Causes and risk factors
Non-Hodgkin's Lymphoma News
In order to remember the chromosomal abnormalities involved in the pathogenesis of NHL we must first understand the key genes involved in the various NHL subtypes and their corresponding chromosome number.
Since the primary function of lymphocytes is the formation of antibodies, a common set of genes affected in NHL are those responsible for the formation of the heavy and light chains of the antibody. These genes are found on the following chromosomes:
- Heavy chain: chromosome 14.
- Light chain kappa: chromosome 2.
- Light chain lambda: chromosome 22.
Besides the above set of genes there are key genes that are specific to each particular subset of NHL.
- The main gene (in up to 90% of cases) affected is the bcl-2 gene located on chromosome 18.
- Hence, follicular lymphoma is characterized by a translocation involving both the bcl-2 gene and the heavy chain gene that is: t(14;18).
Small noncleaved NHL and Burkitt lymphoma
The main gene involved is the c-myc gene located on chromosome 8.
Translocations in Burkitt's lymphoma will involve c-myc and all the 'antibody genes': t(8;14), t(2;8), t(8;22).
Large cell lymphoma
- The main gene involved is bcl-6 located on chromosome 3.
- Translocations found in large cell NHL are: t(3;14), t(2;3) and t(3;22)
Small lymphocytic type
- The main gene involved is bcl-3 located on chromosome 19.
- The translocation found in small lymphocytic lymphoma is t(14;19).
Mantle cell lymphoma
- The main gene involved is bcl-1 located on chromosome 11.
- The translocation found in mantle cell lymphoma is t(11;14).
The translocation found in plasmacytoid lymphoma is t(9;14).
Lymphoblastic T-cell lymphoma
- Variable involvement of T-cell receptor genes.
Anaplastic large cell lymphoma
- This results from the fusion of the nucleophosmin gene (NPM) to a tyrosine kinase ALK (anaplastic lymphoma kinase): t(2;5).
Certain workers have a slightly increased risk of developing NHL, including farmers; pesticide applicators; grain (flour) millers; meat workers; wood and forestry workers; chemists; painters; mechanics; machinists; printers; and workers in the petroleum, rubber, plastics, and synthetics industries.
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 tetrachloride), wood preservatives, dusts (wood, cotton), and some components in hair dye.
Chemotherapy and radiotherapy
Patients who receive cancer chemotherapy and/or radiation therapy are also at increased risk of developing NHL.
Several viruses have been implicated in the pathogenesis of NHL, including:
- EBV: EBV is a DNA virus that has been associated with Burkitt lymphoma, particularly in endemic areas of Africa; Hodgkin?s disease; lymphomas in immunocompromised patients (i.e. organ transplantation and HIV infection); sinonasal lymphoma (Asia and South America); and sporadically in other B- and T-cell lymphomas. EBV can transform lymphocytes in culture. B lymphocytes from normal EBV-positive subjects grow as tumors in mice with severe combined immunodeficiency.
- HTLV-1: HTLV-1 is a human retrovirus that is endemic in certain areas of Japan and the Caribbean. HTLV-1 establishes a latent infection via reverse transcription in activated T-helper cells. A minority (5%) of carriers develop adult T-cell leukemia/ lymphoma. A HTLV-1?like provirus has been detected in some patients with mycosis fungoides, although conflicting findings have been reported.
HHV-8: Kaposi?s sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8, or HHV- 8) KSHV-like DNA sequences are frequently detected in body cavity-based lymphomas in patients with HIV infection and in those with multicentric (plasma cell variant) Castleman?s disease.
- HCV: Hepatitis C virus (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.
HIV: NHL occurs in 2% to 3% of newly diagnosed AIDS cases. Pathologically, AIDS-related lymphomas are comprised of a narrow spectrum of histologic types consisting almost exclusively of B-cell tumors of aggressive type. These include: Diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, small noncleaved lymphoma, either Burkitt or Burkitt-like. The HIV-associated lymphomas can be categorized into: Aggressive B-cell lymphoma, primary central nervous system lymphoma (PCNSL), which represents 20% of all NHL cases in AIDS patients, primary effusion lymphoma, plasmablastic multicentric Castleman disease, Hodgkin's lymphoma.
- Borrelia burgdorferi: Infection with Borrelia burgdorferi, the etiologic agent in Lyme disease, has been detected in about 35% of patients with primary cutaneous B-cell lymphoma 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.
- H. pylori: The bacteria Helicobacter pylori has been shown to cause MALT in the digestive system in about 90% of cases.
Patients with congenital and acquired states of immunosuppression are at increased risk of NHL.
Congenital immunodeficiency states that are associated with an increased risk include ataxia- telangiectasia, Wiskott-Aldrich syndrome, common variable hypogammaglobulinemia, X-linked lymphoproliferative syndrome, and severe combined immunodeficiency.
- Acquired immunodeficiency states, such as HIV infection, iatrogenic immunosuppression (ie, organ or blood stem-cell transplantation recipients, long-term survivors of Hodgkin?s disease), and a variety of collagen vascular and autoimmune diseases (eg, Sjögren?s syndrome, rheumatoid vasculitis and Felty?s syndrome, systemic lupus erythematosus, chronic lymphocytic thyroiditis, and angioimmunoblastic lymphadenopathy) also pose an increased risk of NHL.
An increased incidence of 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 techniques.
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is seen most frequently, but not exclusively, in association with Helicobacter pylori infection.
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.
Recent studies indicate that Campylobacter jejuni and immunoproliferative small intestinal disease (α-chain disease) are related.
Ocular adnexal lymphoma
A report from the National Cancer Institute, Aviano, Italy, notes 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.
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