased risk of NHL. The risk of NHL after SOT is 1% to 3% after kidney transplant vs >10% for intestinal, cardiac, or multiorgan transplants, the latter of which warrant higher immunosuppressive therapy.
An increased incidence of gastrointestinal (GI) lymphomas is seen in patients with celiac (nontropical) sprue and inflammatory bowel disease, particularly Crohn's disease. An aberrant clonal intraepithelial T-cell population can be found in up to 75% of patients with refractory celiac sprue prior to the development of overt T-cell lymphoma using immunophenotyping and T-cell receptor gamma gene rearrangement PCR (polymerase chain reaction) techniques. Systemic lupus erythematosus and rheumatoid arthritis have been associated with B-cell lymphoma. Sjögren syndrome has been associated with NHL overall, DLBCL, and marginal zone lymphoma.
Patients who receive chemotherapy and/or radiation therapy are also at increased risk of developing subsequent secondary NHL.
Several studies have reported an excess risk of NHL in association with diets high in fat and meat products. Some studies have suggested that ultraviolet radiation exposure and alcohol(Drug information on alcohol) intake may be linked inversely with NHL risk.
Several reports have implicated a role for genetic variants in the risk of NHL, including genes that influence DNA integrity and methylation, genes that alter B-cell survival and growth, and genes that involve immune function/inflammation, oxidative stress, and xenobiotic metabolism. There is some evidence for positive associations between variant alleles in TNA -308G>A and IL10 -3575T>A genes and risk of DLBCL.