Non-Hodgkin lymphoma refers to a group of cancers that arise in the cells that are part of the body's lymphatic system. The lymph system plays a crucial role in fighting infection and disease in our bodies. It is a complex, intricate operation, but basically it consists of a network of channels or tubes that carry lymph, a fluid that contains the white blood cells. There are a number of different kinds of white blood cells, each with a specific role. These include
Lymphomas can originate in any of these white blood cells. When a lymphoma begins, the affected cells begin to grow and reproduce in an uncontrolled way. They produce too many copies of themselves. The cells are often abnormal in their appearance and function and disobey the body's signals to stop dividing or to die in a scheduled way.
Lymphomas begin in blood cells but they can form solid tumors in the lymph nodes, little bean shaped organs that appear in clusters throughout our bodies, in organs involved in producing blood cells, the spleen and bone marrow, or just about any organ in the body.
In the United States, there are approximately 70,000 new cases of NHL each year. NHL is the sixth leading cause of cancer in men and the fifth in women, accounting for 4-5% of all new cancer cases, and 3-4% of cancer deaths. The number of new cases of NHL increased dramatically in the United States between 1970-1995, but has leveled off since the mid-90s. Researchers attribute this increase to two main causes.
Because there are so many types of NHL, and they can affect so many different organs in the body, there isn't one set of signs or symptoms that indicate the possibility that you might have one of these cancers. The possible symptoms include:
None of these signs and symptoms are specific to NHL. If you are having these problems, you should discuss your concerns with your doctor.
The process of accurately diagnosing and staging NHL is complicated, but it begins with a physical examination and medical history, and requires a biopsy. Diagnosis is the process of identifying exactly what kind of NHL you have; staging is done to determine the extent of the disease once the diagnosis is made. Both are critical in planning your treatment.
The biopsy consists of obtaining cells from the tumor and examining them under the microscope. If you have an enlarged lymph node in your neck, groin or under your arm, it is a relatively simple procedure to remove that node for the pathologist to examine. If the tumor is harder to reach, say in your lung or stomach, it may be necessary to use other techniques to get enough cells to make a diagnosis. Many of these biopsies can be done using imaging techniques, such as endoscopy that allow the doctor to see the area and take a tissue sample. You may also need a biopsy of your skin depending on the subtype of lymphoma.
Once the pathologist identifies the cells as being NHL, you will need a number of blood and laboratory tests. Doctors will also take your overall health and any other medical conditions you have into account when they make decisions about treatment. Depending on what kind of NHL you have and where it is located, you may have different kinds of imaging, including CT scans, PET scans, MRI and/or ultrasound.
In almost every case, you will need a bone marrow biopsy and aspiration to determine if the NHL has spread to the bone marrow. In a bone marrow biopsy, the doctor uses a needle to remove a small amount of the solid tissue inside your bones. An aspiration removes fluid from the bone marrow. The most common site for these procedures is the crest of the pelvic bone, located in the lower back.
Patients diagnosed with NHL should also be tested for Hepatitis B because some of the drugs used to treat the cancer can reactivate the hepatitis.
There are many different types of NHL. Some are identified by specific chromosomal changes, genetic mutations or other factors unique to that subtype. Molecular testing has become an important part of the diagnostic process for NHL--and many other forms of cancers.
As doctors have become more knowledgeable about both normal and abnormal cells and the ways that our immune system works, they have also become specific about the types of NHL that exist. NHLs are divided by the type of cell in which they arise and by how aggressive or non-aggressive they are. The subtypes are also identified by the molecular and genetic factors described above. The basic divisions are:
Lymphomas are also classified as:
Indolent (low grade) NHL: These lymphomas grow slowly and often cause few symptoms. Most patients diagnosed with indolent lymphomas have cancers which have spread at the time they are discovered. Indolent lymphomas generally respond well to various kinds of treatment--and sometimes don't even need to be treated until they begin to grow. Indolent lymphomas often come back months or years following the end of treatment, and are then treated again. Many patients live for long periods of time with these NHLs.
Aggressive (high grade) NHL: These NHLs grow and spread rapidly. They require intense chemotherapy. Because the cells are dividing and growing so rapidly, they are very susceptible to the action of anti-cancer drugs, and for this reason do have the potential to be cured.
There are multiple sub-types of both B and T cell lymphomas--as many as 70 different types in all. Distinguishing among these types can be difficult and requires a pathology team with expertise in NHL and highly specialized techniques available to evaluate the characteristics of the NHL cells. It is very important to get a complete, accurate diagnosis of the NHL and its subtype as this has a direct influence on treatment and prognosis.
More information: common subtypes of NHL: Most experts today use the NHL classification system developed by the World Health Organization. This very complex system divides types of NHL by those that arise from mature blood cells or lymphocytes, and those that arise from immature blood cells or lymphocytes. It also uses a number of genetic and clinical features to define specific subtypes.
This information can be difficult for patients to understand--and many of the specific subtypes are quite rare. The most common subtypes of NHL include:
B Cell lymphomas:
Diffuse large B-cell lymphoma (DLBCL)--About 30% of lymphoma patients have this subtype. It is an aggressive form of lymphoma but responds well to chemotherapy. Many patients. especially those whose disease is confined to a relatively small area are cured using combination chemotherapy with monoclonal antibodies. Some patients also receive radiation therapy to prevent the lymphoma from spreading to the brain. New research has shown that there are actually different subtypes of diffuse large cell B cell lymphoma, and clinical trials are underway to determine how best to treat these subtypes.
Follicular lymphoma--This is the second most common form of lymphoma in the United States, accounting for about 20% of NHL. This is a slow growing or indolent form of lymphoma, and while there is no known cure, approximately 80% of patients with this subtype live at least five years after diagnosis. Some patients are followed with watchful waiting (see Treatment), while others receive combinations of chemotherapy, monoclonal antibodies and radiation therapy. Follicular lymphoma can turn into DLBCL, which requires more aggressive treatment.
Mantle cell lymphoma--This accounts for 7% of lymphomas and most often involves bone marrow, the spleen and the gastrointestinal system. It occurs most often in people older than 60. The treatments for Mantle cell lymphoma are still evolving. Chemotherapy often doesn't work, or stops working. Newer drugs and treatment approaches are being studied in clinical trials. Some patients undergo high dose chemotherapy with stem cell transplant.
Small lymphocytic lymphoma--This is closely related to chronic lymphocytic leukemia (CLL), and affects 5% of people with NHL. It is considered an indolent lymphoma.
Mediastinal large B-cell lymphoma--This is an aggressive form of DLBCL, which appears as a large mass in the chest area. It accounts for 2.5% of NHL and is most common in women between 30 and 40 years of age.
Marginal zone B-cell lymphoma--there are several variations of this subtype, depending on the organs that are involved. Splenic marginal B-cell lymphoma begins in the spleen and is slow growing. Extranodal marginal B-cell lymphoma (MALT) most often occurs in the stomach, but can also begin in the lung, skin, thyroid or salivary gland. MALT patients often have a history of autoimmune disease. MALT that occurs in the stomach can be treated with antibiotics used to treat Heliobacter pylori infection. Other forms are treated with chemotherapy, radiation or antibodies.
Lymphoplasmacytic lymphoma--This is an indolent form of lymphoma that often involves bone marrow, lymph nodes and spleen. In many patients, this kind of lymphoma produces high levels of proteins which thicken the blood--a condition called Waldenstrom's macroglobulinemia. Treatment is similar to chronic lymphocytic leukemia and may involve watchful waiting, chemotherapy and monoclonal antibodies. or stem cell transplant.
T-cell and Natural Killer Cell Lymphomas- This type of lymphoma is more common in Asian countries. Patients often have masses in usual locations such as in the nasal area, skin, blood, or bone marrow. This type of lymphoma is treated with different chemotherapy than other types of lymphoma.
Anaplastic large cell lymphoma/primary cutaneous type--This subtype of NHL involves the skin. It can be either indolent or aggressive. Many patients are treated effectively with radiation therapy. There are also several new drugs that have been shown to be effective in treating this kind of lymphoma.
Peripheral T-cell lymphoma--This is an aggressive form of lymphoma, most commonly found in people over 60. It accounts for 6% of lymphomas in the US. It is treated much like DLBCL, described above.
Anaplastic large cell lymphoma, systemic type--this is more common in children, making up 10% of childhood lymphomas. It is an aggressive form of lymphoma but treatment works well, especially in people who have ALK-1 protein in their blood.
Precursor T-lymphoblastic lymphoma/leukemia--This accounts for 2% of NHL and is most common in young adults. This kind of lymphoma and acute lymphoblastic leukemia (ALL) are basically the same disease. When it occurs in mainly in the lymph nodes, it is classified as a lymphoma. When it occurs in the blood or bone marrow, it is leukemia. This is an aggressive disease that requires intensive treatment, see ALL.
This is not a complete list of all the NHL subtypes. There are many others--and the list continues to grow. For more information on subtypes, go to www.lymphoma.org.
Small lymphocytic lymphoma--This is closely related to chronic lymphocytic leukemia (CLL), and affects 5% of people with NHL. It is considered an indolent lymphoma.
Staging determines the extent of a cancer--how far it has spread and where. It is not the same as diagnosis which identifies the type of NHL, or grade which describes how aggressive a tumor is and how abnormal the cells are in appearance and function. NHLs are staged on a scale of I to IV. If a person has no symptoms, they are categorized as "A." If they do have symptoms, they are "B."
NHL is staged by evaluating these factors:
The stages of NHL are basically the following, although all of these stages have sub-categories which describe specific features of the cancer.
Stage I: The cancer is confined to one lymph node region or the cancer if found in one organ but has not invaded any lymph node regions. (Stage IE)
Stage II: The cancer is found in two or more lymph node regions on the same side of the diaphragm, or the cancer is found in one organ and its lymph nodes (Stage IIE)
Stage III: The cancer is found in lymph nodes of both sides of the diaphragm. There may also be involvement of an organ (Stage IIIE) or the spleen, (Stage IIIES).
Stage IV: The cancer has spread throughout the organs beyond the lymph system.
NHLs that grow during treatment are called progressive or refractory lymphomas.
NHLs that grow or spread after treatment are called recurrent.
Patients who have completed all the diagnostic tests will be given a diagnosis that identifies the specific type of NHL, its grade, and stage. That diagnosis will serve as the basis for deciding on the appropriate treatment for your cancer. The doctors will also take into account a variety of other factors including age, overall health and activity level and a variety of laboratory results and cellular features.
With all these factors, it is clear that there is no one treatment for NHL. There are many. For this reason, NHLs should be treated in centers that have multidisciplinary teams of experts available to plan and deliver the treatment and to provide the necessary supportive care. The treatments for NHL are always advancing though the clinical trials, studies that compare the current standard of treatment to new approaches. New drugs and combinations of drugs are studied as well as ways of delivering effective treatment while minimizing the short and long term side effects. NHL patients may be treated very effectively with established therapies, but they should also be aware of clinical trials and ask their doctors about whether they are candidates to participate in these trials.
The three main treatments for NHL are chemotherapy, radiation therapy and immunotherapy. In some instances, surgery and stem cell transplantation are used as well. Many patients will receive a combination of therapies during their treatment.
If a patient has a very low grade or indolent NHL, is feeling well and has no symptoms, it is sometimes possible to delay treatment. This is called watchful waiting or active surveillance. During this time, the patient is very closely monitored with scans and other tests. If the tests indicate the cancer has begun to grow or symptoms appear, then treatment begins. There is strong evidence that for patients with indolent lymphoma, watchful waiting does not have negative impact on long term survival.
Chemotherapy, the use of drugs to treat cancer, is a mainstay of treatment for many forms of lymphoma. These drugs are given in combinations that attack the cancer cells in different ways. The most common drug combination used to treat NHLs is called CHOP, but there are numerous other drugs and drug combinations that are given depending on the type and grade of the NHL, the patient's stage and previous treatments. In recent years, chemotherapy has also been combined with immunotherapy and targeted therapies. (see below).
also known as biologic therapy works to stimulate the body's own immune system to fight the cancer. The most common type of immunotherapy for NHL uses a monoclonal antibody called rituximab. Virtually all patients with B-cell lymphomas will receive rituxamab during their treatment. It works by attaching to a particular molecule on the cancer cell, causing some cancer cells to die and others to become more susceptible to the effects of chemotherapy. It can be used either by itself or in combination with anti-cancer drugs.
These are relatively new drugs that are designed to carry radioactive particles directly to the lymphoma cells. Radioactive antibodies appear to be stronger than regular monoclonal antibodies but also do more damage to the bone marrow and have more side effects.
Radiation therapy is often combined with chemotherapy especially to treat early stage lymphomas in which the cancer is confined to a small area. It can also be used to treat NHLs located in the chest area or to help control pain.
A stem cell transplant is a procedure that replaces a person's diseased bone marrow with highly specialized blood cells called hematopoietic stem cells. These cells can come either from a donor whose blood matches the patients, or is some instances, from the patient's own blood and bone marrow. If the cells come from a donor, it is called an ALLO transplant; if they are the patient's own, it is an AUTO transplant. Stem cell transplants are difficult and even life threatening procedures. In order to do inject the healthy, new marrow it is necessary to destroy the old marrow with radiation and chemotherapy--a process that can make a person very sick and susceptible to infection. ALLO transplants can also be rejected as "foreign" by the body, which can also lead to serious problems. For this reason, stem cell transplants are generally only used for NHL patients whose disease does not respond to treatment or recurs. For the right patients, stem cell transplants do offer the possibility of a long term remission.
The primary goal of treating NHL is of course to get rid of the cancer, either permanently or for as a long a period as possible. Doctors are very aware though that the treatments they use can cause side effects while they are being taken as well as long term effects. People who are treated for NHL have an increased risk of developing second cancers later in life, including leukemias and breast cancer in women who receive radiation to the chest. Treatments can also cause infertility in both men and women. Some patients also develop thyroid, heart or lung problems. One of the major goals of cancer research is to develop therapies which effectively treat the cancer but minimize both the short and long term effects on the patient.
All of these issues should be discussed with your team before, during and after your treatment. The possibility of having long term problems is another reason for making sure you are treated in a center that has expertise and experience in every phase of diagnosing, treating and caring for patients with non-Hodgkin lymphomas
NHLs are a diverse and very complex group of cancers that affect that cells of the lymphatic system. There are many types and subtypes, all of which require treatments tailored to the individual cancer. There has been real progress in recent years in understanding the biology of NHLs--knowledge that is rapidly being turned into new and improved treatments for these cancers. NHLs, however, remain, in many ways difficult to diagnose accurately and treat appropriately. Every patient with a suspected or diagnosed NHL should be seen by a multidisciplinary medical team that has the expertise and experience to offer the best available treatments.