Tennessee Oncology

Overview

Non-Hodgkin lymphoma (NHL) is a term that refers to many, very different types of cancer of the lymph system. Lymphoma begins when cells in the lymph system change and grow uncontrollably, which may form a tumor. The lymph system is made up of thin tubes that branch out to all parts of the body. Its job is to fight infection and disease. The lymph system carries lymph, a colorless fluid containing lymphocytes (white blood cells). Lymphocytes fight germs in the body. B-lymphocytes (also called B cells) make antibodies to fight bacteria, and T-lymphocytes (also called T cells) kill viruses and foreign cells and trigger the B cells to make antibodies.

Groups of tiny, bean-shaped organs called lymph nodes are located throughout the body at different sites in the lymph system. Lymph nodes are found in clusters in the abdomen, groin, pelvis, underarms, and neck. Other parts of the lymph system include the spleen, which makes lymphocytes and filters blood; the thymus, an organ under the breastbone; the tonsils, located in the throat; and the bone marrow, the spongy red tissue inside bones that produces white blood cells, red blood cells, and platelets (cells that help the blood clot).

Because lymph tissue is found in so many parts of the body, NHL can start almost anywhere and can spread to almost any organ in the body. It most often begins in the lymph nodes, liver, spleen, or bone marrow, but can also involve the stomach, intestines, skin, thyroid gland, and brain or any other part of the body.

There are different types and many subtypes of NHL. It is very important to know which type and subtype has been diagnosed because the type and subtype help doctors determine the best treatment and a patient’s chance of recovery. Specific information can be found in Subtypes of NHL.

This section covers NHL in adults. Learn more about childhood NHL.

Looking for More of an Overview?

If you would like additional introductory information, explore these related items on Cancer.Net:

• ASCO Answers Fact Sheet: Read a one-page fact sheet (available in PDF) that offers an easy-to-print introduction for this type of cancer.

• Cancer.Net Patient Education Video: View a short video led by an ASCO expert in this type of cancer that provides basic information and areas of research.

Find out more about basic cancer terms used in this section.

Statistics

In 2010, an estimated 65,540 people (35,380 men and 30,160 women) in the United States will be diagnosed with NHL. It is estimated that 20,210 deaths (10,710 men and 9,500 women) from this disease will occur this year.

Although NHL is a common childhood cancer, it is more common in adults. NHL is the sixth most common cancer in both men and women. It is also the eighth most common cause of cancer death in men and sixth most common cause of cancer death among women.

The one-year relative survival rate (the percentage of people who survive at least one year after the cancer is detected, excluding those who die from other diseases) of patients with NHL is 80%. The five-year and 10-year relative survival rates are 67% and 56%, respectively.

Cancer survival statistics should be interpreted with caution. These estimates are based on data from thousands of cases of the many different types of lymphoma in the United States and may not apply to a single person or type of lymphoma. It is not possible to tell a person how long he or she will live with NHL. Because the survival statistics are often measured in multi-year intervals, they may not represent advances made in the treatment or diagnosis of this cancer. Learn more about understanding statistics.

Statistics adapted from the American Cancer Society’s publication, Cancer Facts & Figures 2010.

Subtypes

There are different types and many subtypes of NHL, and it is very important to know which type and subtype has been diagnosed. Below are the most common types and subtypes, including information on how each may be treated. For more information on the treatment information described here, please read the Treatment section.

First, the disease is generally described by how quickly the cancer is growing: indolent or aggressive. Indolent and aggressive NHL are equally common in adults. In children, aggressive NHL is more common.

Indolent (low-grade) NHL. These types of lymphoma grow very slowly and often have spread by the time they are diagnosed. About 85% to 90% of patients with indolent NHL have advanced disease when they first visit an oncologist (a doctor who specializes in treating cancer). This type of lymphoma usually responds well to several different types of treatment, but it may come back months or years after treatment is complete. Sometimes, patients with indolent NHL may be followed closely and start treatment only when necessary; this is called watchful waiting. When the lymphoma is localized disease (stage I-II; see Staging), treatment to cure the NHL with radiation therapy may be possible.

Aggressive (high-grade) NHL. These types of lymphoma usually need more intensive chemotherapy. Treatment is usually started immediately, and radiation therapy may be added to chemotherapy. These lymphomas are often curable.

Some subtypes of lymphoma cannot easily be classified as indolent or aggressive. For example, mantle cell lymphoma (see below) has features of both indolent and aggressive NHL.

Second, the doctor will determine what type of cell the lymphoma started in and classify the disease within two major groups:

B-cell lymphoma. About 90% of people with lymphoma have B-cell lymphoma.

T-cell lymphoma. About 10% of people with lymphoma have T-cell lymphoma.

Subtyping

In addition to determining if the NHL is indolent or aggressive, and whether it is B-cell or T-cell, it is very important to determine the subtype of NHL because each subtype can behave differently and may require different treatments. There are about 35 recognized subtypes of NHL; the most common subtypes are described below. Distinguishing between the different subtypes of NHL can be difficult and requires specialized pathologists (doctors who specialize in interpreting laboratory tests and evaluating cells, tissues, and organs to diagnose disease) who are experienced in the diagnosis of lymphoma. Such specialists will use sophisticated techniques and work closely with experienced oncologists. The diagnosis is based on how the lymphoma looks under the microscope and confirmed by additional information from other tests, including tests of genetic material within the lymphoma cells. For more information on this process, see Diagnosis.

Subtypes of B-cell lymphoma

The most common subtypes of B-cell lymphoma are described below.

Diffuse large B-cell lymphoma (DLBCL). This is the most common form of lymphoma (about 30% of people with NHL have this type). It is an aggressive form of NHL that often involves organs other than lymph nodes (about 40% of the time). DLBCL is often curable with chemotherapy given in combination with rituximab (Rituxan); see the Treatment section. Radiation therapy is also used for some patients, especially if the lymphoma is in only one place. Treatments to prevent the lymphoma from spreading to the brain, called central nervous system (CNS) prophylaxis may be given, but most patients do not need this type of treatment. Recent research has shown that there are different types of DLBCL, known as germinal center and non-germinal center. Clinical trials (research studies) to determine whether different types of treatment should be used for these different types of DLBCL are ongoing.

Follicular lymphoma. This is the second most common form of lymphoma in the United States and Europe. About 20% of people with NHL have this type. It usually begins in the lymph nodes, is most often indolent, and grows very slowly. There is no known cure; about 50% of people survive at least eight to 10 years after diagnosis. Patients with follicular lymphoma may be treated with combination chemotherapy, monoclonal antibodies, radiation therapy, or may be followed closely with watchful waiting (see Treatment).

Over time, follicular lymphoma may transform into DLBCL (see above), which will then require more aggressive treatment. Stem cell transplantation, tumor vaccines, interferon, and monoclonal antibody treatments may also be available in clinical trials. Recent clinical trials have suggested that the survival for patients with follicular lymphoma has improved over the last few years, although this needs more research to confirm. Localized radiation therapy may cure early-stage (stage I-II) disease. Newer drugs such as bortezomib (Velcade), bendamustine (Treanda), and lenalidomide (Revlimid) have been shown to be effective for this subtype and are being studied in clinical trials as part of first line treatment.

Mantle cell lymphoma. This is an aggressive subtype that about 7% of people with NHL have. It most often appears in people over age 60. It usually involves the bone marrow, lymph nodes, spleen, and gastrointestinal system (esophagus, stomach, intestines) and is identified by its expression of a protein called the cyclin D1 protein. Mantle cell lymphoma often does not respond, or stops responding, to chemotherapy. At this time, there is substantial debate about the best way to treat mantle cell lymphoma. Newer drugs such as bortezomib, bendamustine, and lenalidomide have also been shown to be effective for this subtype and are being studied in clinical trials as part of first line treatment. Clinical trials using high-dose chemotherapy followed by stem cell transplantation or monoclonal antibodies after anthracycline-containing chemotherapy regimens are in progress. Other new drugs are also being studied for mantle cell lymphoma.

Small lymphocytic lymphoma. This type of lymphoma is very closely related to a disease called B-cell chronic lymphocytic leukemia (CLL), and about 5% of people with NHL have this subtype. It is considered an indolent lymphoma. Patients with small lymphocytic lymphoma may be treated with a combination of chemotherapy, monoclonal antibodies, radiation therapy, or may be followed closely with watchful waiting. Stem cell transplantation, tumor vaccines, interferon, and monoclonal antibody treatments may also be available in clinical trials.

Mediastinal large B-cell lymphoma. This is an aggressive form of DLBCL (see above). It appears as a large mass in the chest area, which may cause breathing problems or superior vena cava syndrome (SVCS), a collection of symptoms caused by the partial blockage or compression of the superior vena cava, the major vein that carries blood from the head, neck, upper chest, and arms to the heart. Mediastinal large B-cell lymphoma is most common in women between the ages of 30 and 40, and about 2.5% of people with NHL have this subtype. It is treated most often with anthracycline-based chemotherapy, and most patients also receive rituximab and radiation therapy to the chest. Although radiation therapy has traditionally been considered a particularly important part of treatment for mediastinal large B-cell lymphoma for some patients, this is no longer certain because the use of rituximab has improved treatment so that radiation treatments may not be necessary.

Splenic marginal zone B-cell lymphoma. This type of lymphoma begins in the spleen and can also involve the blood. It is usually slow-growing, and the treatment approach is often watchful waiting. Sometimes, surgical removal of the spleen is recommended.

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). This type of lymphoma most commonly occurs in the stomach, but it may also occur in the lung, skin, thyroid, salivary gland, or eye. Patients with this type of lymphoma often have a history of autoimmune disease, such as lupus, rheumatoid arthritis, or Sjögren’s syndrome. When MALT occurs in the stomach, it is often successfully treated with antibiotics to treat a bacterium called Helicobacter pylori, which is thought to cause the lymphoma. Other times, radiation therapy, surgery, chemotherapy, monoclonal antibodies, or a combination of these is the most common treatment.

Nodal marginal zone B-cell lymphoma. This type of indolent lymphoma involves the lymph nodes. It is rare; about 1% of people with lymphoma have this subtype. In general, this subtype of lymphoma is treated similarly to follicular lymphoma (see above).

Lymphoplasmacytic lymphoma. This is an indolent form of lymphoma, and 1% of people with NHL have this subtype. This form of lymphoma most often involves the bone marrow, lymph nodes, and spleen. In many patients, this lymphoma produces protein which is found at high levels in the blood. When this occurs, the condition is known as Waldenstrom’s macroglobulinemia (WM). Patients with WM sometimes have hyperviscosity (thickened blood) that may cause symptoms such as headache, blurry vision, dizziness and shortness of breath. Treatment is similar to chronic lymphocytic lymphoma/leukemia and may include watchful waiting, combination chemotherapy, monoclonal antibodies, or combinations of chemotherapy and monoclonal antibodies. Chemotherapy followed by stem cell transplantation is being studied in clinical trials.

Primary effusion lymphoma. This very aggressive form of lymphoma most often occurs in people with the human immunodeficiency virus (HIV, the virus that causes autoimmune deficiency syndrome or AIDS), with low immunity for other reasons, or are elderly. It appears in the lung, heart, or abdominal cavities; often, there is not one identifiable tumor. It is treated the same as other diffuse large cell lymphoma (see above).

Burkitt lymphoma/Burkitt cell leukemia. This is a very rare and aggressive form of lymphoma. There are three forms of Burkitt lymphoma: endemic, sporadic, and immunodeficiency-related lymphoma. It occurs most commonly in Africa, appears most often in the jawbones of children, and is usually associated with the Epstein-Barr virus (EBV, the virus that causes infectious mononucleosis, also known as "mono"). In the United States, Burkitt lymphoma appears most commonly with a mass in the abdomen. Because this type of lymphoma spreads quickly, it needs immediate treatment that includes intensive chemotherapy, usually with some treatment for the central nervous system to prevent it from spreading to the brain. This type of NHL is often curable.

Subtypes of T-cell lymphoma

The most common subtypes of T cell and natural killer (NK) lymphoma are described below.

Anaplastic large cell lymphoma, primary cutaneous type. This subtype of lymphoma involves the skin only. It is often indolent, although aggressive subtypes of the disease are possible. When the cancer is localized, radiation therapy is often effective. If it has spread, doxorubicin-based chemotherapy is the usual treatment.

Peripheral T-cell Lymphoma, NOS. This is an aggressive form of lymphoma that is most often discovered at an advanced stage. It is most common in people older than 60 and makes up about 6% of all lymphomas in the United States and Europe. The cells of this lymphoma are variable in size, and they express certain types of proteins (called CD4 or CD8) on their surface. It is treated like DLBCL (see above), with doxorubicin-based chemotherapy. Stem cell transplantation may sometimes be considered.

Angioimmunoblastic T-cell lymphoma. This is an aggressive form of lymphoma with specific symptoms: swollen lymph nodes, fever, weight loss, rash, and high levels of antibodies called gamma globulin in the blood. Since patients with angioimmunoblastic lymphoma have lowered immune systems, infections are also common. This type of lymphoma is identified by specific genetic changes found on the T-cell receptors. It is treated like other diffuse large cell lymphomas.

Anaplastic large cell lymphoma, systemic type. This form makes up about 2% of all lymphomas and about 10% of all childhood lymphomas. An increased amount of the ALK-1 protein in the cancer cells is characteristic of this subtype. It occurs in both adults and children. It is an aggressive form of lymphoma that often responds well to treatment.

Precursor T-lymphoblastic lymphoma/leukemia (precursor T-cell acute lymphoblastic leukemia). This is a rare type of lymphoma, accounting for about 2% of all NHL. It is most commonly seen in young adults and is more common for men than women. This type of lymphoma is the same as a form of leukemia called acute lymphoblastic leukemia (ALL). When it mainly affects lymph nodes it is called lymphoblastic lymphoma, and when it mainly affects the blood or bone marrow it is called ALL. When it mainly affects the lymph nodes, it most commonly involves the lymph nodes in the center of the chest. Both lymphoblastic lymphoma and ALL are aggressive diseases which require intensive chemotherapy, including treatment for the central nervous system to prevent it from spreading to the brain. Stem cell transplantation is sometimes used. It is often cured with these treatments.

Adult T-cell lymphoma/leukemia (human T-cell lymphotropic virus type I positive). This type of lymphoma is caused by a virus called the human T-cell lymphotropic virus type I. It is an aggressive disease that most often involves the bone and skin; often, lymphoma cells are found in the blood, which is why this condition is sometimes also called leukemia. This form of lymphoma usually does not respond well to chemotherapy, although some success has been seen with zidovudine (Retrovir) and interferon. About two-thirds of patients experience remission (temporary or permanent absence of symptoms).

Extranodal NK/T-cell lymphoma, nasal type. This is an aggressive type of lymphoma that is very rare in the United States and Europe but more common in Asian and Hispanic communities. It can occur in children or adults, most often involving the nasal area and sinuses. But, it can also involve the trachea, gastrointestinal tract, testicles (in men), or skin. It often does not respond well to standard chemotherapy, but it may be treated with radiation therapy followed by chemotherapy. Stem cell transplantation for this type of lymphoma is being studied in clinical trials.

Enteropathy-associated T-cell lymphoma. This type of lymphoma is rare in the United States but more common in Europe. This is an aggressive form of T-cell lymphoma that involves the intestines of patients who have celiac disease (gluten intolerance). High-dose chemotherapy may be used to treat enteropathy type T-cell lymphoma.

Gamma/delta hepatosplenic T-cell lymphoma. This is an aggressive form of peripheral T-cell lymphoma that involves the liver and spleen. It occurs most often in male adolescents and young men. It is treated as a high-risk diffuse large cell lymphoma (see above).

Subcutaneous panniculitis-like T-cell lymphoma. This is a form of peripheral T-cell lymphoma that is similar to gamma/delta hepatosplenic T-cell lymphoma (see above). It involves the tissue under the skin and is often first diagnosed as panniculitis (inflammation of fatty tissues). It is treated as a high-risk aggressive lymphoma.

More information on the specific treatment options described above can be found in the Treatment section.

Risk Factors

A risk factor is anything that increases a person’s chance of developing cancer. Although risk factors can influence the development of cancer, most do not directly cause cancer. Some people with several risk factors never develop cancer, while others with no known risk factors do. However, knowing your risk factors and communicating them to your doctor may help you make more informed lifestyle and health-care choices.

The exact cause of NHL is not known, but the following factors may raise a person’s risk of developing NHL:

Age. The risk of NHL increases with age. The most common types occur most often in people in their 60s and 70s.

Gender. Men are more likely to develop NHL than women.

Infections. Some types of NHL are associated with specific infections. For example, MALT lymphoma of the stomach is thought to be caused by a bacterium known as Helicobacter pylori. If this lymphoma is diagnosed very early, it will sometimes go away if the bacterium is eliminated from the stomach with antibiotics. Other types of MALT lymphoma, including those affecting the lungs and the tear glands, may also be caused by infections.

Virus exposure. Viruses cause some types of NHL. For example, EBV is associated with some types of NHL, including Burkitt lymphoma and lymphomas occurring after solid organ transplantations. EBV may also be responsible for causing some types of NHL in people ages 60 to 90. However, the virus is probably not the only factor, so people who have had mono do not necessarily have an increased risk of developing NHL in the future. Other viruses have also been identified as being important in causing other rare types of lymphoma.

Immune deficiency disorders. Immune system disorders, such as HIV/AIDS, increase the risk of NHL, especially the aggressive B-cell lymphomas.

Autoimmune disorders. People with autoimmune disorders, such as rheumatoid arthritis and Sjögren syndrome, are at an increased risk for developing certain types of NHL. Also, some drugs used to treat autoimmune disorders may increase the risk of NHL.

Organ transplantation. Organ transplant recipients are at a higher risk for NHL because of the immune-suppressing drugs that must be taken.

Previous cancer treatment. Previous treatment with certain drugs for other types of cancer may increase the risk of NHL.

Chemical exposure. Exposure to certain chemicals, such as pesticides and petrochemicals, may increase the risk of NHL.

Symptoms

People with NHL may experience a variety of symptoms or signs. Many of these symptoms can also be caused by conditions other than cancer or lymphoma. There are very few symptoms that are specific to lymphoma, and this explains why it can sometimes be difficult to make the diagnosis. If you are concerned about a symptom or sign on this list, please talk with your doctor.

The symptoms of NHL depend on where the cancer starts and the organ that is involved.

General symptoms:

• Enlarged lymph nodes in the abdomen, groin, neck, or underarms

• Enlarged spleen or liver

• Fever that cannot be explained by an infection or other illness

• Weight loss with no known cause

• Sweating and chills

Examples of symptoms related to a specific tumor location:

• A tumor in the abdomen can cause a distended (stretched) belly or pain.

• A tumor in the center of the chest pressing on the windpipe can cause difficulty breathing or other respiratory problems.

The doctor may use certain symptoms to help describe the disease, called Staging. Each stage may be subdivided into "A" and "B" categories.

A means that an individual did not experience B symptoms, listed below.

B means that an individual experienced the following symptoms:

• Unexplained weight loss of more than 10% of original body weight during the six months before diagnosis

• Unexplained fever with temperatures above 38º C (100.4º F)

• Drenching night sweats. Most patients report that either their nightclothes or the sheets on the bed are actually wet. Sometimes, heavy sweating occurs during the day.

Diagnosis

Doctors use many tests to diagnose cancer and find out if it has spread. Some tests may also determine which treatments may be the most effective. A biopsy is the only way to make a definitive diagnosis of lymphoma. Imaging tests may be used to find out whether the lymphoma has spread. Your doctor may consider these factors when choosing a diagnostic test:

• Age and medical condition

• The type of lymphoma suspected

• Severity of symptoms

• Previous test results

To determine if a person has NHL, the doctor will first take a complete medical history and do a physical examination, paying special attention to the lymph nodes, liver, and spleen. The doctor will also look for signs of infection that may cause the lymph nodes to swell and may prescribe an antibiotic. If the swelling in the lymph nodes still does not go down after antibiotic treatment, the swelling may be caused by something other than an infection. If the doctor suspects lymphoma, he or she will recommend a biopsy, as well as laboratory and imaging tests.

In addition to a physical examination, the following tests may be used to diagnose NHL:

Biopsy. A biopsy is the removal of a small amount of tissue for examination under a microscope. To diagnose lymphoma, the most common type is a biopsy from lymph nodes in the neck, under the arms, or in the groin. A biopsy may also be taken from the chest or abdomen during a computed tomography (CT) scan or from the stomach or intestine during an endoscopy (a test that allows the doctor to see inside the body with a thin, lighted, flexible tube). A biopsy is the only way to make a definite diagnosis of lymphoma and determine the subtype. Having enough tissue is important to make a diagnosis. The tissue sample removed during the biopsy should be analyzed by a pathologist experienced in the diagnosis of lymphoma; second opinions may also be helpful.

Cytogenetic and molecular testing. Since many subtypes of lymphoma are identified by specific genetic changes or molecular activity, cytogenetics (the study of genetic changes in cells) and molecular studies may be performed on the tissue sample removed during the biopsy.

Bone marrow aspiration and biopsy. Lymphoma often spreads to the bone marrow, the spongy material in the center of bones where blood cells are produced. Looking at a sample of the bone marrow can be important for doctors to diagnose lymphoma and to determine if it has spread.

The most common site to biopsy the bone marrow is the back of the pelvic (hip) bone. The skin is numbed, and a needle is inserted into a bone in the hip until it reaches the marrow. A small amount of bone marrow is removed and examined under a microscope.

Computed tomography (CT or CAT) scan. A CT scan creates a three-dimensional picture of the inside of the body with an x-ray machine. A computer then combines these images into a detailed, cross-sectional view that shows any abnormalities or tumors. Sometimes, a contrast medium (a special dye) is injected into a patient’s vein to provide better detail and locate the exact position of a tumor. CT scans of the chest, abdomen, and pelvis can help find cancer that has spread to the lungs, lymph nodes, and liver.

Magnetic resonance imaging (MRI) scan. An MRI uses magnetic fields, not x-rays, to produce detailed images of the body. A contrast medium may be injected into a patient’s vein to create a clearer picture.

Bone scan. A bone scan uses a radioactive tracer to look at the inside of the bones. The tracer is injected into a patient’s vein. It collects in areas of the bone and is detected by a special camera. Healthy bone appears gray to the camera, and areas of injury, such as those caused by cancer, appear dark.

Positron emission tomography (PET) scan. A PET scan is a way to create pictures of organs and tissues inside the body. A small amount of a radioactive substance (called radioactive glucose) is injected into a patient’s body. This substance is absorbed mainly by organs and tissues that produce the most energy. Because cancer tends to use energy actively, it absorbs more of the radioactive substance. A scanner then detects this substance to produce images of the inside of the body. The accuracy and role of PET scanning for NHL is not yet clear, although aggressive lymphomas often show up on PET scans. Many doctors will recommend a PET scan as part of the initial diagnosis, especially for aggressive lymphomas. In the future, a PET scan may help monitor the disease’s response to treatment. There is also some evidence that using a PET scan after one or two cycles of treatment may be a useful way of predicting whether that treatment is likely to completely get rid of the lymphoma. This is not yet proven, but it is being studied in clinical trials around the world.

Learn more about what to expect when having common tests, procedures, and scans.

Find out more about common terms used during a diagnosis of cancer.

Staging

Staging helps to define where NHL is located, if or where it has spread, and if it is affecting the functions of other organs in the body. Doctors use diagnostic tests to determine the cancer’s stage, so staging may not be complete until all of the tests are finished. Knowing the stage helps the doctor to decide what kind of treatment is best and can help predict a patient’s prognosis (chance of recovery). There are different stage descriptions for different types of cancer.

When staging NHL, doctors evaluate the following:

• The number of cancerous lymph node areas

• The location of the cancerous lymph nodes: regional (in the same area the cancer began) or distant (in other parts of the body)

• Whether the cancerous lymph nodes are on one or both sides of the diaphragm (the thin muscle under the lungs and heart that separates the chest from the abdomen)

• Whether the disease has spread to the bone marrow, spleen, or extralymphatic organs (organs outside the lymphatic system) such as the liver, lungs, or brain

The stage of lymphoma describes the extent of spread of the tumor, using Roman numerals one through four (I, II, III, or IV). As explained in Symptoms, each stage may also be subdivided into “A” and “B” categories, based on the presence or absence of specific symptoms.

Stage I: Either one of these conditions:

• The cancer is found in one lymph node region (stage I).

• The cancer has invaded one extralymphatic organ or site (identified using the letter “E”) but not any lymph node regions (stage IE).

Stage II: Either one of these conditions:

• The cancer is in two or more lymph node regions on the same side of the diaphragm (stage II).

• The cancer involves a single organ and its regional lymph nodes, with or without cancer in other lymph node regions on the same side of the diaphragm (stage IIE).

Stage III:

• There is cancer in lymph node areas on both sides of the diaphragm (stage III).

• There may also be involvement of an extralymphatic organ (stage IIIE), the spleen using the letter “S” (stage IIIS), or both (stage IIIES).

Stage IV: Lymphoma is called stage IV if it has spread throughout organs beyond the lymph nodes. Common sites for spread are the liver, bone marrow, or lungs.

Progressive or recurrent: Progressive disease is present if the cancer becomes larger or spreads while the patient is being treated for the original lymphoma. Recurrent lymphoma is lymphoma that comes back after treatment. It may return in the area where it first started or in another part of the body. Recurrence may occur shortly after the first treatment or years later.

Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer-Verlag New York, www.cancerstaging.net.

International Prognostic Index

In addition to stage, a scale called the International Prognostic Index (IPI) is important in planning treatment for aggressive lymphomas. The IPI was developed based on evidence from thousands of patients with lymphoma. The results showed that certain features could help predict how successful treatment will be, with patients classified into low-risk or high-risk groups depending on the risk factors listed below that they do or do not have.

Features that the IPI identifies as risk factors:

• Age 60 or older

• Stage III or stage IV disease

• Blood test results showing higher than normal levels of LDH (a group of enzymes called lactate dehydrogenase)

• Lower overall health or performance status

• Presence of cancer in multiple organs or sites outside the lymph node region

• For patients with follicular lymphoma, additional features, such as the level of a patient’s hemoglobin and the number of lymph node groups involved, are also used.

These factors are used to estimate the chance of cure. For noncurable lymphoma, they help to predict how aggressive the lymphoma will be for a patient. This index is now used widely to help doctors make decisions about treatment.

Functional status

To determine a patient’s prognosis, the doctor may also test how well a patient is able to function and carry out normal activities by using a functional assessment scale, such as the Eastern Cooperative Oncology Group (ECOG) Performance Status or the Karnofsky Performance Scales (KPS).

ECOG Performance Status. A lower score indicates a better functional status. Typically, the better someone is able to walk and care for themselves indicates a better prognosis.

0 Fully active, able to carry on all pre-disease performance without restriction

1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work

2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours

3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours

4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair

5 Dead

KPS. A higher score indicates a better functional status.

100 Normal, no complaints, no evidence of disease

90 Able to carry on normal activity; minor symptoms of disease

80 Normal activity with effort; some symptoms of disease

70 Cares for self; unable to carry on normal activity or active work

60 Requires occasional assistance but is able to care for needs

50 Requires considerable assistance and frequent medical care

40 Disabled: requires special care and assistance

30 Severely disabled; hospitalization is indicated, but death not imminent

20 Very sick, hospitalization necessary; active treatment necessary

10 Moribund, fatal processes progressing rapidly

0 Dead

Treatment

The treatment of NHL depends on the subtype of NHL, the stage of the cancer, whether the cancer has spread, and the person’s overall health. In many cases, a team of doctors will work with the patient to determine the best treatment plan.

This section outlines treatments that are the standard of care (the best treatments available) for this specific type of cancer. Patients are also encouraged to consider clinical trials when making treatment plan decisions. A clinical trial is a research study to test a new treatment to prove it is safe, effective, and possibly better than standard treatment. Your doctor can help you review all treatment options. For more information, see the Clinical Trials section.

There are three main treatments for NHL: chemotherapy, radiation therapy, and immunotherapy. Occasionally, surgery or stem cell transplantation may play a role. Often, combinations of these treatments are used. Descriptions of these treatment options are listed below

Watchful waiting

Some patients with indolent lymphoma may not need immediate treatment if they are otherwise healthy and the lymphoma is not causing any symptoms or problems with other organs. During watchful waiting (also called watch-and-wait and active surveillance), patients are closely monitored using physical examinations, CT and PET scans, and other laboratory tests on a regular basis. Treatment begins only if symptoms or tests indicate that the cancer is progressing. There is very good evidence that, for some patients with indolent lymphoma, the watch-and-wait approach does not affect the chances of survival as long as regular and careful follow-up is performed.

Chemotherapy

Chemotherapy is the use of drugs to kill cancer cells and bone marrow. It is the primary treatment for NHL. Chemotherapy may be given by mouth or injected into a vein. Systemic chemotherapy is delivered through the bloodstream, targeting cancer cells throughout the body. Chemotherapy is given by a medical oncologist, a doctor who specializes in treating cancer with medication, or a hematologist, a doctor who specializes in treating blood disorders. Some people may receive chemotherapy in their doctor’s office; others may go to the hospital. A chemotherapy regimen (schedule) usually consists of a specific number of cycles given over a specific time.

The chemotherapy regimen used depends on the stage and type of the cancer. The most common chemotherapy combination for the initial treatment of NHL is called CHOP and contains four drugs: cyclophosphamide (Cytoxan, Clafen, Neosar), doxorubicin (Adriamycin), vincristine (Vincasar), and prednisone (a type of corticosteroid). Recent evidence has shown that for most patients with B-cell lymphoma, the addition of rituximab (see the section on monoclonal antibodies below) to CHOP gives better results than the use of CHOP alone.

The side effects of chemotherapy depend on the individual, type of drug and dose used, and how long it is taken, but can include fatigue, risk of infection, nausea and vomiting, loss of appetite, and diarrhea. These side effects can be controlled during treatment and usually go away once treatment is finished. Chemotherapy may also cause long-term side effects, also called late effects.

Learn more about chemotherapy and preparing for treatment. The medications used to treat cancer are continually being evaluated. Talking with your doctor is often the best way to learn about the medications prescribed for you, their purpose, and their potential side effects or interactions with other medications. Learn more about your prescriptions by using searchable drug databases.

Radiation therapy

Radiation therapy is the use of high energy x-rays or other particles to kill cancer cells and shrink cancerous tumors. A doctor who specializes in giving radiation therapy to treat cancer is called a radiation oncologist. Radiation treatment for NHL is usually external-beam radiation therapy, which is radiation given from a machine outside the body. It is mainly used for patients who have a tumor in the early-stage disease or have a lymph node that is particularly large (usually more than 10 centimeters). Radiation therapy is usually given following or in addition to chemotherapy. It is often given to patients who have mediastinal B-cell lymphoma, which is more similar to a tumor, lymphomas that are located in only one area of the body, or for the treatment of pain for some patients. A radiation therapy regimen usually consists of a specific number of treatments given over a specific time.

Side effects from radiation therapy may include fatigue, mild skin reactions, upset stomach, and loose bowel movements. Most side effects go away soon after treatment is finished. Radiation therapy may also cause late effects.

Learn more about radiation therapy.

Immunotherapy

Immunotherapy (also called biologic therapy) is designed to boost the body’s natural defenses to fight the cancer. It uses materials either made by the body or in a laboratory to bolster, target, or restore immune system function. Monoclonal antibodies, interferon, and vaccines are biologic therapies being tested in clinical trials as treatments for NHL.

Monoclonal antibodies. The monoclonal antibody rituximab is used to treat many different types of B-cell lymphoma. Rituximab works by targeting a molecule called CD20 that is located on the surface of all B cells and B-cell lymphomas. When the antibody attaches to this molecule, some lymphoma cells die and others appear to become more susceptible to chemotherapy. Although it is quite effective by itself, there is increasing evidence that, when added to chemotherapy for patients with most types of B-cell NHL, it is more effective than chemotherapy alone.

Radiolabeled antibodies. Radiolabeled antibodies are monoclonal antibodies with radioactive particles attached that are designed to focus radioactivity directly on the lymphoma cells. This type of drug (ibritumomab [Zevalin] and tositumomab [Bexxar] and iodine I-131 are the drugs currently available) is relatively new and much is still being learned. In general, the radioactive antibodies are thought to be stronger than regular monoclonal antibodies but more damaging to the bone marrow. This type of therapy is called radioimmunotherapy (RIT).

Interferon. Interferons are proteins that help strengthen the immune system and are given alone or together with chemotherapy for some types of low-grade lymphoma.

Learn more about immunotherapy.

Stem cell transplantation/bone marrow transplantation

A stem cell transplant is a medical procedure in which diseased bone marrow is replaced by highly specialized cells, called hematopoietic stem cells. Hematopoietic stem cells are found both in the bloodstream and in the bone marrow. Today, this procedure is more commonly called a stem cell transplant, rather than a bone marrow transplant, because blood stem cells are typically what is being transplanted (injected into a vein), not the actual bone marrow. It is a difficult treatment and is generally used only for patients with NHL whose disease is progressive or recurrent.

There are two types of stem cell transplantation depending on the source of the replacement blood stem cell: allogeneic (ALLO) and autologous (AUTO).

In AUTO transplant, the patient’s own stem cells are used. The stem cells are obtained from the patient when he or she is in remission from previous treatment. The stem cells are then frozen until they are needed, usually after the high-dose treatment (explained below) is completed.

In an ALLO transplant, stem cells are obtained from a donor whose tissue matches the patient’s on a genetic level; this testing is called HLA-typing. Most often, a patient’s brother or sister serves as the donor, although unrelated donors can serve as the donor too. Millions of people worldwide have volunteered to donate stem cells for patients who do not have matched family members; your health care team will search a computer registry to look for a match. In addition, a donation of stem cells derived from umbilical cord blood is sometimes considered if family donors are not available.

In both types, the goal of transplantation is to destroy cancer cells in the marrow, blood, and other parts of the body and have replacement blood stem cells create healthy bone marrow. In most stem cell transplants, the patient is treated with high doses of chemotherapy and/or radiation therapy to destroy as many cancer cells as possible. These high doses are used since patients who undergo this treatment have disease that has proven to be resistant to normal chemotherapy doses. Higher doses of chemotherapy are more effective against recurrent NHL than standard doses of chemotherapy. This chemotherapy and/or radiation therapy also destroys the patient’s bone marrow tissue and suppresses the patient’s immune system so that, in an ALLO transplant, the donor cells are not rejected by the body. After the high-dose treatment is given, blood stem cells are infused into the patient’s vein to replace the bone marrow and restore normal blood counts from donor cells. Sometimes, ALLO transplants can also be performed after giving lower doses or chemotherapy and/or radiation therapy that are still sufficient to suppress the immune system and allow growth of the donor cells. (These transplants, sometimes termed “mini-transplants” or “reduced intensity transplants” have less immediate side effects, allowing the procedure to be used for older patients.) It is sometimes given to patients who may not have the strength to go through the standard bone marrow transplantation process and is being studied in clinical trials to determine if it is effective to treat lymphoma.

Before recommending transplantation, doctors will talk with the patient about the risks of this treatment and consider several other factors, such as the type of cancer, results of any previous treatment, and patient’s age and general health.

For both ALLO and AUTO transplant types, the replacement cells engraft (begin to make new blood cells) and turn into healthy, blood-producing tissue in 10 days to three weeks. Destroying the patient’s own marrow reduces the body’s natural defenses, temporarily leaving the patient at an increased risk of infection. Until the patient’s immune system is back to normal, patients may need antibiotics and blood transfusions.

In ALLO transplant, another major risk is that the donor’s cells will recognize the patient’s body as foreign, causing graft-versus-host disease (GVHD). GVHD may be a serious complication of allogeneic transplants and can be fatal. Other side effects may include liver problems, diarrhea, infections, and rashes. However, GVHD can also be a benefit, in that the donor cells can recognize the cancer cells as foreign and destroy these cells, a mechanism that is one of the major reasons why ALLO transplantation generally works so well over the long term. The risk of GVHD can be reduced with exact HLA-type matching and the use of preventative drugs.

In AUTO transplant, there is little risk of GVHD because the replacement stem cells are the patient’s own cells. However, there is a risk in an autologous transplant that some of the cells that are put back into the patient could still be cancerous. Learn more about bone marrow and stem cell transplantation.

Refractory NHL and recurrent NHL treatment

If NHL is still in the body after initial treatment, the disease is called refractory NHL. As explained earlier, recurrent NHL is when the disease comes back after initial treatment. Choice of treatment for refractory and recurrent NHL depends on three factors: where the cancer is, the type of treatment given previously, and the patient’s overall health. The doctor may use chemotherapy or bone marrow transplantation or may recommend a clinical trial.

Find out more about common terms used during cancer treatment.

Clinical Trials Resources

Doctors and scientists are always looking for better ways to treat patients with NHL. A clinical trial is a way to test a new treatment to prove that it is safe, effective, and possibly better than a standard treatment. The clinical trial may be evaluating a new drug, a new combination of existing treatments, a new approach to radiation therapy or surgery, or a new method of treatment or prevention. Patients who participate in clinical trials are among the first to receive new treatments before they are widely available. However, there is no guarantee that the new treatment will be safe, effective, or better than a standard treatment.

Patients decide to participate in clinical trials for many reasons. For some patients, a clinical trial is the best treatment option available. Because standard treatments are not perfect, patients are often willing to face the added uncertainty of a clinical trial in the hope of a better result. Other patients volunteer for clinical trials because they know that finding new drugs and other therapies is the only way to make progress in treating NHL. Even if they do not benefit directly from the clinical trial, their participation may benefit future patients with NHL.

Sometimes people have concerns that, by participating in a clinical trial, they may receive no treatment by being given a placebo or a “sugar pill”. The use of placebos in cancer clinical trials is rare. When a placebo is used in a study, it is done with the full knowledge of the participants. Find out more about placebos in cancer clinical trials.

To join a clinical trial, patients must participate in a process known as informed consent. During informed consent, the doctor should list all of the patient's options, so the person understands how the new treatment differs from the standard treatment. The doctor must also list all of the risks of the new treatment, which may or may not be different than the risks of standard treatment. Finally, the doctor must explain what will be required of each patient in order to participate in the clinical trial, including the number of doctor visits, tests, and the schedule of treatment. Learn more about clinical trials, including patient safety, phases of a clinical trial, deciding to participate in a clinical trial, questions to ask the research team, and links to find cancer clinical trials.

For specific topics being studied for NHL, learn more in the Current Research section.

Side Effects

Cancer and its treatment can cause a variety of side effects. However, doctors have made major strides in recent years in reducing pain, nausea and vomiting, and other physical side effects of cancer treatments. Many treatments used today are less intensive but as effective as treatments used in the past. Doctors also have many ways to provide relief to patients when side effects do occur.

Fear of treatment side effects is common after a diagnosis of cancer, but it may be helpful to know that preventing and controlling side effects is a major focus of your health-care team. Before treatment begins, talk with your doctor about the possible side effects of the specific treatments you will be receiving, The specific side effects that can occur depend on a variety of factors, including the type of cancer, its location, the individual treatment plan (including the length and dosage of treatment), and the person’s overall health.

Ask your doctor which side effects are most likely to happen (and which are not), when side effects are likely to occur, and how they will be addressed by the health-care team if they do happen. Also, be sure to communicate with the doctor about side effects you experience during and after treatment. Learn more about the most common side effects of cancer and different treatments, along with ways to prevent or control them.

In addition to physical side effects, you may experience psychosocial (emotional and social) effects as well. Learn more about the importance of addressing such needs, including concerns about managing the cost of your medical care.

Learn more about late effects or long-term side effects by reading the Late Effects and After Treatment sections or talking with your doctor.

Late Effects of Treatment

Patients who have been treated for lymphoma have an increased risk of developing other diseases or conditions later in life, as chemotherapy or radiation treatment can cause permanent damage to healthy parts of the body while it is damaging and treating the cancer. Treatments have improved in the last 30 years, and now patients who have been through treatment for lymphoma are less likely to experience late effects, but there is still some risk. Therefore, it is important that people receive follow-up care to watch for the late effects explained below.

• People who have received radiation therapy to the pelvis, high doses of cyclophosphamide, and high-dose chemotherapy for stem cell transplantation are at risk for infertility (inability to have children).

• All survivors of lymphoma have a higher risk than the general population of developing a secondary cancer; this increased risk continues for up to 20 years after treatment. The most common secondary cancers include cancer of the lung, brain, kidney, bladder, or melanoma, Hodgkin lymphoma, or leukemia.

• Women who received radiation therapy to the chest have an increased risk of breast cancer.

• Patients who receive doxorubicin-based chemotherapy or radiation treatment to the chest may be at higher risk for developing heart problems.

• Adults who receive certain types of chemotherapy (alkylating agents and methotrexate [multiple brand names]) or radiation treatment to the chest area may be at risk for lung damage and shortness of breath later in life.

• Patients who receive radiation treatment to the neck are at increased risk for thyroid deficiency (low levels of the hormones made by the thyroid) later in life.

• Patients who receive bone marrow transplantation or peripheral blood stem cell support may be at higher risk for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

• Children who receive radiation treatment and chemotherapy to the brain and spinal cord area may be at risk for growth problems, learning disabilities, and delayed puberty. Teenagers who receive chemotherapy may be at higher risk for low sperm counts (for boys) or damage to the ovaries (for girls).

• Children who receive total body irradiation (TBI) as part of the stem cell transplantation process may experience thyroid problems.

Learn more about late effects of cancer treatment.

After Treatment

After treatment for NHL ends, talk with your doctor about developing a follow-up care plan. This plan may include regular physical examinations and/or medical tests to monitor your recovery for the coming months and years. For the first two years, visits to the doctor are usually every two or three months. If there is no evidence of disease, patients will not have to see the doctor as often, but should still return at least once a year for a checkup. Normally, follow-up visits are most frequent in the first three years after treatment. Follow-up visits should continue throughout the person’s lifetime.

ASCO offers cancer treatment summary forms to help keep track of the cancer treatment you received and develop a survivorship care plan once treatment is completed.

People recovering from NHL are encouraged to follow established guidelines for good health, such as maintaining a healthy weight, not smoking, eating a balanced diet, and having recommended cancer screening tests. Talk with your doctor to develop a plan that is best for your needs. Moderate physical activity can help rebuild your strength and energy level. Your doctor can help you create an appropriate exercise plan based upon your needs, physical abilities, and fitness level. Learn more about healthy living after cancer.

Find out more about common terms used after cancer treatment is complete.

Current Research

Research for NHL is ongoing. The following advances may still be under investigation in clinical trials and may not be approved or available at this time. Always discuss all diagnostic and treatment options with your doctor.

Gene profiling. As scientists learn more about the genetics and the specific role that gene mutations (changes) have in the development of cancer, they are better able to classify and diagnose subtypes of NHL. These gene profiling methods can help estimate prognosis for patients with certain types of lymphoma and are used primarily in lymphoma research, but in the next few years it is likely that treatments will be designed that work against specific genetic changes and counteract their effects.

Immunotherapy. Many new antibodies are being developed that boost the body’s natural defenses against cancer. Some use antibodies that attach to the surface of tumor cells. Some have radioactive substances attached that can direct radiation treatment to the lymphoma.

Targeted therapies. There are many new targeted treatments for lymphoma in early clinical trials and being studied in laboratories. Targeted therapies are drugs that have been developed against specific genes or proteins within the lymphoma cells that are thought to be important in the development of cancer. It is hoped that because these drugs are directed against very specific targets that found only in lymphoma cells, they will have fewer side effects than chemotherapy or radiation therapy.

Vaccines. Several therapeutic vaccines have been studied in clinical trials, mostly for low-grade lymphoma. They are not meant to prevent lymphoma, but to lower the chance that a lymphoma will come back after treatment with chemotherapy or antibody therapy. So far, results from vaccines have been disappointing but research is continuing to make better vaccines.

Other advances. Different combinations of chemotherapy agents and different chemotherapy schedules (sometimes with antibodies or radiolabeled antibodies) are being studied in clinical trials. Also, many new drugs that work differently from standard chemotherapy are now being evaluated in clinical trials. The use of different types of stem cell transplantation, including allogeneic or mini-allogeneic transplants, is also being tested for patients with newly diagnosed disease, and for those who have had a recurrence after the initial treatment. For many types of lymphoma, the best way to use stem cell transplantation is still uncertain, which is why clinical trials of this treatment are in progress.

To find clinical trials specific to your diagnosis, talk with your doctor or search online clinical trial databases now.

Questions to Ask the Doctor

Regular communication with your doctor is important in making informed decisions about your health care. Consider asking the following questions of your doctor:

• Which type and subtype of lymphoma do I have?

• Did a pathologist experienced in the diagnosis of lymphoma review the biopsy?

• Can you explain my pathology report (laboratory test results) to me?

• How many patients do you see with this type of lymphoma each year?

• Where in my body has the disease spread?

• What stage is the lymphoma? What does this mean?

• What are the treatment options? What is the goal of each treatment?

• Will I need surgery?

• Will I need radiation therapy?

• Will I need chemotherapy?

• What is immunotherapy? Is this treatment appropriate for me?

• What clinical trials are open to me?

• Who will be part of my health care team, and what does each member do?

• Who will be coordinating my overall treatment and follow-up care?

• Why is it sometimes appropriate to “watch and wait?” Is this an option for me?

• What treatment plan do you recommend?

• Is my lymphoma curable? If so, what are the chances for a cure?

• What are the possible side effects of this treatment, both in the short term and the long term?

• How will this treatment affect my daily life? Will I be able to work, exercise, and perform my usual activities?

• If I’m worried about managing the costs related to my cancer care, who can help me with these concerns?

• Will this affect my ability to have children in the future?

• Should I get a second opinion? Will this include a specialized pathologist reviewing the biopsy?

• What caused my lymphoma?

• How can I stay as healthy as possible during and after treatment?

• What follow-up tests will I need, and how often will I need them?

• What support services are available to me? To my family?

Patient Information Resources

In addition to Cancer.Net, there are other sources of information about this type of cancer available online. Cancer.Net maintains a list of national, not-for-profit organizations that may be helpful in finding additional information, services, and support. As always, be sure to talk with your doctor about questions you may have about information you find about this disease.

View organizations that offer information on this specific type of cancer.