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Lymphoma

Causes and Risk Factors

Demographics

At least two-thirds of NHL patients are 60 years or older, and men are more likely to be affected than women (Shankland 2012; Kobrinsky 2012).

Immunosuppression

The most well established risk factor for the development of NHL is immunosuppression. Hence, autoimmune disease, immunodeficiency syndromes, HIV infection, and organ or stem cell transplantation all increase risk.

Inherited. Some inherited (genetic) immunodeficiency syndromes are associated with up to a 10% increased risk of developing lymphoma (Chua 2008; Leechawengwongs 2012). Males are affected more than females by these inherited immunodeficiency syndromes; the resulting lymphomas are often associated with the EBV. Infections or autoimmune deficiency occur initially and lymphoma occurs as a later complication (Leechawengwongs 2012).

Acquired. Lymphomas have been associated with acquired immunodeficiency disorders (eg, AIDS) (Lim 2005), including those acquired due to the use of immunosuppressant medications for autoimmune disorders and for the prevention of transplant rejection (MacKenzie 2010). Posttransplantation lymphomas are generally B cell derived and frequently associated with EBV infection (Trofe 2002; Garfin 2013; Taylor 2005). The incidence and severity of lymphomas have increased with the use of immunosuppressive agents such as cyclosporine (Yamazaki 2013). Indeed, discontinuation of immunosuppressants (eg, cyclosporine, methotrexate, tacrolimus) has been shown to result in a partial or complete remission of lymphoma in some cases (Minauchi 2011; MacKenzie 2010; Yuan 2011; Baird 2002).

Autoimmunity. Autoimmune disorders including systemic lupus erythematosus (SLE), Sjögren’s syndrome, autoimmune thyroid disease, autoimmune hemolytic anemia, and rheumatoid arthritis are associated with an increased incidence of NHL (Caligaris-Cappio 2008; Mellemkjaer 2008). Primary Sjögren’s syndrome is associated with a 16-fold increased risk of NHL (particularly DLBCL and follicular lymphomas) (Solans-Laqué 2011). In one study, a 1000-fold increased risk of parotid gland MALT lymphoma was reported in those with Sjögren’s syndrome (Ekström Smedby 2008). Celiac disease is also associated with an increased risk of lymphoma (Mathus-Vliegen 1995; Catassi 2002). Psoriasis is associated with an increased risk of both NHL and HL (Gelfand 2006).

Diet

Being obese (Skibola 2007; Larsson 2007; Larsson 2011) and/or consuming a high-fat diet, high-calorie diet (particularly sugar and refined grains), or a diet rich in animal protein and meat products containing nitrites increases the risk of developing lymphoma (Aschebrook-Kilfoy 2013; Mozaheb 2012). In a Mayo clinic-based study of 603 lymphoma patients, diets high in trans-fatty acids, processed meats, and high-fat dairy products were associated with increased NHL risk (Charbonneau 2013). Phytanic acid, a saturated fatty acid from ruminant meat and dairy products, may also increase NHL risk (Ollberding, Aschebrook-Kilfoy, Caces, Wright 2013).

By contrast, diets high in omega-3 fatty acids and fresh fish and seafood have been associated with reduced NHL risk (Charbonneau 2013).

Noteworthy, men who drink ≥1 daily serving of soda, whether diet soda containing the artificial sweetener aspartame or regular (sugar-sweetened) soda, have an increased risk of NHL (Schernhammer 2012).

Recent findings suggest that eating vegetables and fruits combined, but not fruits alone, significantly reduces NHL risk. Specifically, a high intake of vegetables lowers the risk of DLBCL and follicular lymphoma by 30% (Chen 2013). Furthermore, one study assessing fruit and vegetable intake in relation to NHL survival in women reported an association between higher intake of fruits and vegetables, particularly green leafy vegetables, one year prior to diagnosis and overall survival in NHL patients (Han 2010).

In addition, nutrients found in fruits and vegetables may prevent lymphoma development. In a study of 35 159 women (55-69 years of age), it was found that vitamin C, alpha-carotene (α-carotene), proanthocyanidins, and dietary manganese reduced the risk of NHL – in particular follicular lymphoma. Greater intake of fruits and vegetables (particularly yellow/orange vegetables, broccoli, and apple juice/cider) were associated with lower NHL risk (Thompson 2010).

Nutrients, specifically vitamins A and C, reduce the risk of NHL, probably by affecting mechanisms that may contribute to lymphoma development. In a study of 154 363 postmenopausal women followed for an average of 11 years, it was found that the higher the intake of vitamins A and C from a combination of both diet and supplements, the lower the risk of lymphoma (Kabat 2012).

In a recent study on 301 newly diagnosed patients with NHL, the frequency and amount of food intake in the year prior to diagnosis was assessed and patients were followed for a median of 8.2 years. Higher intakes of carotene-rich vegetables and α-carotene were associated with better overall survival among those patients who had ever smoked (Ollberding, Aschebrook-Kilfoy, Caces, Smith 2013).

Environment

Living near (within 1/2 mile) of stone, clay, or glass industry facilities increases NHL risk (Linos 1991). Gardeners and farmers also have an increased incidence of lymphoma, most likely due to exposure to chemicals, including organochlorines, benzene, organophosphates, and herbicides (Smedby 2011; Alexander 2007).

Infectious Agents

Infection, whether viral or bacterial, is associated with an increased risk of several types of lymphoma. Several mechanisms by which infectious agents may drive lymphomas have been posited. First, some viruses such as EBV can directly cause malignant transformation of immune cells, but the mechanisms by which this occurs are not thoroughly understood (Cohen 2003). Second, infection with human immunodeficiency virus (HIV) can give rise to aberrant immune cell proliferation as a consequence of dramatic immunodeficiency (Engels 2007). Lastly, some chronic infections, for example with the hepatitis C virus (HCV), contribute to rapid immune cell proliferation and subsequent increased potential for malignant transformation.

Another less well established hypothesis is that some transient infectious agents can inflict sufficient damage to immune cells so as to cause genetic mutations that give rise to lymphoma even after the offending agent has been eradicated from the body (Engels 2007; Vendrame 2011).

Human T-cell leukemia/lymphoma virus. One of the most well established examples of a virus causing lymphoma is that of the human T-cell leukemia/lymphoma virus (HTLV-1), which is known to cause adult T-cell lymphoma (Mahieux 2007). 

Epstein-Barr virus. Epstein-Barr virus (EBV) infection is associated with the development of EBV-positive Hodgkin lymphoma. Additionally, EBV is strongly implicated in Burkitt’s lymphoma and nasal natural killer (NK)-cell and T-cell lymphomas (Hjalgrim 2012; Engels 2007).

Other microorganisms (viruses/bacteria) implicated in the development of lymphoma include (De Falco 2011; Smedby 2011; Schöllkopf 2008; Lin 2010; Kobrinsky 2012; Dalia 2013):

  • Hepatitis B virus (follicular lymphoma)
  • Hepatitis C virus (diffuse large B-cell lymphoma [DLBCL], marginal-zone lymphoma, and lymphoplasmacytic lymphoma)
  • H. pylori (gastric mucosa-associated lymphoid tissue lymphoma [MALT])
  • Borrelia burgdorferi (mantle cell lymphoma)
  • Chlamydia psittaci (ocular adnexal lymphoma)
  • Human herpesvirus-8 (HHV-8) (primary effusion lymphoma)
  • HIV infection (by causing immunodeficiency, HIV infection increases susceptibility for an EBV-induced or HHV-8-induced lymphoma)

The clinical implications of understanding the causative microorganisms implicated in lymphoma are that potential treatments and preventive measures can be targeted to the causative agent, whether viral, bacterial, fungal, or parasitic (Ferreri 2009).