Causes and Risk Factors of Lymphoma

Lymphoma develops when lymphocytes (a type of white blood cell) mutate and grow out of control. When this happens, the cancerous cells no longer die but continue to multiply and invade different parts of the body. Although genetics plays a central role in the development of lymphoma, no one knows for sure what causes the cells to mutate.

What scientists do know is that certain risk factors can increase your risk of lymphoma. Having one or more of these risk factors does not mean you will get lymphoma. In most cases, they can't even predict your likelihood of developing the disease. Still, they may provide your healthcare provider with valuable clues that can lead to an early diagnosis and treatment.

The key risk factors associated with lymphoma include:

• Age
• Sex
• Immune dysfunction
• Family history
• Certain infections
• Chemical exposure
• Previous cancers and cancer treatments

Obesity and diet may also play a part.

Common Risk Factors

Lymphoma is not a single disease but a group of related blood cancers with numerous types and subtypes. The two main types are Hodgkin lymphoma and non-Hodgkin lymphoma. Both of these lymphomas differ not only in their disease pattern and cell types but also in many of their risk factors.

Many of these risk factors are non-modifiable, meaning that there is nothing you can do to change them. Chief among them are age, sex, and immune dysfunction.

Age

Age plays a key role in the development of lymphoma. Although lymphoma can occur at any age, including childhood, the majority are diagnosed in adults over 60.

However, unlike non-Hodgkin lymphoma, a significant number of Hodgkin lymphoma cases are diagnosed between the ages of 15 and 40. Because of this, the median age for diagnosis of non-Hodgkin lymphoma is 55, whereas the median age for diagnosis of Hodgkin lymphoma is 39.

Sex

Sex is another risk factor that places some individuals at greater risk of lymphoma than others. While men are slightly more likely to develop lymphoma than women, there are certain types of lymphoma for which women are at greater risk. This includes nodular sclerosing Hodgkin's lymphoma (the most common and treatable form of Hodgkin lymphoma) as well as non-Hodgkin lymphoma of the breast, thyroid, and the respiratory tract.

It is believed that the hormone estrogen influences which types of lymphoma are more or less common in women. There are also variations in how women respond to certain therapies, with women generally responding better to drugs like Rituxan (rituximab) and Revlimid (lenalidomide) than men.

Immune Dysfunction

The immune system plays a central role in the development of lymphoma, in part by suppressing mutations in the two main types of lymphocytes (called B-cells and T-cells) that can lead to cancer.

As you get older, your immune response will invariably begin to weaken. This may explain why lymphoma is more common in people over 60 and why the risk continues to grow every year thereafter. But, age is not the only factor that contributes to the loss of immune function.

A similar situation is seen with organ transplant recipients who need immunosuppressant drugs to prevent organ rejection. In this group of people, there is a high risk of non-Hodgkin lymphomas, most especially hepatosplenic T-cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma.

Certain autoimmune diseases are also linked to increased rates of lymphoma, although it is not entirely clear why. According to a 2008 study published in the journal Blood, people with lupus and Sjögren syndrome have as much as a seven-fold increased risk of non-Hodgkin lymphoma compared to the general population.

Genetics

Another risk factor you can't change are your genetics. Although there is no single gene that "causes" lymphoma, there are some that may predispose you to the disease. In recent years, scientists have begun to link specific genetic mutations to specific types of lymphoma.

These include mutations involving oncogenes, which help cells grow and divide, and tumor suppressor genes, which tell a cell when it is time to die. If either (or both) of these genes mutate, cells can suddenly multiply and spread out of control without end. Many scientists believe that a combination of mutations is needed to induce lymphoma (a hypothesis referred to as the "multi-hit theory"),

This is evidenced in part by the pattern of inheritance in families. Unlike autosomal dominant disorders in which there is a 50/50 chance of developing a disease if a gene is inherited, lymphoma doesn't have a clear pattern of inheritance. Still, family history plays a central role in the overall risk, most specifically with Hodgkin lymphoma.

The inheritance pattern in families with non-Hodgkin lymphoma is far less clear. Although there is a modest familial risk, the current body of evidence suggests that the genetic mutations are more often acquired than inherited. This may be caused by exposure to radiation, chemicals, or infections or occur spontaneously with advancing age or for no apparent reason at all.

Infectious and Environmental Causes

A number of infections, environmental toxins, and medical treatments have been linked to lymphoma. Scientists believe that they either trigger the disease in people genetically predisposed to lymphoma or cause the mutations themselves.

Infections

A number of bacterial, viral, and parasitic infections are known to increase the risk of lymphoma. Among them:

• Campylobacter jejuni is a common cause of bacterial food poisoning that is linked to a type of abdominal lymphoma known as immunoproliferative small intestinal disease.
• Cellulitis, a severe bacterial skin infection, is with a 15% to 28% increased risk of non-Hodgkin lymphoma, most especially cutaneous T-cell lymphoma.
• Chlamydophila psittaci, a bacteria associated with the lung infection psittacosis, is linked to ocular adnexal marginal zone lymphoma (lymphoma of the eye).
• Epstein-Barr virus (EBV) is closely linked to both Burkitt lymphoma and post-transplant lymphoma, as well as 20% to 25% of all Hodgkin lymphoma cases.
• Helicobacter pylori (H. pylori), a bacterial infection associated with gastric ulcers, is linked to mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach.
• Hepatitis C virus (HCV) can increase the risk of non-Hodgkin lymphoma by causing the excessive production of lymphocytes, many of which are malformed and vulnerable to malignancy. Lymphomas linked to HCV are generally low-grade and slow-growing.
• Human herpesvirus 8 (HHV8), a virus associated with a rare skin cancer called Kaposi sarcoma in people with HIV, can increase the risk of an equally rare lymphoma known as primary effusion lymphoma (PEL).
• Human T-cell lymphotropic virus (HTLV-1), a virus spread by blood transfusions, sexual contact, and shared needles, is closely linked to highly aggressive adult T-cell leukemia/lymphoma (ATL).

Environmental Toxins

Some studies have suggested that chemicals like benzene and certain insecticides are linked with an increased risk of both Hodgkin and non-Hodgkin lymphoma. It is a highly contentious topic, with some studies suggesting an increased risk of lymphoma and others showing no risk at all.

A 2013 study published in Cancer Causes and Control found a close association between Hodgkin lymphoma and the use of insecticides and fungicides (especially those containing acetylcholinesterase inhibitors found in products like Baygon). Interestingly, the risk was limited to adults who used five or more insecticides, making it less clear which substances pose the greatest harm.

A Canadian study published in the International Journal of Cancer similarly found that people with non-Hodgkin lymphoma had higher levels of pesticide chemicals in their blood than people without. Chief among these were pesticides containing chlordane (a chemical banned in the United States since 1988), which reportedly increased the risk of non-Hodgkin lymphoma by 2.7-fold.

Further research is needed to determine how these chemical toxins contribute to lymphoma and what risk they actually pose.

Cancer Therapy

Both chemotherapy and radiation therapy used to treat cancer can increase a person's risk of lymphoma. With that said, the risk has been decreasing in recent years due to newer drugs and safer radiotherapy techniques.

The risk of lymphoma is seen to increase with the aggressiveness of the therapy. For example, BEACOPP chemotherapy, involving seven different drugs, is more likely to cause second cancers than CHOP regimens involving four. The duration of therapy and the incidence of relapse also play a part.

BEACOPP also increases the risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) by 450%.

People previously exposed to high levels of radiation therapy are also at an increased risk of lymphoma. The risk is especially high in people with non-small cell lung cancer in whom radiation can increase the risk of non-Hodgkin lymphoma by as much as 53%. The risk is further increased when radiation and chemotherapy are combined.

To reduce the risk, radiology oncologists have largely replaced extended field radiation (EFR) with involved-field radiation therapy (IFRT) which employs a narrower, more focused beam of radiation.

Lifestyle Factors

Certain lifestyle factors can increase your risk of lymphoma. Although there are things you can do to modify these factors, it is not entirely clear how much the changes will impact your risk.

Obesity

A number of studies have found a direct link between obesity and Hodgkin lymphoma, with an increasing body mass index (BMI) corresponding to an increased risk of lymphoma.

The study, which looked at the impact of obesity in 5.8 million people in the United Kingdom, concluded that 7.4% percent of adult lymphoma cases can be attributed to being overweight (BMI over 25) or obese (BMI over 30).

Despite early claims that certain fats are linked to gastrointestinal lymphoma, most scientists agree that the type of fat consumed is less important than the impact of body weight on lymphoma. With that said, trans fats are linked to a significantly higher incidence of non-Hodgkin lymphoma in women.

Whether losing weight will reduce the risk of lymphoma on an individual basis is unclear. Even so, maintaining a healthy diet and an ideal weight is beneficial to your health and can help support immune function.

Breast Implants

Another less common risk factor involves breast implants. Although rare, some women with implants have been known to develop anaplastic large cell lymphoma (ALCL) in their breast. This seems more likely with implants that are textured rather than those that are smooth.

While selecting a smooth implant can theoretically reduce your risk, the overall risk irrespective of implant type is only around one per 1,000 procedures.