The non-Hodgkin's lymphomas (NHL) are a group of cancers that develop in the body's lymphatic system. There are many different types of non-Hodgkin's lymphoma. Most types of NHL involve B cells, while a small percentage involve T cells. Common types of B-cell non-Hodgkin's lymphomas include diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma.
Non-Hodgkin's lymphomas are classified as indolent (slow-growing) or aggressive (fast-growing). Aggressive lymphomas, such as DLBCL, are often curable. Indolent lymphomas, such as follicular lymphoma, are more difficult to treat and tend to recur after periods of remission. With the advancement of new treatments and drugs, survival rates for patients with NHL have significantly improved.
The risk of NHL increases with age. Most patients are diagnosed when they are in their 60s and 70s. However, NHL can develop in people of any age, including children. People who have immune system impairment because of infections, disease, or exposure to certain types of chemicals appear to have increased risk. Still, people without any known risk factors can develop NHL.
The most common first sign of lymphomas is painless enlargement of one or more lymph nodes, usually in the neck, armpits, or groin.
More generalized symptoms can include:
NHL is diagnosed based on the results of physical examination, blood tests, imaging tests, and biopsy. A lymph node biopsy is the definitive test for diagnosing NHL, determining the type of NHL, and distinguishing NHL from Hodgkin's disease.
Radiation, chemotherapy, monoclonal antibodies (such as rituximab, or Rituxan), and targeted therapies are the main treatments for NHL. For some patients, stem cell transplantation may be an option.
Lymphomas are malignancies of the lymph system that are generally subdivided into two groups: Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Hodgkin's disease accounts for about 10% of all lymphomas, and NHL for the remaining 90% of lymphomas.
Non-Hodgkin's lymphoma is a term for malignancies that range from a very slow disease to an extremely aggressive but curable condition. They have certain features in common.
The lymphatic system filters fluid from around cells. It is an important part of the immune system. When people say they have swollen glands in the neck, they are usually referring to enlarged lymph nodes. Common areas where lymph nodes can be easily felt, especially if they are enlarged, include the groin, armpits (axilla), above the clavicle (supraclavicular), in the neck (cervical), and the back of the head just above hairline (occipital).
Lymphomas, such as non-Hodgkin's lymphomas and Hodgkin's disease, represent tumors of the lymphatic system. This system is a network of organs, ducts, and nodes. The lymphatic system interacts with the blood's circulatory system to transport a watery clear fluid called lymph throughout the body. The lymphatic system contains lymphocytes, important cells involved in defending the body against infectious organisms.
Non-Hodgkin's lymphomas occur most often in lymph nodes in the chest, neck, abdomen, tonsils, and the skin. NHL may also develop in sites other than lymph nodes such as the digestive tract, central nervous system, and around the tonsils.
There are more than 30 distinct types of non-Hodgkin's lymphomas. Lymphomas are categorized in a several ways:
The following are common types of B-cell lymphoma.
Non-Hodgkin'non-Hodgkin's lymphomas, and about 19,000 people die of the disease. Since the 1970s, NHL incidence rates have doubled. Part of the reason for this dramatic rise may be due to AIDS, which increases the risk for high-grade lymphomas.
The cause of non-Hodgkin's lymphoma is unknown, but certain factors may increase a person's risk of developing this cancer.
Non-Hodgkin's lymphoma can develop in people of all ages, including children, but it is most common in adults. The most common types of NHL usually appear in people in their 60s and 70s.
NHL is more common in men than women. In the United States, NHL is the sixth most common cancer in men, and the seventh most common cancer in women.
Overall, the risk for NHL is slightly higher in Caucasians than in African-Americans and Asian Americans.
People who have close family relatives who have developed NHL may be at increased risk for this cancer. However, no definitive hereditary or genetic link has been established.
Viral or bacterial infections may play a role in some lymphomas. These include:
Patients with diseases or conditions that affect the immune system may be at higher risk for lymphomas:
Patients with a history of autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus, Hashimoto's thyroiditis, Crohn's disease, and Sjögren's syndrome, are at an increased risk for certain NHLs, such as marginal zone lymphomas.
Overexposure to a number of industrial and agricultural chemicals (such as pesticides, herbicides, and petrochemicals) has been linked to an increased risk for lymphomas. The data, however, are not consistent.
Researchers are investigating whether some chemotherapy drugs may increase the risk for later developing non-Hodgkin's lymphoma. At this point, it is not clear whether it is these drugs or the other cancers themselves that increase risk. Other types of drugs, such as tumor necrosis factor (TNF) inhibitors that are used to treat autoimmune disorders, are also being studied as possible risk factors for lymphomas.
People who have had radiation treatment for cancers such as Hodgkin's disease appear to have an increased risk for later developing non-Hodgkin's disease. The risk may be higher for patients treated with both chemotherapy and radiation.
Survivors of nuclear reactor disasters have an increased risk of developing NHL, as well as other types of cancers.
Lifestyle does not seem to be a major risk factor for NHL. Some studies have suggested that obesity may increase risk, but this association is not definite. Other studies have investigated the role of diet. Although some research has indicated an increased risk for diets high in consumption of red meat and lower risk for diets high in vegetables, the association remains speculative. There is no evidence that smoking increases the risk for NHL itself, although it has been linked with high-grade and follicular NHLs in people with lymphoma.
The most common first sign of lymphoma is painless enlargement of one or more lymph node, usually in the neck, armpits, or groin. These enlarged lymph nodes may cause discomfort depending on where they are located. For example, abdominal tumors may cause stomach distention or pain, while lymph nodes in the chest may cause coughing or difficulty breathing. Patients should see their doctors if these symptoms do not go away within 2 to 3 weeks.
Sometimes patients with NHL do not experience any symptoms, or symptoms may not appear until the cancer is very advanced. Enlarged lymph nodes can also be caused by many noncancerous conditions, such as infections.
The most common lumps or swellings in the neck are enlarged lymph nodes. They can be caused by bacterial or viral infections, cancer, and other rare causes.
Lymphomas sometimes cause systemic symptoms -- symptoms that affect the whole body, rather than a specific location. Some systemic generalized symptoms are referred to as B symptoms. Patients who have B symptoms have a more severe condition than asymptomatic patients with the same cancer stage or tumor location or size.
B systemic symptoms include:
The doctor will first ask questions about the patient's medical history and perform a physical examination to detect any node enlargements. If these procedures indicate lymphoma, additional tests will be done to rule out other diseases or to confirm the diagnosis and extent of the lymphoma.
The doctor will examine not only the affected lymph nodes but also the surrounding tissues and other lymph node areas for signs of infection, skin injuries, or tumors. The consistency of the node sometimes indicates certain conditions. For example, a stony, hard node is often a sign of cancer, usually one that has metastasized (spread to another part of the body). A firm, rubbery node may indicate lymphoma. Soft tender nodes suggest infection or inflammatory conditions.
A biopsy is the most important test for diagnosing non-Hodgkin's lymphoma and determining the subtype. Tissue samples retrieved from biopsy are examined under a microscope to find out if the cell type involved indicates Hodgkin's disease or non-Hodgkin's. (Hodgkin's disease is marked by the presence of Reed-Sternberg cells, which are not found in non-Hodgkin's lymphomas.) Sometimes a doctor may choose to wait and observe the involved lymph nodes, which will usually go away on their own if a temporary infection is causing the swelling. (However, some lymphomas may go away and appear to be benign, only to reappear at a later time.)
Bone marrow aspirate and biopsy are routinely performed to determine whether the disease has spread. With bone marrow aspirate, bone marrow cells are sucked out through a special needle. A biopsy may be performed before or after the aspiration. In this procedure, a special needle removes a core of the marrow that is structurally intact.
Blood tests help rule out infection and other diseases. Such tests include a complete blood count to measure the number of white blood cells. In a patient already diagnosed with lymphoma, blood tests that measure the enzyme lactate dehydrogenase are important in determining the prognosis of patients with fast-growing lymphomas. High levels indicate bulkier tumors.
Tests of lymphoma's DNA are in use or are being developed to detect particular gene defects that help determine prognosis and response to treatment. Examples of such abnormal genetic arrangements are those that affect normal cell death, resist chemotherapy, or trigger aggressive cancer growth.
Survival rates for NHL vary widely, depending on the lymphoma type, stage, age of the patient, and other variables. According to the American Cancer Society, the overall 5-year relative survival rate for patients with non-Hodgkin's lymphoma is 68% and the 10-year relative survival rate is 57%. (The relative survival rate estimates the likelihood that a patient will survive a certain number years after diagnosis. It is calculated to exclude the likelihood of death from diseases other than the cancer.)
Because so many different factors affect survival, it is difficult to make general statements about prognosis. For example, patients with very slow growing (indolent) lymphomas can live many years. However, they are usually diagnosed at a late stage, after the cancer has spread, which gives a poorer outlook. Without treatment, aggressive lymphomas are more likely to cause early death, but they are also often curable. In fact, aggressive lymphomas usually have better chances for cure than indolent lymphomas.
Survival rates for patients with all types of NHL have greatly improved since the early 1990s, especially for patients under age 45. Advances in treatment have contributed to this improvement.
Follicular lymphomas, the most common indolent (slow-growing) NHLs, are potentially curable in early stages I and II. Unfortunately, these slow-growing malignancies may not produce symptoms until they are in advanced stages. In most cases, these lymphomas are not diagnosed until they have spread to other sites, including the spleen and bone marrow. In such cases, they are difficult to cure. Predicting outcome for indolent follicular lymphomas is more difficult than for aggressive lymphomas. Even if treatment achieves a response, these tumors almost always recur. Even after relapse, however, the tumors can be treated again if they are still very slow-growing.
In general, the average survival rate for follicular lymphoma is 7 to 10 years after diagnosis, depending on other risk factors. New drug treatments, particularly monoclonal antibodies, have significantly improved survival rates.
High-grade aggressive lymphomas are often symptomatic early on and are potentially curable with aggressive treatments. Diffuse large B-cell lymphoma (DLBLC), the most common aggressive non-Hodgkin's lymphomas, while fatal if not treated, is often curable with intensive chemotherapy combinations. If relapse occurs after chemotherapy, it usually does so within 2 years.
Most other aggressive lymphomas respond to aggressive chemotherapy. Some aggressive lymphomas, such as mantle cell lymphoma, are sometimes less responsive to standard chemotherapy.
Doctors often use a scoring system called the International Prognostic Index for predicting outcome in patients with more aggressive B-cell lymphomas such as DLBCL. It uses five risk factors to help predict survival odds:
Having one or none of these risk factors indicates the best outlook. Two factors indicate a low-to-intermediate likelihood of a poor outlook. Three factors predict an intermediate-to-high likelihood of poor outlooks. Finally, four or five factors pose the highest likelihood of poor survival. However, the International Prognostic Index was developed before the introduction of newer drug therapies like rituximab, which has dramatically improved the outcome of patients with DLBCL. A newer version of the index has been developed since the use of rituximab became more widespread.
A similar prognostic index is used for follicular lymphoma.
The radiation and chemotherapy treatments used for treating NHL can potentially have long-term effects on many organs in the body and can increase the risk for serious illnesses, including heart disease and certain cancers. Other long-term effects of cancer treatments include somatic symptoms such as fatigue and generalized aches and pains.
Some cancer treatments can cause infertility. Patients who may wish to have children in the future should ask their doctors about fertility-preserving treatments. It is very important to have these discussions before cancer treatment starts. The American Society for Clinical Oncology (ASCO) has guidelines for the best fertility preservation methods for male and female cancer patients. They include sperm freezing and banking (sperm cryopreservation) for men, and egg (oocyte) and embryo cryopreservation for women.
Treatment for non-Hodgkin's lymphoma is highly specific for each patient and is determined by the tumor classification. It includes the following factors:
Grading refers to how fast the tumor cells grow and divide, and for how fast the tumor itself spreads. In NHL, indolent lymphomas are slow growing and referred to as low grade. Aggressive lymphomas are fast growing and referred to as high grade. Aggressive lymphomas are considered more curable than indolent lymphomas. Indolent lymphomas may respond to treatment but tend to recur. (Recurrence is also called relapse.)
Staging refers to where the tumor is contained and where it has spread. The stages of non-Hodgkin's lymphoma are:
The main treatments for non-Hodgkin's lymphoma are:
In early stages of lymphoma, doctors may recommend watchful waiting where treatment is delayed until symptoms appear or worsen. Treatment for lymphomas generally uses chemotherapy (particularly intensive regimens using several drugs) or a combination of chemotherapy and radiation. Monoclonal antibody biologic drugs, (a treatment approach also called immunotherapy), are now being used more frequently in combination with chemotherapy drugs. Transplantation is mainly used to treat patients who relapse. Surgery is not a usual treatment option.
Patients may also wish to consider enrolling in a clinical trial that tests new and experimental drugs or treatments.
In assessing the success of a clinical trial, doctors often refer to the tumor response. A complete response, for example, means that there is no longer any evidence of the disease by examination, blood tests, or x-ray studies. It does not necessarily mean that the disease is cured. It may still recur later on.
Imaging such as CT scans, MRI scans, or a PET may be done after a course of chemotherapy. At times, a PET scan may be done after just 1 to 3 cycles of chemotherapy (but before the full course of chemotherapy is completed) to assess if it appears there is a response. A change in the chemotherapy regimen may be instituted if it does not appear the tumor is improving after the PET scan.
In judging the success of a treatment for NHL, the most important criteria are overall survival and the duration of time until the disease progresses or the patient dies.
Chemotherapy plays a role in the treatment of nearly all patients with lymphoma and has achieved remarkable results, even in late stages. It uses drugs to kill cancer cells. Such drugs are called cytotoxic drugs. Chemotherapy is referred to as systemic therapy because the drugs travel throughout the bloodstream to the entire body.
Chemotherapy may also be used along with radiation.
A chemotherapy cycle is usually 21 to 28 days. Patients take the drugs for a few days, then have a period of rest. The drugs may be taken as pills at home or given by injection or infusion in a medical center or doctor's office. Chemotherapy is injected into the spinal fluid if the cancer has spread to the brain. This approach is called intrathecal chemotherapy. Intrathecal chemotherapy is also used as a preventive measure in patients at high risk for central nervous system involvement. Some patients receiving chemotherapy need to remain in the hospital for several days so the effects of the drug can be monitored.
Side effects and complications of any chemotherapeutic regimen are common. They are more severe with higher doses. Side effects may increase over the course of treatment. Radiation treatment may worsen chemotherapy side effects.
Common side effects include:
These side effects are nearly always temporary. Most patients are able to continue with normal activities for all but perhaps a few days a month.
Serious chemotherapy side effects can also occur and may vary depending on the specific drugs used. They include:
In general, these serious late side effects depend on the type of drug used and cumulative drug dose.
Biological response modifier therapy, also called immunotherapy, uses the body's own immune system to fight cancer. These biologic drugs are often combined with other treatments.
Monoclonal antibodies (MAbs) are the main drugs used in biologic therapy. MAbs are designed in the laboratory to mimic the body's natural antibodies and attack specific antigens (foreign substances) produced by the cancer. Lymphomas carry antigens that provoke strong immune responses and so are particularly good candidates for MAb therapy.
Rituximab (Rituxan) was the first monoclonal antibody approved for cancer. This drug targets the CD-20 antigen, which is found on most B-cell lymphomas. It is the most commonly used biologic drug, particularly in combination with standard chemotherapy regimens.
Rituximab is used to treat many types of CD20-positive tumors. Rituximab is used as a single drug or in combination with chemotherapy for low-grade or follicular lymphoma. It is also used in combination with other drugs for other types and stages of lymphomas including diffuse large B-cell (DLBC). Rituximab in combination with CHOP (a regimen called R-CHOP, or CHOP-R) is used for first-line treatment of aggressive lymphomas.
Rituximab is given by infusion. The treatment has mild-to-moderate short-term side effects, including nausea, fever, chills, hives, dizziness, and headache. Uncommon and more serious side effects are severe allergic reactions, very low blood pressure, blood abnormalities, wheezing, infections, and sudden heart events.
Rituximab has also been associated with cases of progressive multifocal leukoencephalopathy (PML), a rare and potentially deadly brain disorder. Patients who experience any of the following symptoms should immediately contact their doctors:
Patients who have previously had hepatitis B, or who are at high-risk for this viral infection, should be tested before taking rituximab because the drug has been linked to reactivation of the hepatitis B virus. Patients who are HIV-positive may experience more adverse effects from rituximab than with CHOP alone.
Some newer MAbs are used to treat NHL by attaching radioactive molecules to them. When the drug is injected, the monoclonal antibody targets an antigen (protein) on the surface of the tumor. The radioisotope is then delivered directly into the tumor where it kills the cancer. Ibritumomab targets the CD-20 antigen. Treatment takes about 7 to 9 days to complete, compared to several months for traditional chemotherapy treatments.
In general, these drugs cause fewer side effects than traditional chemotherapy. However, serious complications may include skin infections, severe allergic reactions, and temporary lowering of blood counts. Due to the radioisotope component, these drugs are also more difficult to administer than rituximab. They tend to be used if patients do not respond to rituximab.
Three biologic drugs are FDA-approved for treatment of mantle cell lymphoma:
Radiation therapy uses high-energy x-rays to kill cancer cells and shrink tumors. It may also be used as palliative therapy to relieve symptoms in advanced cancer. Radiation may be used as the sole therapy for some early-stage (I or II) lymphomas, or may be used along with chemotherapy for later-stage (III or IV) lymphomas.
Radiation is tailored to the individual and usually limited to the diseased areas and possibly nearby regions:
Fatigue, nausea, diarrhea, dry mouth, skin irritation, and increased risk for infections are common short-term side effects of radiation therapy. These side effects generally clear up after treatment is completed.
Radiation therapy can cause more serious long-term complications. These side effects generally depend on the radiation target site in the body. They include:
Stem cell transplantation involves removing and replacing
Stem cell transplantation usually follows an intensive regimen of high-dose chemotherapy, which is sometimes given along with radiation. The goal of the high-dose chemotherapy is to destroy as many cancer cells as possible, including cancer cells that have been resistant to standard-dose treatment. However, high-dose chemotherapy also destroys bone marrow and the stem cells it contains. Transplantation allows for the re-introduction of healthy blood-forming stem cells.
Stem cells must first be collected in one of the following ways:
Peripheral blood stem cell transplantation is the most commonly performed type of stem cell transplantation. .
The marrow or blood stem cells can be taken from the patient (autologous) or from a matched donor (allogeneic):
With peripheral blood stem cell transplantation:
Blood transports oxygen and nutrients to body tissues, and returns waste and carbon dioxide. Blood also distributes nearly everything that is carried from one area in the body to another place within the body. For instance, blood helps transport hormones from the endocrine organs to their target organs. Blood also helps maintain body temperature. The protective functions of blood include clot formation and the prevention of infection.
Stem-cell transplantation is a serious and complex procedure that can cause many short- and long-term side effects and complications.
Early side effects of transplantation are similar to chemotherapy and include nausea, vomiting, fatigue, mouth sores, and loss of appetite. Bleeding due to reduced platelets is a high risk during the first four weeks.
Later side effects include fertility problems (if the ovaries are affected), thyroid gland problems (which can affect metabolism), lung damage (which can cause breathing problems) and bone damage. In younger people, there is a small long-term risk for development of secondary cancers such as leukemia.
Two of the most serious complications of transplantation are infection and graft-versus-host disease.
Many patients develop severe herpes zoster virus infections (shingles) or have a recurrence of herpes simplex virus infections (cold sores and genital herpes). Pneumonia, and infection with germs that normally do not cause serious infections such as cytomegalovirus, aspergillus (a type of fungus), and Pneumocystis jiroveci (a fungus) are among the most important life-threatening infections.
Too much sun exposure can trigger GVHD. Be sure to always wear sunscreen (SPF 15 or higher) on areas of the skin that are exposed to the sun. Stay in the shade when you go outside.
It is very important to take precautions to avoid infections. Guidelines for post-transplant infection prevention include:
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Reviewed By: Todd Gersten, MD, Hematology/Oncology, Florida Cancer Specialists & Research Institute, Wellington, FL. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Isla Ogilvie, PhD, and the A.D.A.M. Editorial team.