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Lymphoma Non-Hodgkins

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What is non-Hodgkin lymphoma?

Non-Hodgkin lymphoma (also known as non-Hodgkin’s lymphoma, NHL, or sometimes just lymphoma) is a cancer that starts in cells called lymphocytes, which are part of the body’s immune system. Lymphocytes are in the lymph nodes and other lymphoid tissues (such as the spleen and bone marrow). These will be described in more detail below.

Some other types of cancer – lung or colon cancers, for example – can spread to lymph tissue such as the lymph nodes. But cancers that start in these places and then spread to the lymph tissue are not lymphomas.

There are 2 main types of lymphomas.

Hodgkin lymphoma (also known as Hodgkin’s lymphoma, Hodgkin disease, or Hodgkin’s disease), which is named after Dr. Thomas Hodgkin, who first described it

Non-Hodgkin lymphoma

These 2 types of lymphomas behave, spread, and respond to treatment differently.

Doctors can usually tell the difference between them by looking at the cancer cells under a microscope. In some cases, sensitive lab tests may be needed to tell them apart.

The lymph system and lymphoid tissue

To know what lymphoma is, it helps to understand the body’s lymph system.

The lymph system (also known as the lymphatic system) is composed mainly of lymphoid tissue, lymph vessels, and a clear fluid called lymph. Lymphoid tissue includes the lymph nodes and related organs that are part of the body’s immune and blood-forming systems, such as the spleen and bone marrow.

Lymphocytes: Lymphoid tissue is made up of several types of immune system cells that help the body fight infections. Most of the cells in lymphoid tissue are lymphocytes, a type of white blood cell. The 2 main types of lymphocytes are B lymphocytes (B cells) and T lymphocytes (T cells). Normal B cells and T cells do different jobs within the immune system.

B lymphocytes: B cells normally help protect the body against germs (bacteria or viruses) by making proteins called antibodies. The antibodies attach to the germs, marking them for destruction by other immune system cells. Antibodies also attract certain blood proteins that can kill bacteria.

T lymphocytes: There are several types of T cells, each with a special job. Some T cells can directly destroy cells infected with viruses, fungi, or certain kinds of bacteria. T cells can also release substances that attract other types of white blood cells, which then digest the infected cells. Some types of T cells play a role in either boosting or slowing the activity of other immune system cells.

Both types of lymphocytes can develop into lymphoma cells, but B-cell lymphomas are much more common in the United States than T-cell lymphomas. Different types of lymphoma can develop from each type of lymphocyte, based on how mature the cells are when they become cancerous and other factors.

Treatment for each lymphoma depends on which type it is, so determining the exact type of lymphoma is important.

Organs that have lymphoid tissue: Lymphoid tissue is found in many places throughout the body. Because lymphoid tissue is in many parts of the body, lymphomas can start almost anywhere. The major sites of lymphoid tissue are:

Lymph nodes: Lymph nodes are bean-sized organs found throughout the body, including inside the chest, abdomen, and pelvis. They can sometimes be felt under the skin in the neck, under the arms, and in the groin. Lymph nodes are made up mainly of lymphocytes.

The lymph nodes in the body are connected by a system of lymph vessels. These vessels are like veins, except that instead of carrying blood, they carry lymph and lymphocytes.

Lymph nodes get bigger when they fight infection. Lymph nodes that grow in reaction to infection are called reactive nodes or hyperplastic nodes and are often tender to the touch. An enlarged lymph node is not always a sign of a serious problem. People with sore throats or colds often feel enlarged lymph nodes in the neck. But a large lymph node is also the most common sign of lymphoma. 

Spleen: The spleen is an organ under the lower part of the rib cage on the left side of the body. An average adult spleen weighs about 5 ounces. The spleen makes lymphocytes and other immune system cells to help fight infection. It also stores healthy blood cells and filters out damaged blood cells, bacteria, and cell waste.

Thymus: The thymus is a small organ behind the upper part of the breastbone and in front of the heart. Before birth, the thymus plays a vital role in development of T lymphocytes. The thymus shrinks and becomes less important over the first 20 years of life. Despite this, it continues to play a role in immune system function.

Adenoids and tonsils: These are collections of lymphoid tissue at the back of the throat. They help make antibodies against germs that are breathed in or swallowed. They are easy to see when they become enlarged during an infection or if they become cancerous.

Digestive tract: The stomach and intestines as well as many other organs also have lymphoid tissue.

Bone marrow: The bone marrow (the soft inner part of certain bones) makes red blood cells, blood platelets, and white blood cells. Red blood cells carry oxygen from the lungs to the rest of the body. Platelets plug up small holes in blood vessels caused by cuts or scrapes. White blood cells’ main job is fighting infections. The 2 main types of white blood cells are granulocytes and lymphocytes. Bone marrow lymphocytes are primarily B cells. Lymphomas sometimes start from bone marrow lymphocytes.

Types of non-Hodgkin lymphoma

Classifying non-Hodgkin lymphoma can be quite confusing (even for doctors) because there are so many types and because several different systems have been used. The most recent system is the World Health Organization (WHO)classification. The WHO system groups lymphomas based on how they look under a microscope, the chromosome features of the lymphoma cells, and the presence of certain proteins on the surface of the cells. (Older systems classified lymphomas only by how they looked under a microscope.)

The more common types of lymphoma are listed below according to whether they are B-cell or T-cell lymphomas. Some rarer forms of non-Hodgkin lymphoma are not discussed here.

B-cell lymphomas; B-cell lymphomas make up most (about 85%) of non-Hodgkin lymphomas in the United States.

Diffuse large B-cell lymphoma: This is the most common type of non-Hodgkin lymphoma in the United States, accounting for about 1 out of every 3 cases. The cells are fairly large when seen using a microscope.

Diffuse large B-cell lymphoma (DLBCL) can affect any age group but occurs mostly in older people (the average age is mid-60s). It usually starts as a quickly growing mass in a lymph node deep inside the body, such as in the chest or abdomen, or in a lymph node that you can feel, such as in the neck or armpit. It can also start in other areas such as the intestines, bone, or even the brain or spinal cord.

About 1 in 3 of these lymphomas is confined to one part of the body (localized) when it is found. Lymphomas are easier to treat when they are localized than when they have spread to other parts of the body.

Genetic tests have shown that there are different subtypes of DLBCL, even though they look the same under the microscope. These subtypes seem to have different outlooks (prognoses) and responses to treatment.

DLBCL is a fast growing lymphoma, but it often responds well to treatment. Overall, about 3 out of 4 people will have no signs of disease after the initial treatment, and about half of all people with this lymphoma are cured with therapy.

Primary mediastinal B-cell lymphoma: This is a subtype of DLBCL in which the lymphoma cells are large but there is a lot of fibrosis (scar-like tissue) in the background. It accounts for about 2% of all lymphomas. About 2 out of 3 people with this lymphoma are women. Most are young – in their 30s.

This lymphoma starts in the mediastinum (the area in the middle of the chest behind the breastbone). It is usually localized when it is found. It can cause trouble breathing because it often presses on the windpipe (trachea) leading into the lungs. It can also block the superior vena cava (the large vein that returns blood to the heart from the arms and head), which can make the arms and face swell.

This is a fast-growing lymphoma, but it usually responds well to treatment. About half of patients can be cured.

Intravascular large B-cell lymphoma: In this rare subtype of DLBCL, the lymphoma cells are only found inside blood vessels, not in the lymph nodes or bone marrow. It is treated like DLBCL.

Follicular lymphoma: About 1 out of 5 lymphomas in the United States is follicular lymphoma. The term follicular means that the cells tend to grow in a circular pattern in lymph nodes.

The average age for people with this lymphoma is about 60. It’s rare in very young people. Most of the time, this lymphoma occurs in many lymph node sites in the body, as well as in the bone marrow.

Follicular lymphomas are often slow-growing and respond well to treatment, but they are hard to cure. These lymphomas may not require treatment when they are first diagnosed. Instead, treatment may be delayed until the lymphoma is causing problems. Over time, about 1 in 3 follicular lymphomas turns into a fast-growing diffuse B-cell lymphoma.

Chronic lymphocytic leukemia /small lymphocytic lymphoma: These are closely related diseases. In fact, many doctors consider them different versions of the same disease. The same type of cancer cell (known as a small lymphocyte) is seen in both chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). The only difference is where the cancer cells are found. In CLL most of the cancer cells are in the blood and bone marrow. In SLL, the cancer cells are mainly in the lymph nodes and spleen. SLL accounts for about 5% to 10% of all lymphomas.

Both CLL and SLL are slow-growing diseases, although CLL, which is much more common, tends to grow more slowly. CLL and SLL are treated the same way. They are usually not curable with standard treatments, but depending on the stage and growth rate of the disease, most patients live longer than 10 years. Sometimes, these slow-growing lymphomas turn into a more aggressive type of lymphoma.

Mantle cell lymphoma: Only about 5% of lymphomas are this type. The cells are small to medium in size.

Men are affected most often. The average age of patients is in the early 60s. When this lymphoma is diagnosed, it is usually widespread in the lymph nodes, bone marrow, and often the spleen.

This usually isn’t a very fast-growing lymphoma, but it can be challenging to treat. Newer treatments might be more effective than those used in the past, and may offer a better chance for long-term survival for patients now being diagnosed.

Marginal zone B-cell lymphomas: Marginal zone lymphomas account for about 5% to 10% of lymphomas. The cells in these lymphomas look small under the microscope. There are 3 main types of marginal zone lymphomas.

Extranodal marginal zone B-cell lymphomas, also known as mucosa-associated lymphoid tissue (MALT) lymphomas: These lymphomas start in places other than the lymph nodes (extranodal) and are the most common type. Most MALT lymphomas start in the stomach and are linked to infection by the bacteria Helicobacter pylori, which is also the cause of stomach ulcers. Other possible sites of MALT lymphomas include the lung, skin, thyroid, salivary glands, and tissues surrounding the eye. Usually it is confined to the area where it begins and is not widespread. Many of these other MALT lymphomas have also been linked to infections with bacteria or viruses.

The average age of patients with MALT lymphoma is about 60. It is a slow-growing lymphoma and is often curable in its early stages. Doctors often use antibiotics as the first treatment for MALT lymphoma of the stomach, because treating the Helicobacter pylori infection often cures the lymphoma.

Nodal marginal zone B-cell lymphoma: This is a rare disease, found mainly in older women. It usually stays in the lymph nodes, although lymphoma cells can also sometimes be found in the bone marrow.

This tends to be a slow-growing lymphoma (although not usually as slow as MALT lymphoma), and many patients are cured if they are diagnosed when the disease is in the early stages.

Splenic marginal zone B-cell lymphoma: This is a rare lymphoma. Most often the lymphoma is found only in the spleen and bone marrow.

Patients are often elderly and male and have fatigue and discomfort caused by an enlarged spleen. Because the disease is slow-growing, treatment may not be needed unless the symptoms become troublesome. This type of lymphoma has been linked to infection with the hepatitis C virus.

Burkitt lymphoma: This type makes up about 1% to 2% of all lymphomas. It is named after the doctor who first described this disease in African children and young adults. The cells are medium sized. Another kind of lymphoma, called Burkitt-like lymphoma, has slightly larger cells. Because this second kind of lymphoma is hard to tell apart from Burkitt lymphoma, the WHO classification combines them.

This is a very fast-growing lymphoma. In the African (or endemic) variety, it often starts as tumors of the jaws or other facial bones. This type is linked to infection with the Epstein-Barr virus (which can also cause infectious mononucleosis or “mono”). The endemic type of Burkitt lymphoma is rare in the United States. In the types seen more often in the United States, the lymphoma usually starts in the abdomen, where it forms a large tumor mass. It can also start in the ovaries, testicles, or other organs, and can spread to the brain and spinal fluid. The type seen in the United States is usually not linked to Epstein-Barr viral infection.

Close to 90% of patients are male, and the average age in the US is about 30. Although this is a fast-growing lymphoma, more than half of patients can be cured by intensive chemotherapy.

Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia): This type is not common, accounting for 1% to 2% of lymphomas. The lymphoma cells are small and found mainly in the bone marrow, lymph nodes, and spleen. 

Hairy cell leukemia: Despite the name, this is sometimes considered to be a type of lymphoma. Hairy cell leukemia (HCL) is rare – about 700 people in the United States are diagnosed with it each year. The cells are small B lymphocytes with projections coming off them that give them a “hairy” appearance. They are typically found in the bone marrow and spleen and in the blood.

Men are more likely to get HCL than women, and the average age is around 50.

Hairy cell leukemia is slow-growing, and some patients may never need treatment. An enlarging spleen or dropping blood cell counts (due to cancer cells invading the bone marrow) are the usual reasons to begin treatment. If treatment is needed, it’s usually very effective.

Primary central nervous system (CNS) lymphoma: This lymphoma usually involves the brain (called primary brain lymphoma), but it may also be found in the spinal cord and in tissues around the spinal cord and the eye. Over time, it tends to become widespread in the central nervous system.

Primary CNS lymphoma is rare overall, but it’s more common in people with immune system problems, such as those infected with HIV, the virus that causes AIDS. Most people develop headaches and confusion. They can also have vision problems; weakness or altered sensation in the face, arms, or legs; and in some cases, seizures.

The outlook for people with this condition has always been thought to be fairly poor, but some people can live at least 5 years with today’s treatments.

T-cell lymphomas: T-cell lymphomas make up less than 15% of non-Hodgkin lymphomas in the United States. There are many types of T-cell lymphoma, but they are all fairly rare.

Precursor T-lymphoblastic lymphoma/leukemia: This disease accounts for about 1% of all lymphomas. It can be considered either a lymphoma or leukemia, depending on how much of the bone marrow is involved (leukemias have more bone marrow involvement). The cancer cells are small-to-medium sized, immature T-cells.

This lymphoma often starts in the thymus . This is where many T cells are made. This lymphoma can develop into a large tumor in the mediastinum (the area in the middle of the chest and behind the breast bone). If the tumor presses on the windpipe (trachea) that carries air into the lungs, it can cause trouble breathing. The tumor can also press on or even block the superior vena cava (the large vein that returns blood to the heart from the arms and head), which can make the arms and face swell.

Patients are most often young adults, with males being affected more often than females.

This lymphoma is fast-growing, but if it hasn’t spread to the bone marrow when it is first diagnosed, the chance of cure with chemotherapy is quite good.

What are the risk factors for non-Hodgkin lymphoma?

A risk factor is something that affects your chance of getting a disease such as cancer. Different cancers have different risk factors. Some risk factors, like smoking, can be controlled. Others, like a person’s age or family history, can’t be changed.

But risk factors don’t tell us everything. Having a risk factor, or even many risk factors, does not mean that you will get the disease. And many people who get the disease may have few or no known risk factors. Even if a person with non-Hodgkin lymphoma has a risk factor, it’s often very hard to know how much that risk factor may have contributed to the lymphoma.

Researchers have found several factors that may affect a person’s chance of getting non-Hodgkin lymphoma. There are many types of lymphoma, and some of these factors have been linked only to certain types.

Age: Getting older is a strong risk factor for lymphoma overall, with most cases occurring in people in their 60s or older. But some types of lymphoma are more common in younger people.

Gender: Overall, the risk of non-Hodgkin lymphoma is higher in men than in women, but there are certain types of non-Hodgkin lymphoma that are more common in women. The reasons for this are not known.

Worldwide, non-Hodgkin lymphoma is more common in developed countries, with the United States and Europe having the highest rates. Some types of lymphoma that have been linked to specific infections (described further on) are more common in certain parts of the world.

Exposure to certain chemicals: Some studies have suggested that chemicals such as benzene and certain herbicides and insecticides (weed- and insect-killing substances) may be linked with an increased risk of non-Hodgkin lymphoma. Research to clarify these possible links is still in progress.

Some chemotherapy drugs used to treat other cancers may increase the risk of developing non-Hodgkin lymphoma many years later. For example, patients who have been treated for Hodgkin disease have an increased risk of later developing non-Hodgkin lymphoma. But it’s not totally clear if this is related to the disease itself or if it is an effect of the treatment.

Radiation exposure: Studies of survivors of atomic bombs and nuclear reactor accidents have shown they have an increased risk of developing several types of cancer, including leukemia, thyroid cancer, and non-Hodgkin lymphoma.

Patients treated with radiation therapy for some other cancers, such as Hodgkin disease, have a slightly increased risk of developing non-Hodgkin lymphoma later in life. This risk is greater for patients treated with both radiation therapy and chemotherapy.

Immune system deficiency: People with weakened immune systems have an increased risk for non-Hodgkin lymphoma. For example, people who receive organ transplants (kidney, heart, liver) are treated with drugs that suppress their immune system to prevent it from attacking the new organ. These people have a higher risk of developing non-Hodgkin lymphoma.

The human immunodeficiency virus (HIV) can also weaken the immune system, and people infected with HIV are at increased risk of non-Hodgkin lymphoma.

Some genetic (inherited) syndromes can cause children to be born with a deficient immune system. Along with an increased risk of serious infections, these children also have a higher risk of developing non-Hodgkin lymphoma. These inherited immune deficiency diseases can be passed on to children, but people with non-Hodgkin lymphoma who don’t have these inherited diseases do not pass an increased risk of lymphoma on to their children.

Autoimmune diseases: Some autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE or lupus), celiac sprue (gluten-sensitive enteropathy), and others have been linked with an increased rate of non-Hodgkin lymphoma.

In autoimmune diseases, the immune system sees the body’s own tissues as foreign and attacks them, as it would a germ. Lymphocytes (the cells from which lymphomas start) are part of the body’s immune system. The overactive immune system in autoimmune diseases may cause lymphocytes to grow and divide more often than normal. This may increase the risk of them developing into lymphoma cells.

Certain infections: Some types of infections may raise the risk of non-Hodgkin lymphoma in different ways.

Infections that directly transform lymphocytes: Some viruses can directly affect the DNA of lymphocytes, helping to transform them into cancer cells. The human T-cell leukemia/lymphoma virus (HTLV-1) and the Epstein-Barr virus (EBV) seem to work in this way.

Infection with HTLV-1 increases a person’s risk of developing certain types of T-cell lymphoma. This virus is most common in some parts of Japan and in the Caribbean region, but is found throughout the world. In the United States, it causes less than 1% of lymphomas. HTLV-1 spreads through sex and contaminated blood and can be passed to children through breast milk from an infected mother.

Infection with the Epstein-Barr virus (EBV) is an important risk factor for Burkitt lymphoma in areas of Africa where this type of lymphoma is common. In developed countries such as the United States, EBV is more often linked with lymphomas in patients also infected with HIV, the virus that causes AIDS. It has also been linked with developing nasal-type extranodal natural killer/ T-cell lymphoma, lymphomatoid granulomatosis (a form of B-cell lymphoma), and post-transplant lymphoproliferative disorder.

Human herpes virus 8 (HHV8) can also infect lymphocytes, leading to a rare type of lymphoma called primary effusion lymphoma. This lymphoma is most often seen in patients who are infected with HIV. HHV8 infection is also linked to another cancer, Kaposi sarcoma. For this reason, another name for this virus is Kaposi sarcoma-associated herpes virus (KSHV).

Infections that weaken the immune system: Infection with human immunodeficiency virus (HIV), also known as the AIDS virus, commonly causes immune system deficiency. HIV infection is a risk factor for developing certain types of non-Hodgkin lymphoma, such as Burkitt lymphoma and diffuse large B-cell lymphoma.

Infections that cause chronic immune stimulation: Some long-term infections may increase the risk of lymphoma by forcing a person’s immune system to be constantly activated. As more lymphocytes are made to fight the infection, there is a greater chance that genetic mistakes can occur, which might eventually lead to lymphoma.

Helicobacter pylori, a type of bacteria known to cause stomach ulcers, has also been linked to mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach. The body’s immune reaction to this infection increases the risk of lymphoma. This is important because antibiotics can help treat some patients who have MALT lymphomas of the stomach that test positive for H. pylori.

Chlamydophila psittaci (formerly known as Chlamydia psittaci) is a bacteria that can infect both human and animals. In humans, it can cause a lung infection called psittacosis. DNA from this bacterium has been found in biopsies of MALT lymphoma in the tissues around the eye (called ocular adnexal marginal zone lymphoma). This is a sign of infection. A recent study has shown that treating the infection with an antibiotic (doxycycline) can make this lymphoma get better and even go away.

Infection with the bacterium Campylobacter jejuni has been linked to a type of MALT lymphoma calledimmunoproliferative small intestinal disease. This type of lymphoma, which is also sometimes called Mediterranean abdominal lymphoma, typically occurs in young adults in eastern Mediterranean countries. Antibiotics can be helpful in treating this lymphoma, especially in early stages.

The hepatitis C virus (HCV) can also cause long-term infections. Infection with HCV seems to be a risk factor for certain types of lymphoma. In splenic marginal zone lymphoma, successful treatment of the HCV infection can lead to the lymphoma getting better and even going away.

Body weight and diet: Some studies have suggested that being overweight or obese may increase your risk of non-Hodgkin lymphoma. Other studies have suggested that a diet high in fat and meats may raise your risk. More research is needed to confirm these findings. In any event, staying at a healthy weight and eating a healthy diet have many known health benefits outside of the possible effect on lymphoma risk.

Do we know what causes non-Hodgkin lymphoma?

Researchers have found that non-Hodgkin lymphoma is linked with a number of risk factors, but the causes of most lymphomas are unknown. This is complicated by the fact that lymphomas are actually a diverse group of cancers.

Still, scientists have made a lot of progress in understanding how certain changes in DNA can cause normal lymphocytes to become lymphoma cells. Normal human cells grow and function mainly based on the information contained in each cell’s chromosomes. Human DNA is packaged in 23 pairs of chromosomes, which are long molecules of DNA in each cell. DNA is the chemical that makes up our genes – the instructions for how our cells function. We look like our parents because they are the source of our DNA. But DNA affects more than how we look.

Some genes contain instructions for controlling when cells grow and divide. Certain genes that speed up cell division or help cells live longer are called oncogenes. Others that slow down cell division or cause cells to die at the right time are called tumor suppressor genes.

Each time a cell prepares to divide into 2 new cells, it must make a new copy of the DNA in its chromosomes. This process is not perfect, and errors can occur that may affect genes within the DNA. Cancers can be caused by DNA mutations (changes) that turn on oncogenes or turn off tumor suppressor genes.

Some people inherit DNA mutations from a parent that increase their risk for some types of cancer. But non-Hodgkin lymphoma is not one of the cancer types often caused by these inherited mutations. In other words, there’s no increased risk of lymphoma in the children of patients with lymphoma.

DNA changes related to non-Hodgkin lymphoma are usually acquired after birth, rather than being inherited. Acquired changes may result from exposure to radiation, cancer-causing chemicals, or infections, but often these changes occur for no apparent reason. They seem to happen more often as we age, and lymphomas for the most part are a cancer of older people.

Translocations are a type of DNA change that can cause non-Hodgkin lymphoma to develop. A translocation means that DNA from one chromosome breaks off and becomes attached to a different chromosome. When this happens, oncogenes can be turned on or tumor suppressor genes can be turned off. Some lymphomas tend to have specific chromosome defects. For example, most cases of follicular lymphoma have a translocation between chromosomes 14 and 18, which turns on the bcl-2 oncogene. This stops the cell from dying at the right time, which can lead to lymphoma.

Scientists are learning much about the exact gene changes involved in lymphoma. This information is being used to develop more accurate tests to detect and classify certain types of lymphoma. Hopefully, these discoveries can be used to develop new treatments as well.

Researchers are beginning to understand how these gene changes develop in people with certain risk factors, but they still do not know why most lymphomas develop in people with no apparent risk factors.

Lymphocytes (the cells from which lymphomas start) 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 lymphoma.

People with immune deficiencies (due to inherited conditions, drug treatment, organ transplants, or HIV infection) have a much higher chance of developing lymphoma than people without an immune deficiency.

People with certain autoimmune diseases (where the immune system constantly attacks a certain part of the body) have an increased risk of getting lymphoma.

People with certain chronic infections are also at increased risk, probably because the immune system is constantly making new lymphocytes to fight the infection, which increases the chances for mistakes in their DNA.

How is non-Hodgkin lymphoma diagnosed?

Most people with non-Hodgkin lymphoma see their doctor because they have felt a lump that hasn’t gone away, they develop some of the other symptoms listed below, or they just don’t feel well and go in for a check-up.

If signs or symptoms suggest that a person might have non-Hodgkin lymphoma, exams and tests are done to find out for certain if they do and, if so, to determine the exact type of lymphoma.

Signs and symptoms of non-Hodgkin lymphoma: Non-Hodgkin lymphoma can cause many different signs and symptoms, depending on where it is in the body. In some cases it might not cause any symptoms until it grows quite large. Common symptoms include: (a) Enlarged lymph nodes, (b) Swollen abdomen (belly), (c) Feeling full after only a small amount of food, (d) Chest pain or pressure, (e) Shortness of breath or cough, (f) Fever, (g) Weight loss,  (e) Night sweats, (f) Fatigue (extreme tiredness)

Swollen lymph nodes: Non-Hodgkin lymphoma can cause lymph nodes to become enlarged. When this occurs in lymph nodes close to the surface of the body (such as on the sides of the neck, in the groin or underarm areas, or above the collar bone), they may be seen or felt as lumps under the skin. These are often found by the patient, a family member, or a health care professional. Although enlarged lymph nodes are a common symptom of lymphoma, they are much more often caused by infections.

Lymphoma in the abdomen: Lymphomas in the abdomen may cause it to become swollen and tender. This may be because of lymph nodes in the abdomen enlarging, but it can also be caused by the build-up of large amounts of fluid.

Lymphoma can cause the spleen to become enlarged and press on the stomach. This can cause a person to feel full after eating only a small amount of food.

When lymphoma is in the intestines or causes swelling near the intestines, bowel movements may be blocked, which may lead to abdominal pain, nausea, or vomiting. Lymphoma in the intestines can also cause holes to develop in the intestine wall (called perforations). This allows the contents of the intestines to leak out into the abdominal cavity, leading to serious infection and severe pain with nausea and vomiting.

Lymphomas of the stomach often cause stomach pain, nausea, and reduced appetite.

Lymphoma in the chest: When lymphoma starts in the thymus or lymph nodes in the chest, it may press on the nearby trachea (windpipe), which can cause coughing or trouble breathing. Lymphomas in this area can also cause a feeling of chest pain or pressure.

The superior vena cava (SVC) is the large vein that carries blood from the head and arms back to the heart. It passes near the thymus and lymph nodes inside the chest. Lymphomas in this area may push on the SVC, which can cause the blood to back up in the veins. This can lead to swelling (and sometimes a bluish-red color) in the head, arms, and upper chest. It can also cause trouble breathing and a change in consciousness if it affects the brain. This condition, known as SVC syndrome, can be life-threatening and must be treated right away.

Lymphoma affecting the brain: Lymphomas of the brain, called primary brain lymphomas, can cause headache, trouble thinking, weakness in certain parts of the body, personality changes, and sometimes seizures.

Other types of lymphoma can spread to the area around the brain and spinal cord. This can cause problems such as double vision, facial numbness, and trouble speaking.

Lymphoma in the skin: Lymphomas of the skin may be seen or felt. They often appear as extremely itchy, red or purple lumps or nodules under the skin. 

General symptoms

Along with causing symptoms and signs in the part of the body where it starts, non-Hodgkin lymphoma can also cause general symptoms, such as: (a) Unexplained weight loss, (b) Fever, (c) Drenching night sweats (enough to soak clothing and sheets)

When talking about lymphoma, doctors call these B symptoms. The presence of B symptoms is most common in more rapidly growing lymphomas. These symptoms are important not only in helping diagnose non-Hodgkin lymphoma, but also in determining the stage and prognosis (outlook) if lymphoma is found.

Other symptoms can be caused by low blood counts. Blood counts can become low when lymphoma spreads to the bone marrow and crowds out the normal, healthy cells that make new blood cells. This can lead to problems like: (a) Severe or frequent infections (from low white blood cell counts), (b) Easy bruising or bleeding (from low blood platelet counts), (c) Fatigue (from low red blood cell counts [anemia])

Medical history and physical exam: If the symptoms suggest you might have non-Hodgkin lymphoma, your doctor will want to get a thorough medical history, including information about your symptoms, possible risk factors, family history, and other medical conditions.

Next, the doctor will examine you, paying special attention to the lymph nodes and other areas of the body that might be involved, including the spleen and liver. Because infections are the most common cause of enlarged lymph nodes, the doctor will look for an infection in the part of the body near the swollen lymph nodes.

If the doctor suspects that non-Hodgkin lymphoma might be causing the symptoms, he or she will recommend a biopsy of the area.

Biopsy: Many of the symptoms of non-Hodgkin lymphoma are not specific enough to say for certain if they are being caused by cancer. Most of these symptoms can also be caused by non-cancerous problems, like infections, or by other kinds of cancers.

For example, enlarged lymph nodes are more often caused by infections than by non-Hodgkin lymphoma. Because of this, doctors often prescribe antibiotics and wait a few weeks to see if the nodes shrink.

If the nodes stay the same or continue to grow, the doctor might then advise a biopsy. Either a small piece of a node or, more commonly, the entire node is removed for viewing under the microscope and for other lab tests.

A biopsy might be needed right away if the size, texture, or location of the node or the presence of other symptoms strongly suggests cancer. But a delay in diagnosis of a few weeks is not likely to be harmful unless it’s a very rapidly growing lymphoma.

Types of biopsies used to diagnose non-Hodgkin lymphoma:  A biopsy is the only way to diagnose non-Hodgkin lymphoma. There are several types of biopsies. Doctors choose which one to use based on the unique aspects of each person’s situation.

Excisional or incisional biopsy: This is the most common type of biopsy if lymphoma is suspected. In this procedure, a surgeon cuts through the skin to remove either the entire node (excisional biopsy) or a small part of a large tumor (incisional biopsy).

If the node is near the skin surface, this is a simple operation that can often be done with local anesthesia (numbing medicine). But if the node is inside the chest or abdomen, the patient is sedated or given general anesthesia (drugs are used to put the patient into a deep sleep).

This method almost always provides enough of a sample to diagnose the exact type of non-Hodgkin lymphoma. It is the preferred type of biopsy, if it can be done without too much discomfort to the patient.

Fine needle aspiration (FNA) or core needle biopsy: In an FNA biopsy, the doctor uses a very thin, hollow needle attached to a syringe to withdraw (aspirate) a small amount of tissue from an enlarged lymph node or a tumor mass. For a core needle biopsy, the doctor uses a larger needle to remove a slightly larger piece of tissue.

For an enlarged node near the surface of the body, the doctor can aim the needle while feeling the node. If the tumor is deep inside the body, the doctor can guide the needle using a computed tomography (CT) scan or ultrasound (see descriptions of imaging tests later in this section).

A needle biopsy does not require surgery, but in some cases it might not remove enough of a sample to make a definite diagnosis. Most doctors do not use needle biopsies to diagnose lymphoma. But if the doctor suspects that your lymph node swelling is caused by an infection or by the spread of cancer from another organ (such as the breast, lungs, or thyroid), a needle biopsy may be the first type of biopsy done. An excisional biopsy might still be needed to diagnose and classify lymphoma, even after a needle biopsy has been done.

Once lymphoma has been diagnosed, needle biopsies are sometimes used to check areas in other parts of the body that might be lymphoma spreading or coming back after treatment.

Other types of biopsies: These procedures are not normally done to diagnose lymphoma, but they might be done to help determine the stage (extent) of a lymphoma that has already been diagnosed.

Bone marrow aspiration and biopsy: These procedures are often done after lymphoma has been diagnosed to help determine if it has reached the bone marrow. The two tests are often done at the same time. The samples are usually taken from the back of the pelvic (hip) bone, although in some cases they may be taken from the sternum (breast bone) or other bones.

In bone marrow aspiration, you lie on a table (either on your side or on your belly). After cleaning the skin over the hip, the doctor numbs the area and the surface of the bone with local anesthetic, which can cause a brief stinging or burning sensation. A thin, hollow needle is then inserted into the bone and a syringe is used to suck out a small amount of liquid bone marrow (about 1 teaspoon). Even with the anesthetic, most patients still have some brief pain when the marrow is removed.

A bone marrow biopsy is usually done just after the aspiration. A small piece of bone and marrow is removed with a slightly larger needle that is twisted as it is pushed into the bone. The biopsy might also cause some brief pain. Once the biopsy is done, pressure will be applied to the site to help stop any bleeding.

Lumbar puncture (spinal tap): This test looks for lymphoma cells in the cerebrospinal fluid (CSF), which is the liquid that bathes the brain and spinal cord.

For this test, the patient may lie on their side or sit up. The doctor first numbs an area in the lower part of the back over the spine. A small, hollow needle is then placed between the bones of the spine to withdraw some of the fluid.

Most people with lymphoma will not need this test. But doctors may order it for certain types of lymphoma or if a person has symptoms that suggest the lymphoma may have reached the brain.

Pleural or peritoneal fluid sampling: Spread of lymphoma to the chest or abdomen can cause fluid to build up. Pleural fluid (inside the chest) or peritoneal fluid (inside the abdomen) can be removed by placing a hollow needle through the skin into the chest or abdomen. The doctor uses a local anesthetic to numb the skin before inserting the needle. The fluid is then withdrawn and looked at under the microscope to check for lymphoma cells. When this procedure is used to remove fluid from the area around the lung, it is called a thoracentesis. When it is used to collect fluid from inside the abdomen, it’s known as a paracentesis.

Lab tests on biopsy samples to diagnose and classify lymphoma: All biopsy samples and fluids are looked at under a microscope by a pathologist (a doctor with special training in recognizing cancer cells), who studies the size and shape of the cells and how they are arranged. This may reveal not only if the person has a lymphoma, but also what type of lymphoma it is. Because diagnosing lymphoma can be tricky, it helps if the pathologist specializes in diseases of the blood.

Pathologists can sometimes tell which kind of lymphoma a patient has by looking at the cells, but usually other types of tests are needed to confirm the diagnosis.

Immunohistochemistry: In this test, a part of the biopsy sample is treated with special antibodies (man-made versions of immune system proteins) that attach only to specific molecules on the cell surface. These antibodies cause color changes, which can be seen under a microscope. This test may be helpful in distinguishing different types of lymphoma from one another and from other diseases.

Flow cytometry: Like immunohistochemistry, this test looks for certain substances on the outside surface of cells that help identify what types of cells they are. But this test can look at many more cells than immunohistochemistry.

For this test, a sample of cells is treated with special antibodies that stick to the cells only if certain substances are present on their surfaces. The cells are then passed in front of a laser beam. If the cells now have antibodies attached to them, the laser will cause them to give off light, which can be measured and analyzed by a computer. Groups of cells can be separated and counted by these methods.

This is the most commonly used test for immunophenotyping (classifying lymphoma cells according to the substances [antigens] on their surfaces). Different types of lymphocytes have different antigens on their surface. These antigens may also change as each cell matures.

Flow cytometry can help determine whether the lymph node is swollen because of lymphoma, some other cancer, or a non-cancerous disease. It has also become very useful in helping doctors determine the exact type of lymphoma so that they can select the best treatment.

Cytogenetics: This technique allows doctors to evaluate the chromosomes (long strands of DNA) in the lymphoma cells. The cells are looked at under a microscope to see if the chromosomes have any translocations (where part of one chromosome has broken off and is now attached to another chromosome), as happens in certain types of lymphoma. Some lymphoma cells may have too many chromosomes, too few chromosomes, or other chromosome abnormalities. These changes can help identify the type of lymphoma.

Cytogenetic testing usually takes about 2 to 3 weeks because the lymphoma cells must grow in lab dishes for a couple of weeks before their chromosomes are ready to be viewed under the microscope.

Molecular genetic tests: These tests look more closely at lymphoma cell DNA. They can detect most changes that are visible under a microscope in cytogenetic tests, as well as others that can’t be seen.

Fluorescent in situ hybridization (FISH): FISH uses special fluorescent dyes that only attach to specific genes or parts of chromosomes. FISH can find most chromosome changes (such as translocations) that can be seen under a microscope in standard cytogenetic tests, as well as some gene changes too small to be seen with usual cytogenetic testing.

FISH can be used to look for specific genes or changes in chromosomes. It can be used on regular blood or bone marrow samples. It is very accurate and can usually provide results within a couple of days, which is why this test is now used in many medical centers.

Polymerase chain reaction (PCR): PCR is a very sensitive DNA test that can find gene changes and certain chromosome changes too small to be seen under a microscope, even if very few lymphoma cells are present in a sample. .

Blood tests: Blood tests measure the amounts of certain types of cells and chemicals in the blood. They are not used to diagnose lymphoma, but they can sometimes help determine how advanced the lymphoma is.

Patients with known or suspected lymphoma will have a complete blood count (CBC) checked. This test measures the different cells in the blood, such as the red blood cells, the white blood cells, and the platelets. In patients already known to have lymphoma, low blood cell counts can mean that the lymphoma is growing in the bone marrow and affecting new blood cell formation.

Many patients will also have blood chemistry tests run, to look at kidney and liver function. If lymphoma has been diagnosed, another blood test called lactate dehydrogenase (LDH) may be checked. LDH levels are often increased in patients with lymphomas.

For some types of lymphoma or if certain treatments may be used, your doctor may also advise other blood tests to see if you have been infected with certain viruses, such as the hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). Infections with these viruses may affect your treatment.

Imaging tests: Imaging tests use x-rays, sound waves, magnetic fields, or radioactive particles to produce pictures of the inside of the body. In someone with known or suspected lymphoma, these tests might be done to look more closely at an abnormal area that might contain lymphoma, to learn how far the lymphoma may have spread, or to find out if treatment has been effective.

Chest x-ray: X-rays of the chest may be done to look for enlarged lymph nodes in this area.

Computed tomography (CT) scan: The CT scan is an x-ray test that produces detailed, cross-sectional images of your body. Instead of taking one picture, like a regular x-ray, a CT scanner takes many pictures as it rotates around you. A computer then combines these pictures into an image of a slice of your body.

Unlike a regular x-ray, CT scans can show the detail in soft tissues (such as internal organs). This scan can help tell if any lymph nodes or organs in your body are enlarged. CT scans are useful for looking for lymphoma in the abdomen, pelvis, chest, head, and neck.

Before the test, you may be asked to drink a contrast solution and/or get an intravenous (IV) injection of a contrast dye that helps better outline abnormal areas in the body. You may need an IV line through which the contrast dye is injected. The injection can cause some flushing (a feeling of warmth, especially in the face). Some people are allergic and get hives or, rarely, more serious reactions like trouble breathing and low blood pressure. Be sure to tell the doctor if you have any allergies or have ever had a reaction to any contrast material used for x-rays.

CT scans take longer than regular x-rays. You need to lie still on a table while they are being done. During the test, the table slides in and out of the scanner, a ring-shaped machine that completely surrounds the table. You might feel a bit confined by the ring you have to lay in when the pictures are being taken.

In some cases, CT can be used to guide a biopsy needle into a suspicious area. For this procedure, called a CT-guided needle biopsy, you remain on the CT scanning table while a radiologist moves a biopsy needle through the skin and toward the location of the mass. CT scans are repeated until the needle is within the mass. A biopsy sample is then removed to be looked at under a microscope.

Magnetic resonance imaging (MRI) scan: This test is not used as often as CT scans for lymphoma, but if your doctor is concerned about spread to the spinal cord or brain, MRI is very useful for looking at these areas.

Like CT scans, MRI scans provide detailed images of soft tissues in the body. But MRI scans use radio waves and strong magnets instead of x-rays. The energy from the radio waves is absorbed by the body and then released in a pattern formed by the type of body tissue and by certain diseases. A computer translates the pattern into a very detailed image of parts of the body.

A contrast material called gadolinium may be injected into a vein before the scan to better see details. This material is different from what is used for CT scans, so being allergic to one doesn’t mean you are allergic to the other. This material should be used with caution (if at all) in people on dialysis (for kidney failure).

MRI scans take longer than CT scans – often up to an hour. You may have to lie inside a narrow tube, which is confining and can be distressing to some people. Newer, more open MRI machines may be another option. The MRI machine makes loud buzzing and clicking noises that you may find disturbing. Some places provide headphones or earplugs to help block this noise out.

Ultrasound: Ultrasound uses sound waves and their echoes to produce a picture of internal organs or masses. In the most common type of ultrasound, a small, microphone-like instrument called a transducer is placed on the skin (which is first lubricated with a gel). It emits sound waves and picks up the echoes as they bounce off the organs. The echoes are converted by a computer into a black and white image that is displayed on a computer screen.

Ultrasound can be used to look at lymph nodes near the surface of the body or to look inside your abdomen for enlarged lymph nodes or organs such as the liver and spleen. It can also detect kidneys that have become swollen because the outflow of urine has been blocked by enlarged lymph nodes. (It can’t be used to look at organs or lymph nodes in the chest because the ribs block the sound waves.)

This is an easy test to have done, and it uses no radiation. For most ultrasounds, you simply lie on a table, and a technician moves the transducer over the part of your body being looked at.

Positron emission tomography (PET) scan: For a PET scan, a form of radioactive sugar (known as fluorodeoxyglucose or FDG) is injected into the blood. Because cancer cells in the body grow rapidly, they absorb large amounts of the radioactive sugar. After about an hour, you will be moved onto a table in the PET scanner. You lie on the table for about 30 minutes while a special camera creates a picture of areas of radioactivity in the body. The picture is not finely detailed like a CT or MRI scan, but it can provide helpful information about your whole body.

PET scans can help tell if an enlarged lymph node contains lymphoma. It can also help spot small areas that might be lymphoma, even if the area looks normal on a CT scan.

PET scans can be used to tell if a lymphoma is responding to treatment. Some doctors will repeat the PET scan after 1 or 2 courses of chemotherapy. If the chemotherapy is working, the lymph nodes will no longer take up the radioactive sugar. PET scans can also be used after treatment in helping decide whether an enlarged lymph node still contains lymphoma or is merely scar tissue.

Often, for patients with lymphoma, a machine that combines the PET scan with a CT scan (PET/CT scan) is used. This allows the doctor to compare areas of higher radioactivity on the PET scan with the more detailed appearance of that area on the CT.

Gallium scan; For this test, a solution containing slightly radioactive gallium is injected into a vein. It is attracted to lymph tissue in the body. A few days later a special camera is used detect the radioactivity, showing the location of the gallium. The gallium scan will not detect most slow-growing lymphomas but will find many fast-growing (aggressive) lymphomas.

This test is not used as much now as in the past, as many doctors may do a PET scan instead. It can still sometimes be useful in finding areas of lymphoma that the PET scan may miss. It can also help distinguish an infection from a lymphoma when the diagnosis is not clear.

Bone scan: For bone scans, a radioactive substance called technetium is used. After being injected into a vein, it travels to damaged areas of the bone. Lymphoma often causes bone damage, and a bone scan will find it. But a bone scan may also pick up non-cancerous problems, such as arthritis and fractures.

This test is not usually done unless a person is having bone pain or has lab test results that suggest the lymphoma may have reached the bones.

Tests of heart and lung function: These tests are not used to help diagnose non-Hodgkin lymphoma, but they may be done if you are going to get certain chemotherapy drugs commonly used to treat lymphoma that may affect the heart or the lungs.

Your heart function may be checked with an echocardiogram (an ultrasound of the heart) or a MUGA scan.

Your lung function may be checked with pulmonary function tests, in which you breathe into a tube connected to a machine.

How is non-Hodgkin lymphoma staged?

Once non-Hodgkin lymphoma is diagnosed, tests are done to determine the stage (extent of spread) of the disease. The treatment and prognosis (outlook) for a patient with non-Hodgkin lymphoma depend on both the exact type and the stage of the lymphoma.

Tests used to gather information for staging include:

Physical exam

Biopsies of enlarged lymph nodes or other abnormal areas

Blood tests

Imaging tests, such as CT scans

Bone marrow aspiration and biopsy (often but not always done)

Lumbar puncture (spinal tap – this may not need to be done)

Ann Arbor staging system

A staging system is a way for members of the cancer care team to summarize the extent of a cancer’s spread. The staging system most often used to describe the extent of non-Hodgkin lymphoma in adults is called the Ann Arbor staging system.

The stages are described by Roman numerals I through IV (1-4). Lymphomas that affect an organ outside of the lymph system (an extranodal organ) have E added to their stage (for example, stage IIE), while those affecting the spleen have an S added.

Stage I: Either of the following means the disease is stage I:

The lymphoma is in only 1 lymph node area or lymphoid organ such as the thymus (I).

The cancer is found only in 1 area of a single organ outside of the lymph system (IE).

Stage II: Either of the following means the disease is stage II:

The lymphoma is in 2 or more groups of lymph nodes on the same side of (above or below) the diaphragm (the thin band of muscle that separates the chest and abdomen). For example, this might include nodes in the underarm and neck area but not the combination of underarm and groin nodes (II).

The lymphoma extends from a single group of lymph node(s) into a nearby organ (IIE). It may also affect other groups of lymph nodes on the same side of the diaphragm.

Stage III: Either of the following means the disease is stage III:

The lymphoma is found in lymph node areas on both sides of (above and below) the diaphragm.

The cancer may also have spread into an area or organ next to the lymph nodes (IIIE), into the spleen (IIIS), or both (IIISE).

Stage IV: Either of the following means the disease is stage IV:

The lymphoma has spread outside of the lymph system into an organ that is not right next to an involved node.

The lymphoma has spread to the bone marrow, liver, brain or spinal cord, or the pleura (thin lining of the lungs).

Other modifiers may also be used to describe the lymphoma stage:

Bulky disease: This term is used to describe tumors in the chest that are at least one-third as wide as the chest, or tumors in other areas that are at least 10 centimeters (about 4 inches) across. It is usually designated by adding the letter X to the stage. Bulky disease may require more intensive treatment.

A vs. B: Each stage may also be assigned an A or B. The letter B is added (stage IIIB, for example) if a person has any of the B symptoms listed below:

Loss of more than 10% of body weight over the previous 6 months (without dieting)

Unexplained fever of at least 101.5°F

Drenching night sweats

These symptoms usually mean the disease is more advanced. If a person has any of these, then more intensive treatment is usually recommended. If no B symptoms are present, the letter A is added to the stage.

Small lymphocytic lymphoma (SLL) /chronic lymphocytic leukemia (CLL)

The Ann Arbor system is most often used to stage this lymphoma if it is only in lymph nodes. But if the disease is affecting the blood or bone marrow, it is often staged using the systems for CLL. 

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