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Possible Causes

For Non-Hodgkin Lymphoma & Hodgkin Lymphoma

Numerous epidemiological studies have been conducted to examine the role of putative risk factors, and summarising their findings is difficult due to the generally poor exposure classification, poorly defined study populations, small sample sizes, and lack of adjustment for confounding by known risk factors. Furthermore, very few studies have examined interactions between risk factors. Moreover, non-Hodgkin Lymphoma (NHL), and to some extent Hodgkin Lymphoma (HL), consists of a diverse group of neoplasms and few studies have examined risk factors by lymphoma subtype.

The following summarises the available evidence for known or suspected risk factors:

  • Immunodeficiency
  • Infectious Organisms
  • Occupational & Environmnetal Toxins
  • Medical Procedures & Medical History
  • Lifestyle
  • Reproductive & Hormonal Factors
  • Genetic Susceptibility

Immunodeficiency

Post-transplant immunosuppression

  • There is strong evidence that NHL risk is increased in patients undergoing immunosuppression therapy to prevent rejection after transplantation with donor organs or tissues.

HIV/AIDS

  • HIV infection is characterised by a specific deficiency of CD4 positive T cells and the chronic stimulation of B-cells.  There is clear evidence that HIV infection markedly increases risk of NHL.

Congenital/primary immunodeficiency

  • Data shows a predominance of NHL in patients with congenital immune deficiencies.  An excess of NHL occurs in children with congenital X-linked immunodeficiency, severe combined system immunodeficiency and young people with ataxia telangiectasia or Wiskott-Aldrich syndrome.

Autoimmune diseases

  • Autoimmune diseases characterized by persistent antigenic stimulation confer an increased risk of lymphoma.  Risk of NHL and HL is increased 2 to 3-fold in rheumatoid arthritis patient; and risk of NHL is increased in celiac disease, systemic lupus erythematosus and Sjogren's  syndrome.

Infectious Organisms

Epstein-Barr virus (EBV)

  • The EBV virus, a herpesvirus with B-cell-transforming activity, is ubiquitous worldwide. There is strong evidence that EBV infection in conjunction with immune dysfunction, such as post-transplant or HIV/AIDS, is associated with increased risk of NHL. The association between EBV infection and HL is regarded as causal.

Helicobacter pylori (H pylori)

  • H pylori infection is associated with a 6-fold increase in risk of gastric B-cell NHL, known as mucosa-associated lymphoid tissue (MALT) lymphoma.

Human T-lymphotrophic virus types I/II

  • Infection with the human retrovirus HTLV-I/II is rare in Australia.  In regions where HTLV-I is endemic, such as southern Japan and the Caribbean, infection is associated with increased risk of adult T-cell leukemia/lymphoma, a form of NHL.

Hepatitis C virus (HCV)

  • HCV infection is the main cause of mixed cryoglobulinemia, a benign lymphoproliferation that can evolve into B-cell NHL.  There is mixed evidence for an association between HCV infection and NHL.

Human herpesvirus-8 (HHV8)/Kaposi's sarcoma herpesvirus (KSHV)

  • HHV8 is a human herpesvirus that is widespread in homosexual men in Australia. In addition to Kaposi's sarcoma, it is associated with a rare form of B-cell NHL, primary effusion lymphoma, in adults with immunosuppression related to HIV infection or organ transplantation.

Simian virus 40 (SV40)

  • Australian children were inadvertently exposed to SV40, a macaque polyomavirus, via contaminated polio vaccines in the 1950s and 1960s. SV40 causes B-cell lymphomas in rodents, but there are very limited data to suggest a role in human oncogenesis.

Exposure to infection

  • There is limited evidence of an association between NHL risk and factors indicating potential for infection and immunological stimulation, such as socioeconomic status and childhood crowding. Risk of HL in young adulthood is consistently associated with indicators of higher childhood social class, such as single-family housing, small family size, early birth order, and high maternal education. These associations generate the hypothesis that HL in young adults is caused by delayed exposure to common childhood infections.

Occupational & Environmental Toxins

Pesticides, herbicides and agricultural exposures

  • Chemical exposure to both the use and production of pesticides and herbicides suggests an increased risk of NHL, but an inconclusive relationship with HL.
  • Farmers are at increased risk of NHL and may be at slightly increased risk of HL. Farmers may be exposed to pesticides, herbicides, fungicides, infectious microorganisms, solvents, paints, fuels, oils, and dusts; each of these agents has been inconsistently positively associated with risk of NHL and HL.
  • Other occupations that involve work with animals, such as meat (abattoir) workers, meat inspectors, and veterinarians have been inconsistently associated with increased risk of both NHL and HL. Exposure to animal-born viruses has been implicated.

Other chemicals

  • The relationship between occupational exposure to solvents and NHL or HL is not clear.
  • Occupational exposure to hair dyes is inconsistently associated with increased risk of both NHL and HL. The risk associated with occupational exposure to chemical compounds in hair dyes is probably confounded by the potential for increased exposure to infectious agents through personal contact with clients.

Sun exposure

  • There is some evidence to suggest an association between sun exposure and NHL, at present the risk is contradictory. The association between sun exposure and risk of HL has not been examined.

Other occupational exposures

  • Although mixed, the balance of evidence favours a moderate positive association between occupation in a wood-related industry and HL. The evidence with respect to such an association for NHL is weak and inconsistent.
  • Epidemiological studies have inconsistently identified increased risk of NHL in industries with exposure to welding and asbestos, particles, as well as metal workers, rubber workers those in electrical occupations, as well as occupations of higher social class.

Medical Procedures & Medical History

Ionizing radiation

  • There is little convincing evidence of a relationship between ionizing radiation and lymphoma.

Blood transfusion

  • Blood transfusions may expose recipients to oncogenic viruses and other immune-modulating antigenic substances. Some studies have shown a 2-fold increase in risk of NHL with prior receipt of a blood transfusion; with the most recent indicating strongest associations for low-grade NHL. However, case-control studies found no increased risk, and there is evidence that the inclusion of transfusions in the 12-month period prior to diagnosis artificially inflates the risk.
  • The association between blood transfusion and HL has not been examined.

Vaccinations and medications

  • There are no cohort data on the association between vaccination history and risk of lymphoma. One study found a significant protective effect on NHL risk from the receipt of 6 or more vaccinations; subsequent analyses have shown this effect is confined to the diffuse large-cell type. Some studies found increased risk of NHL in association with immunization against tuberculosis. The only HL case-control study found a protective effect from immunization against tetanus and diphtheria, and no association with immunization against smallpox or poliomyelitis.
  • The association between nonsteroidal anti-inflammatory drugs (NSAIDs) and NHL risk is inconclusive and may be confounded by indication for use. Some studies have reported a significant increase in risk while others have found a significant decrease in risk.

Tonsillectomy and appendectomy

  • Tonsillectomy is not a risk factor for NHL. Although mixed, the epidemiological evidence suggests that risk of HL in young and middle-aged adulthood is unrelated to tonsillectomy, but the association with disease onset among older persons is unknown.

Medical conditions

  • Risk of NHL lymphoma is increased subsequent to melanoma and non-melanocytic skin cancers, and vice versa; providing further indirect evidence of a positive association with sun exposure.
  • Those with adult-onset diabetes show an increased risk of NHL, although the magnitude of the increase in risk is unclear.
  • Individuals with a history of tuberculosis show a doubling of risk of NHL.'
  • Despite the requirement for immunosuppressive therapy, inflammatory bowel disease, such as ulcerative colitis and Crohn's disease, appears unrelated to risk of NHL, but may increase the risk of HL by as much as 4-fold.
  • The evidence linking NHL with allergic diseases such as eczema, asthma, hay fever, general allergies and allergies to plants, dust, food, animals, medications, and insect bites/stings is weak and inconsistent.

Lifestyle

Smoking

  • The relationship between cigarette smoking and risk of NHL is unclear. However findings from some recent studies suggest increased risk for follicular lymphoma and high-grade lymphomas. Results from studies support a positive association between cigarette smoking and HL.

Alcohol

  • A number of studies have found a protective effect of alcohol consumption, in particular wine, on risk of NHL. There have been no studies of alcohol consumption and risk of HL.

Physical activity

  • Physical activity and obesity are likely to influence immune function. Physical activity appears unrelated to risk of NHL, while study data with respect to excess weight are equivocal. A single cohort study examining all cancers found a significant association between obesity and HL in men, but there have been no studies of physical activity and risk of HL.

Nutrition

  • Diets high in fat or meat products appear to double the risk of NHL, however, the data is inconsistent. A single study examined fish consumption and found no association with NHL.
  • Results from studies have show no clear association between fruit and vegetable intake and risk of NHL, but there is a tendency towards a protective effect.
  • The balance of evidence suggests there is no protective or harmful effect with respect to NHL from vitamin supplement use.
  • Studies are largely consistent in showing no association between risk of NHL and tea and coffee consumption. The association with milk consumption is unclear. Nitrate, a contaminant in drinking water, can breakdown into carcinogenic compounds.
  • However studies conducted to date have found no association with nitrate levels in drinking water and NHL risk.
  • There is no pattern of risk for diet and HL.

Reproductive & Hormonal Factors

  • Sex hormones have immuno-modulatory effects. Evidence indicates a weakly protective or no effect of pregnancy on risk of NHL. Data for women show a weak positive association with use of hormone replacement therapy (HRT), and a strong positive association for the follicular subtype.
  • An early study supported the hypothesis that childbearing is protective of HL, but it has not been confirmed in more recent studies. No studies have examined use of HRT and HL.

Genetic Susceptibility

  • There is no evidence that NHL occurs more commonly than expected in members of the same family, except in families with a history of NHL, HL or leukaemia among first-degree relatives.
  • There is some evidence of genetic susceptibility in HL. There is a higher than expected incidence of HL among siblings but not spouses, and monozygotic but not dizygotic twins, suggesting a role for both genetic factors associated with immune competence and common childhood environmental exposures.
Adapted from "Epidemiology and Etiology of Non-Hodgkin Lymphoma and Hodgkin's Disease", by Claire M. Vajdic and Andrew E. Grulich, Chapter 2 of Draft ACN Guidelines for the Management and Diagnosis of Lymphoma.