Carolyn Vachani RN, MSN, AOCN
Updated by: Lara Bonner Millar, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: August 24, 2011
The lymph system is essentially the "housekeeping system" of the body. It is a network of vessels (tubes), which connect the lymph nodes. These nodes can vary in size, but are normally up to about 2 centimeters in width. They contain cells that clear bacteria and other foreign debris from the body. Lymph is a watery liquid that flows between cells in the body, picking up foreign debris and taking it into the lymph node for filtering. From the lymph node, the debris may pass through several more nodes in the system before being dumped into the bloodstream to ultimately be cleared by the liver. The lymph system flows throughout the body, and also includes the spleen and thymus gland.
Lymphocytes are a type of white blood cell. These cells (called B cells and T cells) are important in fighting infection and mount what is called the "immune response." B cells produce proteins called antibodies, which move through the bloodstream and attack a specific target as directed by the B cell. They start their lives in the bone marrow and then develop fully in the lymph nodes. T cells are developed in the thymus gland and directly attack the cells identified as foreign by the B cells. In addition, both of these cells are able to remember bacteria from previous infections, and thus respond quicker to future infections.
Simply put, the non-Hodgkin's lymphomas (NHLs) are a group of cancers that affect the immune system, the very system that is supposed to protect our body against disease. NHLs begin in the lymph nodes and are made up of malignant (cancerous) lymphocytes (either B cells or T cells). In 2001, the World Health Organization developed a comprehensive classification system for the 30+ different types of non-Hodgkin's lymphomas (NHLs), which are then further divided according to the cell type involved (either B cell or T cell). (See WHO classification at the end of this article) These 30+ types of NHLs are different in their growth rates and aggressiveness, and are often treated differently.
In the U.S., B cell lymphomas account for about 90% of all NHL cases, but this rate varies in different regions of the world. Nationally, there are approximately 66,000 new cases each year, making NHL the fifth most common cancer in both men and women. Rates have been increasing 3-4% annually in the U.S. since the 1950's, but incidence varies widely throughout the world. For instance, in the United Kingdom, there are approximately 10 cases for every 100,000 people, whereas in Asia there are only 2 cases for every 100,000 people, compared to approximately 20 per 100,000 in the U.S. NHL is slightly more prevalent in males than females: 55% of lymphomas are diagnosed in men. The average age at diagnosis is 65 years and only 5% of cases occur in children.
The non-Hodgkin's lymphomas should not be confused with Hodgkin's disease, as these are two distinct diseases. Although Hodgkin's disease also occurs in the lymph system, doctors are able to differentiate between the two because of the presence of Reed-Sternberg cells in Hodgkin's tumors. (Read about Hodgkin's disease in adults or in children).
The actual cause of NHLs is still unknown in most cases, but there are some factors known to increase a person's risk. These factors are related to the immune system, and cause either a chronic decrease or chronic increase in immune response. Certain viruses and bacteria increase the risk of certain types of NHLs, possibly because they cause a long-term increase in immune response. For instance, MALT lymphoma is associated with Helicobacter pylori infection, the same bacteria that causes stomach ulcers. Epstein-Barr (EBV) virus is associated with 30% of Burkitt's lymphoma cases in the U.S., but 95% of Burkitt's cases are in Africa, and nearly all of these cases are associated with EBV. This points to the fact that there are genetic differences in the types of Burkitt's (and probably all NHLs) found in different areas of the world. Other viruses thought to increase risk include: human T-cell leukemia/lymphoma virus 1 (HTLV-1), human herpes virus 8 (HHV-8), and hepatitis C virus.
Suppression of the immune system is thought to cause increased risk of NHLs. This includes infection with the human immunodeficiency virus (HIV), organ or bone marrow transplant (requiring immune suppression medications), rheumatoid arthritis, and inherited immune deficiencies. The use of pesticides and herbicides was studied by the National Academy of Sciences (NAS) as a risk factor because agricultural workers had higher rates of NHLs. The NAS found a "positive association" between exposure to herbicides and NHL, meaning there is an increased risk with herbicide exposure. It is thought that the use of protective equipment (gloves, jumpsuits, and face protection) can decrease this risk. Permanent hair-darkening dyes have also been the subject of many studies, but the majority of these studies did not find an increased risk in hair dye users.
Rates are much higher among persons over the age of 65 (68 for every 100,000 people). NHL occurs more often in whites than in blacks, and it is more common among men than women.
Because no one knows exactly what causes Hodgkin's disease, there are no specific steps anyone can take to prevent it. The factors that increase risk are generally not things that can be avoided, making it difficult to decrease risk in people affected by these viruses/bacteria and immune syndromes.
Unfortunately, there is no screening test available for NHLs. Because there are so many different types of NHLs, it would be difficult to develop a single effective test that could screen for all types.
Oftentimes, the first sign of NHL is the swelling of lymph nodes, but the symptom is easily ignored because the enlargement can be painless in many cases. Only about 20% of patients have systemic symptoms (symptoms throughout the body). When they do occur, symptoms include: persistent fever, drenching night sweats, or weight loss. These are sometimes referred to as "B symptoms". Other symptoms may include fatigue, itching, and alcohol intolerance.
Because there are so many forms of NHL that can involve all different organs, signs and symptoms can vary depending on the areas of the body that are affected. For instance, MALT lymphoma affects the stomach lining and can cause nausea, vomiting, and abdominal pain. Cutaneous T-cell lymphoma affects the skin and can cause redness, itching, or raised patches on the skin.
When a patient presents with signs or symptoms of NHL, the physician will perform a complete medical health history and a physical exam. A biopsy of the enlarged lymph node is necessary to determine if lymphoma is present, and if so, of what type. This can be done by sticking a needle into the node to remove some tissue, but more often the entire node is removed for examination.
Once NHL is found, a series of other tests are done to determine if the lymphoma has spread, where it has spread to, and other prognostic information. These tests may include further blood tests (complete blood count, sedimentation rate, LDH, albumin and beta-2 microglobulin), chest x-ray, CT scan or MRI of the chest, abdomen and pelvis, PET scan, and bone marrow biopsy.
Staging is then done based on the Ann Arbor Staging Classification
These letters can be added to all stages: (ex: stage IIA, stage IIIB)
A : No symptoms
B : Presence of "B symptoms" (fever, night sweats, weight loss > 10% of body weight)
E: is used if the disease is "extranodal" (not in the lymph nodes) or has spread from lymph nodes to adjacent tissue.
X : is used if the largest tumor is >10 cm large (also called "bulky disease"), or whether the lymph node mass in the center of the chest (mediastinum) is wider than 1/3 of the chest on a chest X-ray.
(Note: Cutaneous T-cell Lymphoma, mycosis fungoides is staged differently)
In addition to staging, the subtype of NHL must be taken into consideration. Some types are classified as aggressive because they grow more quickly and require immediate treatment. The good news is that chemotherapy works by attacking fast-growing cells, so aggressive lymphomas are more sensitive to treatment. Although these lymphomas are aggressive, a percentage of them can be cured by chemotherapy. Indolent lymphomas are those that are considered slow- growing. In some cases, indolent lymphomas may not be treated immediately but rather followed with a "watch and wait" methodology. These lymphomas may respond to treatment, but they often return, requiring more treatment. Although these patients may remain well for many years with little or no therapy, indolent lymphomas are generally not curable, i.e. they do not "go away" permanently or completely.
Treatment is determined by the type of NHL, but in general, chemotherapy is the most commonly used treatment. Other therapies include immunotherapy and radioimmunotherapy. Radiation therapy is only able to treat limited areas, and is typically used after chemotherapy, though certain early stage and low grade lymphomas can be treated with radiation alone. Surgery is generally only used to establish a diagnosis; an exception to this is testicular lymphoma, since most suspicious testicular masses require removal of the testicle.
Chemotherapy is a medication that targets quickly-growing and dividing cells, such as cancer cells. It may be taken in a pill form or given through an intravenous (IV) infusion. Chemotherapy is considered a systemic therapy, meaning it travels throughout the body. This is in contrast to radiation therapy, which is a local treatment that targets a limited area. Chemotherapy medications can be used alone or in combination with other chemotherapies. This combination of different medications is called a "regimen". The regimen combines medications that work to kill cancer cells in different ways, thereby hopefully maximizing the number of cells killed. These regimens are given names based on the medications used. For instance, CHOP, a common regimen for NHL, is made up of cytoxan , adriamycin (hydroxydoxorubicin), oncovin (vincristine), and prednisone . This combination is given in "cycles" (blocks of time). A cycle may be 21 days, with cytoxan, adriamycin and oncovin being given on day 1, prednisone on days 1-5, followed by 16 days off, and then start over again with the next cycle.
Immunotherapy (sometimes called biologic therapy) is aimed at using the body's own immune system to attack the cancer cells and includes several different types of agents. Interferon-alpha is one type of immunotherapy that works by targeting certain receptors on the cancer cells, interfering with cell replication and causing the immune system to attack the cells. Interferon alpha is used in follicular and cutaneous T-cell lymphomas.
Monoclonal antibodies are man-made antibodies. They are designed to target a specific marker found on the tumor cell – this marker varies depending on the particular medication and the cancer it is treating. Once the medication is administered, the monoclonal antibody finds and attaches itself to the cancer cell, activating the body's immune system to attack it. This therapy is used alone or in combination with chemotherapy. Rituxan is the most commonly used monoclonal antibody for NHL and targets the CD20 antigen. This means the lymphoma must express the CD20 antigen for this therapy to work. Since monoclonal antibodies target only specific cells, they may cause less toxicity to normal healthy cells than chemotherapy. For diffuse large B cell lymphoma, Rituxan is frequently combined with CHOP chemotherapy, and in such cases, is known as "R-CHOP."
Radioimmunotherapy combines the technology of monoclonal antibodies and radiation. Man- made antibodies with a form of radiation (called a radioisotope) attached to them are designed to target the CD20 antigen. The antibody seeks out the tumor cells (by finding the antigen), attaches to them, exposes these cells to the radiation, and thus kills them along with any nearby cancer cells. Again, since these agents target specific cells, side effects may be less than those typically seen with chemotherapy. Currently available radioimmunotherapy agents include: Bexxar and Zevalin.
Transplants can be done using a donor's bone marrow or stem cells (allogeneic) or a patient's own bone marrow or stem cells (autologous). Autologous transplants are used to maximize the amount of chemotherapy that a patient can safely receive. The problem with giving large doses of chemotherapy is that this can kill the patient's bone marrow, which would lead to death. However, a patient can tolerate this high dose of chemotherapy if the bone marrow (or stem cells) is replaced soon after the chemotherapy using cells that have been stored ahead of time. In an allogeneic transplant this is also true, but in NHL the role of graft-versus-lymphoma effect is the key to its efficacy. This is the ability of the donor's cells and immune system to attack any remaining cancer cells.
Once a patient has been treated for NHL, they need to be closely followed for a recurrence. At first, follow-up visits will be fairly frequent. The longer a patient is free of disease, the less often the checkups are needed. The oncologist will tell you when he or she wants to perform follow-up CT scans or PET scans. Follow-up schedules will vary depending on the type of NHL.
Clinical trials are extremely important in furthering our knowledge of this disease. It is through clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your doctor about participating in clinical trials in your area.
This article is meant to give you a better understanding of non-Hodgkin's lymphoma. Use this knowledge when meeting with your physician, making treatment decisions, and continuing your search for information. You can learn more about NHL on OncoLink through the related links to the left.
Lymphoma Information Network: This site, hosted by a survivor, has a full complement of lymphoma information.
National Cancer Institute's NHL page
Abeloff, M., Armitage, J., Niederhuber, J., Kastan, M. & McKenna, G. (Eds.): Clinical Oncology (2004). Elsevier, Philadelphia, PA.
The American Cancer Society. Facts and Figures. www.cancer.org
Ansell, SM & Armitage, J (2005) Non-Hodgkin's lymphoma: Diagnosis and treatment. Mayo Clinic Proceedings: 80(8): 1087-1097.
Dummer, R. et al. Maintenance therapy in cutaneous T-cell lymphoma: who, when, what?. European Journal of Cancer. 43(16):2321-9, 2007 Nov.
Ferreri, Andres J & Zucca, Emanuele. Marginal-zone lymphoma. Critical Reviews in Oncology-Hematology. 63(3):245-56, 2007 Sep.
Hiddemann, W. & Unterhalt, M. Current treatment strategies in follicular lymphomas. Annals of Oncology. 17 Suppl 10:x155-9, 2006 Sep.
Morgner, A et al. Therapy of gastric mucosa associated lymphoid tissue lymphoma. World Journal of Gastroenterology. 13(26):3554-66, 2007 Jul 14.
NCCN Guidelines v 3.2011 Non –Hodgkin's Lymphomas http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf
Pereg, David. Et al. The treatment of Hodgkin's and non-Hodgkin's lymphoma in pregnancy. Haematologica. 92(9):1230-7, 2007 Sep.
Weigert, Oliver. Et al. Current management of mantle cell lymphoma. Drugs. 67(12):1689-702, 2007.
Yustein, Jason T. & Dang, Chi V. Biology and treatment of Burkitt's lymphoma. Current Opinion in Hematology. 14(4):375-81, 2007 Jul.
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II. Mature (peripheral) B-cell neoplasms
I. Precursor T cell neoplasm
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