Non-Hodgkin Lymphoma Causes, Risk Factors, and Prevention

Scientists have made a lot of progress in understanding how certain gene changes (mutations) can cause normal lymphocytes to become lymphoma cells. These changes affect how the cells grow, how they signal other cells, and how they avoid being destroyed by the immune system.

Gene changes can be:

• Inherited from a parent
• Acquired during your lifetime

Gene changes related to NHL are usually acquired.

Inherited gene changes: Having a family history of lymphoma does seem to increase your risk. Still, most people with lymphoma do not have a strong family history of it.

Acquired gene changes: These can happen because of exposure to radiation, cancer-causing chemicals, or infections. But they often happen for no clear reason. They seem to happen more often as we age. This might help explain why most lymphomas are seen in older people.

Scientists are learning about the exact gene changes involved in the different types of NHL.

For example, we now know that in follicular lymphoma, the cells often have a cut-and-paste error in the DNA between chromosomes 14 and 18. This type of error is called a translocation. In this case, the error turns on the BCL-2 oncogene. The oncogene stops the cell from dying at the right time, which can lead to lymphoma.

Information about gene changes is being used to develop better tests for detecting and classifying certain types of lymphoma. Hopefully, these discoveries can be used to develop new treatments as well.

Researchers are beginning to understand some of the gene changes that can lead to NHL. However, they still don’t know why many of these gene changes develop, especially in people with no clear risk factors.

Lymphoma starts in a type of cell called a lymphocyte. Lymphocytes are immune system cells, so it’s not surprising that changes in the immune system seem to play an important role in many cases of non-Hodgkin lymphoma.

Weakened immune systems

Some people with weakened immune systems have a much higher chance of developing lymphoma compared to people without weakened immune systems.

This includes people whose immune systems are weakened because of:

• Inherited conditions
• Organ transplants
• Treatment with certain medicines
• Certain viral infections

Autoimmune diseases

People with certain autoimmune diseases have an increased risk of lymphoma. An autoimmune disease causes the immune system to constantly attack a certain part of the body.

Chronic infections

People with certain chronic infections are also at increased risk. This is probably because the immune system is constantly making new lymphocytes to fight the infection. This increases the chance of an accidental change (mutation) in a lymphocyte’s genes.

Getting older is a strong risk factor for lymphoma overall. Most cases happen to people in their 60s or older. However, some types of lymphoma are more common in younger people.

Overall, the risk of NHL is higher in men, but certain types of the disease are more common in women. The reasons for this are not known.

In the United States, White people are more likely than African American people and Asian American people to develop NHL.

Worldwide, NHL is more common in high-income countries. The United States and Europe have some of the highest rates.

Some types of lymphoma are linked to infections that are more common in certain parts of the world.

Having a first-degree relative with NHL increases your risk of developing it. A first-degree relative is a parent, child, or sibling.

Chemicals

Some studies have suggested that exposure to benzene and certain herbicides and insecticides (weed- and insect-killing chemicals) may be linked to an increased risk of NHL. Research to clarify these possible links is still in progress.

Chemotherapy drugs

Some chemotherapy drugs used to treat other cancers may increase the risk of developing NHL many years later.

For example, people who have been treated for Hodgkin lymphoma have an increased risk of later developing NHL. But it’s not totally clear if the increase is related to the chemo drugs or to the disease itself.

Rheumatoid arthritis medicines

Some studies have suggested that certain medicines used to treat rheumatoid arthritis (RA) might increase the risk of NHL. These medicines include methotrexate and the tumor necrosis factor (TNF) inhibitors.

Other studies have not found an increased risk.

Figuring out if these medicines increase risk is complicated, because RA is an autoimmune disease. People with RA already have a higher risk of non-Hodgkin lymphoma.

Accidental radiation exposure

Survivors of atomic bombs and nuclear reactor accidents have an increased risk of developing several types of cancer, including NHL, leukemia, and thyroid cancer.

Radiation treatment

People treated with radiation therapy for some other cancers, such as Hodgkin lymphoma, have a slightly increased risk of developing NHL later in life. This risk is greater for people treated with both radiation therapy and chemotherapy.

People with weakened immune systems have an increased risk of NHL. This includes people whose immune systems are weakened because of organ transplant medicines, HIV infection, and some genetic syndromes.

Organ transplant medicines

People who get organ transplants are treated with medicines that suppress their immune system. This prevents the immune system from attacking the new organ. But it also weakens the immune system, which creates a higher risk of developing NHL.

HIV infection

HIV (human immunodeficiency virus) can weaken the immune system. People infected with HIV are at increased risk of non-Hodgkin lymphoma.

Genetic (inherited) syndromes

In some genetic syndromes, children are born with an immune system that doesn’t work the way it should. These syndromes include ataxia-telangiectasia (AT) and Wiskott-Aldrich syndrome.

Children born with these syndromes have an increased risk of serious infections and a higher risk of developing NHL.

When you have an autoimmune disease, your immune system mistakenly sees your body’s own tissues as foreign. It attacks the tissues, as it would a germ. Lymphocytes are a type of immune system cell. An overactive immune system may cause lymphocytes to grow and divide more often than normal. This could increase the risk of them developing into lymphoma cells.

Some autoimmune diseases have been linked with an increased risk of NHL, including:

• Rheumatoid arthritis
• Systemic lupus erythematosus (SLE or lupus)
• Sjögren disease
• Celiac disease (gluten-sensitive enteropathy)

This risk is linked to other autoimmune diseases as well.

Some types of infection may increase the risk of NHL. This happens in a few different ways.

Infections that directly transform lymphocytes

Some viruses can directly affect the DNA (genes) in lymphocytes, helping to transform them into cancer cells:

• Human T-cell lymphotropic virus (HTLV-1) increases a person’s risk of certain types of T-cell lymphoma. This virus is most common in some parts of Japan and in the Caribbean region, but it is found throughout the world. In the US, it causes less than 1% of lymphomas. In most cases, it is passed on from mother to child during childbirth. Lymphoma develops many decades after the child’s birth. 
• Epstein-Barr virus (EBV) is an important risk factor for Burkitt lymphoma in some parts of Africa. In high-income countries like the United States, EBV is more often linked with lymphomas in people also infected with HIV. EBV has also been linked with some less common types of lymphoma.
• Human herpes virus 8 (HHV-8) can also infect lymphocytes, leading to a rare type of NHL called primary effusion lymphoma. This lymphoma is most often seen in people who are infected with HIV. This virus is sometimes called Kaposi sarcoma-associated herpes virus, because it is also linked to another cancer known as Kaposi sarcoma.

Infections that weaken the immune system

Infection with HIV can weaken the immune system. HIV infection increases the risk of certain types of NHL, such as primary CNS lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma.

Infections that keep the immune system constantly active

Some long-term infections are linked with an increased risk of certain marginal zone lymphomas. These infections force the immune system to keep making new lymphocytes to fight the infection.  The more lymphocytes are made, the greater the chance of a harmful gene change occurring. Some of these lymphomas may improve when the underlying infection is treated.

• Helicobacter pylori (H. pylori) is a bacteria that can cause stomach ulcers. It is linked to MALT lymphoma of the stomach.
• Chlamydophila psittaci is a bacteria that can cause a lung infection called psittacosis. It has been linked to MALT lymphoma in the tissues around the eye.
• Campylobacter jejuni has been linked to a rare MALT lymphoma of the small intestine, also called Mediterranean abdominal lymphoma. It tends to happen in young adults in eastern Mediterranean countries.
• Hepatitis C virus (HCV) increases the risk for certain types of NHL, including splenic marginal zone lymphoma.

Studies suggest that people with excess body weight (overweight or obesity) have a modestly higher risk of NHL, particularly diffuse large B-cell lymphoma.

Researchers believe excess body fat may raise NHL risk by promoting chronic inflammation. This inflammation can affect how lymphocytes behave.

In rare cases, textured breast implants have been linked to a specific type of NHL that develops in the scar tissue surrounding the implant.

Most of these are a T-cell lymphoma called breast implant-associated anaplastic large cell lymphoma (BIA-ALCL).  Other types of NHL have been reported as well.