What is Lymphoma Cancer?

According to Blood Cancer UK, more than 14,000 people in the UK are diagnosed with some form of lymphoma each year, making it the fifth most common cancer as well as the most common type of blood cancer. The two main types of lymphoma are Hodgkin lymphoma and non-Hodgkin lymphoma.

Lymphoma Action says that lymphoma accounts for 1 in 10 children’s cancers. According to the charity, someone in the UK is diagnosed with lymphoma every 27 minutes. Let’s try and understand a little more about what lymphoma cancer is and the signs and symptoms, causes, risk factors, diagnosis and treatments.

What is lymphoma cancer?

Lymphoma is a blood cancer – the most common kind of blood cancer, more common than leukaemia. It is a blood cancer that affects white blood cells called lymphocytes. This means that it affects the immune system as lymphocytes are a very important part of the functioning of this system in the human body. Lymphoma is also called a lymphatic cancer as it affects the lymphatic system.

In lymphoma cancer, something happens with lymphocyte development meaning the lymphocyte cells do not work properly and can multiply in an out-of-control way. The lymphocytes do not divide properly or do not die off when they are supposed to at the end of a typical cell’s lifespan.

The abnormal lymphocyte cells then build up in the lymph nodes, most commonly in the neck, armpits or groin. But they can gather in almost any part of the body as the whole body is served by the lymphatic system.

There are several kinds of lymphoma, but they are largely divided into two main types: Hodgkin lymphoma and non-Hodgkin lymphoma. Non-Hodgkin lymphomas are then further grouped by how fast they develop (low-grade/indolent or high-grade/aggressive). The different types of lymphoma cancers behave differently and so require different treatments.

What are the signs and symptoms of lymphoma cancer?

There are several symptoms of lymphoma cancer but, most often, the most obvious sign that something is wrong is by finding a lump. The lumps from lymphoma cancer occur in the lymph nodes, commonly referred to as glands.

You have many lymph glands in your body so a person may find a lump in their neck, armpit, collarbone or groin, as well as other places. The lumps are usually painless but they can cause pain by pressing on organs such as the stomach or lungs, for example.

There are also some other symptoms to be aware of. The first three symptoms in the list are called B symptoms.

These symptoms help doctors to tell how advanced someone’s lymphoma is:

• Fever – Temperature over 38°C, presenting of unknown origin. The fever may persist for days or weeks on and off. This is called Pel-Ebstein Fever.
• Unexplained weight loss – Usually defined as more than 10% of body mass within the previous six months.
• Night sweats – Sweats that soak bedding and nightwear.
• Nausea or feeling ‘full’ despite not eating much – Can be caused by swelling in the stomach area.
• Extreme fatigue.
• Coughing or breathlessness.
• Chest pain.
• Bone pain.
• Itching – Either in a specific place or more widespread itching.
• Skin rashes or bumps.
• Frequent/long-lasting infections.
• Unusual bleeding or bruising – This is caused by low platelets in the blood. Platelets are what cause the blood cells to clot.

Not everyone will have all of these symptoms. Some people do not have many symptoms at all before they are given a lymphoma diagnosis. However, those who do have a combination of the symptoms above must seek medical advice as soon as possible. Most people with these symptoms won’t have lymphoma, but if they do, treatment must be started as soon as possible.

There are a few other symptoms that are specific to Waldenström macroglobulinaemia (a type of non-Hodgkin lymphoma).

 This causes particular changes in the blood that can lead to the following symptoms:

• Dizziness.
• Headaches.
• Nose bleeds.
• Blurred vision.
• Numbness in the feet and legs.
• Kidney problems.

What causes lymphoma cancer?

Lymphoma develops in lymphocytes (white blood cells) when they begin to grow uncontrollably. This occurs because the DNA with the lymphocyte cell changes and mutates and it then stops responding to the usual signals that keep its reproduction under control.

Such mutations happen all the time and the majority of the time they’re harmless and we don’t know they’re happening. However, every so often, the mutation can affect a gene that is critical. Sometimes, if more than one gene is critically affected, cancer can develop.

Normally, cancers such as lymphoma are caused by more than one DNA mutation. However, no one really knows what causes such mutations to occur. They are likely to have been random occurrences.

What are the different types of lymphoma cancer?

There are many types of lymphoma but they broadly separate into Hodgkin lymphoma and non-Hodgkin lymphoma.

Hodgkin Lymphoma

The common factor in all types of Hodgkin lymphoma is the appearance of the lymphoma cells under a microscope. Hodgkin lymphoma cells contain abnormal cells that are called ‘Reed-Sternberg cells’. Hodgkin lymphoma gets its name from the first person who described the disease in 1832 – Dr Thomas Hodgkin. Non-Hodgkin lymphoma essentially describes any kind of lymphoma that is not a Hodgkin lymphoma.

Each year, around 2,100 people are diagnosed with Hodgkin lymphoma. This equates to around six people a day. This makes Hodgkin lymphoma quite a rare disease. It occurs at any age but most people are diagnosed in late adolescence and early adulthood (between the ages of about 15 and 34 years old) or when they are over 60 years old. The type of lymphoma affects more males than females and develops in people from all ethnicities.

Hodgkin lymphoma can be subdivided into different types and subtypes:

• Classical Hodgkin lymphoma.
  – Nodular sclerosis classical Hodgkin lymphoma.
  – Mixed cellularity classical Hodgkin lymphoma.
  – Lymphocyte-rich classical Hodgkin lymphoma.
  – Lymphocyte-depleted classical Hodgkin lymphoma.
• Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL).

Classical Hodgkin lymphoma includes the Reed-Sternberg cells, which look a little bit like the eyes of an owl underneath a microscope. NLPHL contains a different variant of Reed-Sternberg cells that are called lymphocyte-predominant or LP cells. Many refer to these as ‘popcorn cells’ too as they resemble the snack under the microscope.

Most people with Hodgkin lymphoma have the classical type, with only 5% of Hodgkin lymphomas being of the NLPHL type. Certain types of Hodgkin lymphoma are also more prevalent in certain age groups. Nodular sclerosis classical Hodgkin lymphoma most commonly affects young adults whereas mixed cellularity classical Hodgkin lymphoma tends to affect older adults.

Regardless of the subtype, all classical Hodgkin lymphomas are treated in the same way. NLPHL is treated differently. However, both types of Hodgkin lymphoma normally respond very well to treatment and are unlikely to return.

Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma (often abbreviated to NHL) refers to any type of lymphoma that is not Hodgkin lymphoma (i.e., it does not contain Reed-Sternberg cells).

Each year, around 14,200 people receive a non-Hodgkin diagnosis in the UK. As well as this, about 3,800 people are diagnosed with chronic lymphocytic leukaemia (CLL) which is also sometimes considered to be a type of non-Hodgkin lymphoma. Adding all this together, about 50 people are diagnosed with these conditions every single day.

Non-Hodgkin lymphoma affects people of all ages but it is much more prevalent in older people. The majority of people diagnosed with NHL are over 55 years old. There are some types that do affect children and young people. More males are affected by NHL than females but it affects all ethnicities equally.

There are more than 60 different kinds of non-Hodgkin lymphoma, with some being rare. The types are often divided into the way that they behave or develop.

The two main ways of categorising NHL are:

• The type of lymphocyte the NHL developed from.
  – B-cell lymphoma – Most non-Hodgkin lymphomas are this type.
  – T-cell lymphoma – Only around 10% of non-Hodgkin lymphomas are T-cell lymphomas.
• The speed of their growth.
  – Low-grade lymphomas grow slowly. B-cell lymphomas can be low-grade. They are sometimes called ‘indolent’ lymphomas. Although they respond well to treatment, they are often more difficult to cure completely. Treatments usually work on controlling the lymphoma rather than completely eradicating the disease. Many people think of it more as a chronic illness that needs repeat treatment.
  – High-grade lymphomas grow faster. T-cell lymphoma tends to be high-grade. B-cell lymphomas can sometimes be high-grade. High-grade lymphoma means that the lymphoma cells are quick to divide, and this can be seen under the microscope. High-grade lymphomas are sometimes referred to as ‘aggressive’. However, this is not always as alarming as it sounds. The majority of high-grade non-Hodgkin lymphomas respond well to treatment and also do not usually recur after treatment has finished.
  – Sometimes lymphomas can undergo ‘transformation’, where they change from low-grade to high-grade.

As mentioned, there are over 60 types of non-Hodgkin lymphoma. Here are a few of the most common types:

• High-grade B-cell non-Hodgkin lymphomas:
  – Burkitt lymphoma.
  – Primary central nervous system lymphoma (also called primary CNS lymphoma).
  – Diffuse large B-cell lymphoma (DLBL).
  – Intravascular large B-cell lymphoma.
  – Primary cutaneous diffuse large B-cell lymphoma, leg-type.
  – Primary mediastinal large B-cell lymphoma (PMBL).
• High-grade T-cell non-Hodgkin lymphomas:
  – Anaplastic large-cell lymphoma (ALCL).
  – Enteropathy-associated T-cell lymphoma (EATL).
  – Angioimmunoblastic T-cell lymphoma.
  – Extranodal NK/T-cell lymphoma (nasal-type).
  – Adult T-cell leukaemia/lymphoma (ATL).
  – Hepatosplenic T-cell lymphoma.
  – Sézary syndrome.
  – Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS).
  – Lymphoblastic lymphoma – a very rare high-grade non-Hodgkin lymphoma developing from immature lymphocytes (B-cells or T-cells). This is typically found in younger people and is similar to ALL – acute lymphoblastic leukaemia – and treated similarly.
• Low-grade B-cell non-Hodgkin lymphomas:
  – Follicular lymphoma (normally low-grade but grade 3B follicular lymphoma is treated similarly to one of a high-grade).
  – Mantle cell lymphoma (again, this is sometimes treated like a high-grade lymphoma).
  – Lymphoplasmacytic lymphoma (also called Waldenström’s macroglobulinaemia).
  – Chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL).
  – Primary cutaneous follicle centre lymphoma.
  – Marginal zone lymphomas:
  Nodal marginal zone lymphoma.
  Splenic marginal zone lymphoma.
  Extranodal marginal zone lymphoma (MALT lymphoma).
• Low-grade T-cell non-Hodgkin lymphomas:
  – Skin lymphomas such as:
  – Mycosis fungoides.
  – Primary cutaneous CD30-positive lymphoproliferative disorders (primary cutaneous anaplastic large-cell lymphoma, lymphomatoid papulosis).
  – Some rare types of T-cell skin lymphomas.

As mentioned, some of these types of lymphomas are much rarer than others. The most common type of non-Hodgkin lymphoma in adults is diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukaemia (not technically a non-Hodgkin lymphoma), marginal zone lymphomas, and follicular lymphoma.

The most common types found in children are Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) and anaplastic large-cell lymphoma (ALCL).

What are the risk factors of lymphoma cancer?

In the majority of lymphoma cancers, nobody understands why they happen. However, there are a few factors that can increase a person’s risk of developing the disease.

The risk factors for lymphoma, like other cancers, work because they increase the likelihood of mutations happening in cells. However, most people who get lymphoma do not have these risk factors.

Specific risk factors:

• Eczema and T-cell skin lymphoma – There is a link between the two conditions. They look very similar and the risk factor may be that, actually, T-cell skin lymphoma is misdiagnosed initially as eczema.
• Previous helicobacter pylori infection. This infection normally causes indigestion and stomach ulcers. However, nearly every person who has gastric MALT lymphoma also has a helicobacter pylori infection. Treating the infection sometimes cures the cancer too, making this not just a risk factor but a cause too.
• Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL). Having breast implants that are textured can increase a person’s risk of developing this specific type of lymphoma. The textured surface of some breast implants is thought to cause an inflammatory response in the breast and it usually develops between 8 and 10 years after the surgery. However, it can occur at any time. It’s important to note that the majority of people with breast implants do not go on to develop BIA-ALCL, but those who do have it, all have breast implants. Removing them can serve as a cure, so they are not only a risk factor but a cause as well.

General risk factors

Aside from the specific risk factors mentioned, there are other risk factors associated with the development of lymphoma cancer:

• Family history – If you have a family history of blood cancers, you are slightly more at risk than people without a family history. This is thought to be because there may be some tiny inherited genetic changes that make you more susceptible.
• Age – Most non-Hodgkin lymphomas are in older people; Hodgkin lymphoma is more common in people aged 15 to 40.
• Viral infections – Some viruses infect lymphocytes and they can sometimes cause damage to the cell DNA and end up becoming out of control.
  – The Epstein-Barr virus (EBV) is a common one that causes glandular fever. Around 90% of adults have had EBV at some stage but many do not know they have had it. Those who have had the virus have a slightly increased risk of developing some kinds of lymphoma such as Burkitt lymphoma, non-Hodgkin lymphoma, post-transplant lymphoproliferative disorder, HIV-associated lymphoma, and T-cell lymphoma.
  – Hepatitis C virus (HCV). This virus increases a person’s risk of developing some types of lymphoma such as DLBCL, nodal marginal zone lymphoma, splenic marginal zone lymphoma and lymphoplasmacytic lymphoma.
  – Human T-lymphotropic virus type 1 (HTLV-1). This infection is rare here in the UK and doesn’t usually cause symptoms. However, it is linked to adult T-cell leukaemia/lymphoma.
  – Human herpes virus-8 (HHV-8) is linked to primary effusion lymphoma (PEL) which mainly affects young HIV sufferers.
• Bacterial infections are also linked to lymphoma:
  – Helicobacter pylori and gastric MALT lymphoma.
  – Campylobacter jejuni and small bowel MALT lymphoma.
  – Chlamydia psittaci – causing a rare lung infection called psittacosis that’s spread by birds. This is connected with the development of MALT lymphoma within the eyes and tear ducts.
  – Moraxella catarrhalis – a chest infection bacteria connected to the development of a rare form of Hodgkin lymphoma.
  – Borrelia burgdorferi – the bacteria that causes Lyme disease and is spread by ticks. This may be connected to the future development of MALT lymphoma of the skin.
• A low immune system – Low immune systems mean less of an ability to fight infections and therefore less of an ability to fight the infections described above that increase a person’s likelihood of developing lymphoma. Specifically, HIV and post-transplant lymphoproliferative disorders (PTLD) increase a person’s risk of lymphoma considerably.
• Autoimmune conditions – With autoimmune conditions, the body’s immune system attacks your own body by mistake. Some conditions of this type increase a person’s risk of developing lymphoma. These include:
  – Hashimoto’s thyroiditis and the risk of MALT lymphoma of the thyroid.
  – Sjögren’s syndrome and the risk of splenic marginal lymphoma, diffuse large B-cell lymphoma, Waldenström’s macroglobulinaemia, and MALT lymphoma of the lungs or salivary glands.
  – Coeliac disease is linked to enteropathy-associated T-cell lymphoma (EATL). This is very rare, however.
  – Systemic lupus erythematosus and rheumatoid arthritis are linked to the development of diffuse large B-cell lymphoma and splenic marginal zone lymphoma. Rheumatoid arthritis is also connected with a chronic leukaemia that affects the lymphocytes called T-cell large granular lymphocytic leukaemia.
• Weight – Research has shown that people who are obese are at increased risk of many types of cancer including non-Hodgkin and Hodgkin lymphoma.
• Previous treatment for cancer – If you’ve been unlucky to have already had cancer, then unfortunately there is some increased risk of going on to develop future cancers, especially if you have had treatment such as radiotherapy.
• Chemical exposure – People who work in certain environments are often more at risk of developing lymphoma. Chemicals such as pesticides, weedkillers and solvents are thought to increase a person’s risk. Some hair dyes have also been thought to increase a person’s risk; however, more modern hair dyes seem to have reduced this somewhat. Working in an industry where such chemical exposure is a regular occurrence may increase a person’s risk of developing lymphoma. That said, most people do not go on to develop it.

Can lymphoma cancer be prevented?

To be able to prevent lymphoma cancer, we would need to know the exact mechanism that causes each type. However, as explained above, in each case of the disease, it’s impossible to know the exact cause in the same way that we do not know the cause or trigger for many types of cancer.

Having said this, there are a few things that people can do to reduce their risk of developing cancer generally and, to a certain extent, lymphoma specifically.

Exercise

Although not specifically a preventor of lymphoma cancer, being physically active improves a person’s health and wellbeing immeasurably. Humans evolved to be active, and it is thought that today’s sedentary lifestyles may be a contributing factor in the prevalence of diseases such as cancer.

Environmental Exposure

There is some evidence to suggest that prolonged exposure to certain chemicals has been linked to cancer development, including lymphoma. By taking steps to limit exposure to certain chemicals, a person can reduce their risk of developing the disease.

Healthy Diet

Having a healthy and well-balanced diet is crucial for optimum health, and that includes preventing cancer. Eating well isn’t specifically linked to preventing lymphoma, but there are lots of reasons why eating a healthy and nutritious diet helps to prevent significant diseases, including cancers.

Bacterial and Viral Infections

Given that some bacterial and viral infections are linked to certain types of lymphoma such as MALT lymphoma, Burkitt’s lymphoma and adult T-cell leukaemia/lymphoma, preventing infection can help prevent the development of these types of lymphoma. However, most of these infections are widespread within the population and therefore it is hard to avoid them. Normally, such infections pass without issue, but certain circumstances can make them progress to specific types of lymphoma.

What are the stages of lymphoma cancer?

When a person is diagnosed with lymphoma, they are often told what stage the disease is at. Staging tells you what parts of the body are affected by lymphoma and how much it has progressed. Staging helps to define what medical treatment a person needs to have. Different lymphomas at different stages require different treatments.

Doctors stage both Hodgkin and non-Hodgkin lymphoma mostly in the same way, but there are some exceptions:

• Staging non-Hodgkin lymphoma in children is a little different than in adults.
• Staging chronic lymphocytic leukaemia (which is often considered to be a type of NHL) is staged differently from other types of non-Hodgkin lymphomas whereas small lymphocytic lymphoma, a form of CLL, is staged in the same way as non-Hodgkin lymphoma.
• Skin lymphomas behave in a different way to other types of lymphoma and so have a different way of being staged. This staging also depends on whether they are B-cell or T-cell skin lymphomas.
• Waldenström’s macroglobulinaemia (WM) is also staged in a different way to the typical system and is given a score between 0 and 5, based on blood results and the person’s age. This is a rare type of non-Hodgkin lymphoma.

Early Stage and Advance Stage Lymphoma

• Stage 1
  Stage 1 lymphoma means that the lymphoma is confined to one group of lymph nodes within the body. They can be in any group of lymph nodes such as the neck or the groin, for example. At stage 1, they would only be in one location.
• Stage 2
  Stage 2 lymphoma means that there is more than one group of lymph nodes that are affected. However, the affected groups of lymph nodes must be on the same side of the diaphragm for it to be classed as stage 2.There is also a stage called Stage 2E. Stage 2E refers to extranodal lymphoma. This means that the lymphoma started in an organ in the body, not the lymphatic system, and is in a group of lymph nodes as well. Again, the location of the lymphoma must all be on one side of the diaphragm.
• Stage 3
  Stage 3 lymphoma simply means that there are groups of lymph nodes that have lymphoma on both sides of the diaphragm.
• Stage 4
  Stage 4 lymphoma is considered the most advanced stage of the disease. It means that the cancer started in the lymph nodes and has spread further to at least one of the organs in the body outside of the lymphatic system. This could be the bones, bone marrow, liver or lungs, for example. If it is in the thymus or spleen, this is considered stage 3 as these organs are part of the lymphatic system.

Staging Letters

Some people may be given a stage with a letter following it. This can be A, B, E, S or X.

If a person has a diagnosis of a stage with the letter A after it, such as Stage 2A, it means that they do not have any of the ‘B’ symptoms described above (unexplained weight loss, night sweats, or fevers). If they have the letter B after their staging, it means that they do have at least one of the B symptoms.

As mentioned, the letter E means ‘extranodal’. This means that the origin of the lymphoma was in an organ, not in the lymphatic system.

The letter S after a stage represents lymphoma in the spleen and thymus. These are organs within the lymphatic system and are therefore considered not to be extranodal. For example, 1S lymphoma is a lymphoma confined just to the spleen.

The letter X means that at least one of the lymph nodes that have been affected is considered ‘bulky’.

Children’s Staging

In children and adolescents (those under 20 years of age), lymphoma does not always behave in the same way as it does in adults. For Hodgkin lymphoma, the staging is the same, but for non-Hodgkin lymphoma, it is done differently.

Stage 1 Lymphoma in Children:

• • Only one lymph node group (not including the abdomen or chest)

or

• • One organ in the body (not lymphatic organs) excluding the abdomen or chest

or

• • One bone

or

• The spleen.

Stage 2 Lymphoma in Children:

• • Two or more lymph nodes on one side of the diagram

or

• • One extranodal body organ and a group of lymph nodes nearby

or

• The gut (possibly with nearby lymph nodes as long as they are localised and able to be removed with surgery).

Stage 3 Lymphoma in Children:

• • Two or more body organs (extranodal organs) that can include the bones or skin

or

• • Lymph nodes on both sides of the diagram

or

• • The chest

or

• • The gut (including the spleen, liver, ovaries or kidneys) unless localised and can be removed with surgery

or

• • Around the spinal cord

or

• One bone and an extranodal organ or lymph nodes in a distant location.

Stage 4 Lymphoma in Children

• • In the central nervous system (spinal cord or brain)

or

• The bone marrow.

Again, letters may be written after the staging.

These are:

• CNS – The central nervous system is affected.
• BM – The bone marrow is affected.
• B – The bones are affected.
• EN – Extranodal – The lymphoma originated outside of the lymphatic system.
• N – Affects the lymph nodes.
• S – Affects the skin.

Can lymphoma cancer be detected early?

There are no specific screening tests that can be carried out routinely to detect lymphoma early. No screening tests have been found that lower a person’s risk of dying from the disease. As such, it is recommended that doctors and the general public are aware of the symptoms of lymphoma and act if they find something unusual, such as lumps in the neck or groin.

For those at risk due to specific conditions like HIV or organ transplants, keeping regular medical and health checks is important to spot signs of lymphoma. The risk of this for these people, as mentioned, is low but it is slightly elevated compared to the general population.

How is lymphoma cancer diagnosed?

A person’s first port of call when they have symptoms that could indicate lymphoma is their GP. The GP may examine any lumps or swellings and will refer the person for tests if the swellings are large and/or haven’t settled within a couple of weeks. The GP will not be able to diagnose lymphoma but will refer you to hospital. For a suspected lymphoma cancer diagnosis, you should be seen for tests within two weeks.

The hospital usually does a biopsy of the lumps and analyses the results which will tell them whether the person has lymphoma or not. It can be an anxious wait for people. There may also be scans such as CT scans and MRI scans to detect any potential spreading of the disease.

How is lymphoma cancer treated?

The treating medical team plans the type of treatment a person receives for their lymphoma cancer based on the type of lymphoma the person has and its stage as well as the person’s general health.

There are many types of treatment which include:

• Watching and waiting – Also called active monitoring.
• Chemotherapy.
• Radiotherapy.
• Antibody therapy and targeted treatments.
• Stem cell transplants.
• Steroids.
• CAR T-cell therapy.
• Skin lymphoma treatment.
• Supportive treatments:
  – Blood transfusions.
  – Complementary therapy.
  – Maintenance therapy.
  – Immunoglobulin replacement therapy.
  – Splenectomy (spleen removal).
  – Palliative care.
  – Growth factors.

The main aim of all the treatments is either to get rid of the lymphoma entirely and induce complete remission from the disease or to treat it and send it into partial remission, where there is less disease in the body than before. Low-grade non-Hodgkin lymphomas are unlikely to ever enter complete remission as the cells are slow growing and are difficult to eradicate completely.

For many people, their high-grade non-Hodgkin lymphoma or Hodgkin lymphoma goes into complete remission, and they do not need any more treatment. For some, however, they relapse and need further treatment.

For people with low-grade non-Hodgkin lymphoma, their partial remission may last for months or even years after their treatment. But it usually relapses or becomes worse at some point, and they then need subsequent treatment.

For others, a ‘watch and wait’ approach is all that’s required initially. The person has regular check-ups to check the progression of their disease.

This is common with low-grade lymphoma for those who do not experience any troublesome symptoms. It’s for this reason that some people describe low-grade lymphomas more like a chronic illness with treatment occasionally.