Introduction

Follicular Lymphoma (FL) is among the most common types of non-Hodgkin lymphoma (NHL), a disease where cancer cells form in the lymphatic system, which is crucial in both immune function and the body’s drainage system.^1,2 FL is a slow-developing disease, and symptoms often only present at advanced stages. As such, the disease is difficult to detect in its early stages, making timely treatment a challenge. Recognising the risk factors and other contributing factors to the development of FL is important in order to aid with early detection, as well as reducing risks of developing the disease and improving patient outcomes. Here, we explore a number of these risk factors. 

What causes follicular lymphoma? 

FL originates from B-cells, otherwise known as B-lymphocytes, which are white blood cells that form part of the immune system by making antibodies to fight infections.³ In FL, these B-cells undergo a transformation that makes them cancerous. This transformation is caused by what is known as a ‘chromosomal translocation’:¹³ A chromosome carries genetic information, and in chromosomal translocation, two chromosomes are rearranged, swapping places. This rearrangement can cause problems like cancer. 

In the case of FL, chromosomal translocation leads to the overexpression of the BCL2 gene.⁴ The BCL2 gene is responsible for producing proteins that promote cell survival and prevent cells from dying.¹² The process of cell death is called apoptosis, or unprogrammed cell death. Apoptosis is normal: the body uses it to get rid of unwanted or abnormal cells. When the BCL2 gene is overexpressed, the affected B-cells become resistant to apoptosis - they can’t die as they should. Instead, they live and accumulate in the lymph nodes, eventually forming tumours - and thus, Follicular Lymphoma is born.⁴ 

Risk factors for developing follicular lymphoma^4,5

Although findings and surveys reflect a decrease in the incidence of FL worldwide, it remains important that the risk factors are recognised and understood, as some populations may still be more vulnerable than others. 

Demographic risk factors

Age and gender have been shown to contribute to the risk of developing FL. Studies have shown that the risk of developing FL increases with age, typically considered to be a disease of older adults over the age of 55.⁶ This is likely due to changes to the body that occur over time, including accumulating genetic mutations or age-related decline of the immune system. Additionally, FL appears to be more common in women than in men. 

Geographic trends in the incidence of FL have also been reflected, with a higher number of cases reported in the USA, Europe, Australia and New Zealand, and a lower incidence in Asia and Africa.^6,7 

Environmental and lifestyle risk factors

Environmental exposure to certain chemicals may increase the risks of developing FL. Such chemicals include hair dye, pesticides, herbicides and other chemicals that are commonly used in agricultural and industrial settings, like benzene and heavy metal.⁸ As such, individuals working in environments where these chemicals are prevalent, like farmers and industrial (petroleum, plastic, rubber, and synthetics) factory workers, are at higher risk of developing FL due to their prolonged exposure to these harmful chemicals.⁷ Similarly, those living near industrial facilities like oil refineries and metal industries/factories are also at higher risk of developing FL. 

Radiation exposure is a risk factor in nearly all cancers.⁹ FL is no exception. This includes both ionising radiation and non-ionising radiation. This is due to the DNA-damaging effects of radiation. Examples of ionising radiation include X-rays, gamma rays, and radiation from radioactive sources. Non-ionising radiation includes UV radiation, infrared radiation, and electromagnetic fields. Everyone is exposed to radiation - it’s all around us. It is the excessive exposure to radiation that may be harmful to our bodies - this may occur through things like radiotherapy or occupational environments.¹⁰ 

Lifestyle choices have also been said to increase the risk of developing FL. This includes smoking, excessive alcohol consumption, lack of physical activity, and an unhealthy diet. Studies have found that a high meat and fat dietary pattern increases the risk of FL, whereas diets with higher fruit and vegetable intake are associated with reduced risk of FL. Obesity has also been found to increase the risk for several types of cancer, including FL. However, a direct link has not yet been established - it is possible that these findings were confounded by dietary choices and low physical activity. 

Genetic risk factors

Genetic susceptibility also plays a role in increasing the risk of developing FL. Individuals with a family history of lymphoma or other related cancers have a higher risk, especially if this family history is found from a direct relative - a parent or a sibling. Genetic studies have found that certain mutations, particularly those impacting immune function and DNA repair, may predispose people to developing lymphoma, including FL.¹¹ However, this is rare and accounts for only a small number of cases. 

Summary of risk factors

• Old Age: higher risk above age 55
• Gender: more common in females than males
• Geography: There is a higher incidence in the USA, Europe, Australia, and New Zealand than in Asia and Africa
• Chemical Exposure
• Radiation Exposure
• Bad Lifestyle: smoking, excessive drinking, unhealthy diet, little exercise
• Genetics: family history of FL or other lymphomas

FAQs

Non-hodgkin's lymphoma genetic testing

Medical professionals sometimes recommend genetic testing to people with a family history of certain cancers. However, this is not the case with the NHL. There are currently no reliable genetic tests for NHL.

What are the causes of lymphoma?

Healthcare professionals aren't sure what causes lymphoma. Lymphoma begins with changes in the DNA of a disease-fighting blood cell called a lymphocyte.

Is non-Hodgkin's lymphoma genetic?

Non-Hodgkin lymphoma isn't infectious and isn't thought to run in families, although your risk may be slightly increased if a close relative (such as a parent or sibling) has had lymphoma.

Conclusion

Follicular Lymphoma (FL) is a complex disease with a large range of contributing risk factors, spanning demographics, environmental exposures, lifestyle choices, and genetic predispositions. Understanding these risk factors is crucial for not only reducing the chances of developing the disease, but also for early detection of the disease and potentially improving the prognosis of FL. Through increased awareness and targeted interventions, significant steps could be taken to reduce the incidence of Follicular Lymphoma.