Non-Hodgkin lymphomas (NHL reference

Non-Hodgkin lymphomas (NHL) are a diverse group of cancers which arise from lymphocytes, a type of white blood cell. NHL is distinct from Hodgkin lymphoma in its pathologic features, epidemiology, common sites of involvement, clinical behavior, and treatment. The broad category of non-Hodgkin lymphoma encompasses diseases with varying courses, treatments, and prognoses.

Non-Hodgkin lymphomas are medically classified as a hematological malignancy, meaning that they are cancers that arises from the blood. Non-Hodgkin lymphomas may develop in any organ associated with the lymphatic system, such as the spleen, lymph nodes, or tonsils. The diagnosis of a non-Hodgkin lymphoma requires a biopsy of involved tissue.

The numerous types of non-Hodgkin lymphoma are typically grouped into three distinct categories based on their aggressiveness. These categories are indolent (or low-grade), aggressive (or intermediate-grade), and highly aggressive (or high-grade). The treatment of indolent or low-grade lymphomas may initially involve a period of observation, while aggressive or highly aggressive non-Hodgkin lymphomas are typically treated with chemotherapy and/or radiation therapy. Some forms of non-Hodgkin lymphoma can be cured with chemotherapy, radiation, or hematopoietic stem cell transplantation.

Symptoms

The most common symptom of a non-Hodgkin's lymphoma is a painless, enlarged, rubbery swelling of the lymph nodes in the neck, underarm (axilla), or groin. However, unlike Hodgkin's disease, which is localized to cervical and supraclavicular nodes 80-90% times, NHLs are localized at diagnosis only 10-20% of the time.

Other symptoms may include the following:

* Unexplained fever
* Unexplained weight loss and poor appetite
* Constant fatigue
* Night sweats
* Itchy skin
* Reddened, dark, or thick patches on the skin[1]
* Chronic abdominal pain
* Swelling in the legs[2]
* Anemia

[edit] Organ-specific symptoms

Symptoms such as shortness of breath, chest pain, cough, abdominal pain and distention, or bone pain, may lead to the identification of specific sites of involvement. Careful evaluation for neurologic symptoms is necessary in order to rule out central nervous system (CNS) involvement, which may occur with aggressive histologies

Such symptoms are non-specific and may be caused by other, less serious conditions.

[edit] Diagnosis

If a non-Hodgkin's lymphoma is suspected, the doctor asks about the person's medical history and performs a physical exam. The exam includes feeling to see if the lymph nodes in the neck, underarm, or groin are enlarged. In addition to checking general signs of health, the doctor may perform blood tests.
Excisional biopsy NHL specimen
Excisional biopsy NHL specimen

Biopsy: A biopsy is needed to make a diagnosis. A surgeon removes a sample of tissue, which a pathologist can examine under a microscope to check for cancer cells. A biopsy for a non-Hodgkin's lymphoma is usually taken from lymph nodes that are enlarged, but other tissues may be sampled as well. Biopsies in internal lymph nodes can also be taken as needle biopsies under the guidance of CT scans. Rarely, an operation called a laparotomy may be performed. During this operation, a surgeon cuts into the abdomen and removes samples of tissue to be checked under a microscope.

Common tests:

* The laboratory workup for NHL includes a complete blood count (CBC) with differential. An examination of a peripheral smear is essential to assess bone marrow function and to investigate for the presence of abnormal circulating cells in the peripheral blood. Screening chemistries to ascertain renal and hepatic function, serum glucose, calcium, albumin, and lactate dehydrogenase (LDH) are also indicated, as they are frequently found to be abnormal. In fact, more than 50% of patients have elevated serum LDH levels. An elevated beta2-microglobulin level is associated with a poor prognosis. A serum protein electrophoresis should also be part of the workup.

The doctor may also order tests that produce pictures of the inside of the body. These may include:

* X-rays: Pictures of areas inside the body created by high-energy radiation.
* CT scan (computed tomography scan, also known as a "CAT scan"): A series of detailed pictures of areas inside the body. The pictures are created by a computer linked to an x-ray machine.
* PET scan (positron emission tomography scan): This is an imaging test that detects uptake of a radioactive tracer by the tumor. More often, the PET scan can be combined with the CT scan.
* MRI (magnetic resonance imaging): Detailed pictures of areas inside the body produced with a powerful magnet linked to a computer.

Less common tests: These tests are only used under certain circumstances.

* Lymphangiogram: Pictures of the lymphatic system taken with x-rays after a special dye is injected to outline the lymph nodes and vessels. This test is not used as often because of the adoption of CT scan and the PET scan technologies.
* Gallium scan: Gallium is a rare metal that behaves in the body in a fashion similar to iron, so that it concentrates in areas of inflammation or rapid cell-division, and hence is useful for imaging the entire lymphatic system for staging the lymphoma once the presence of the disease has been confirmed. PET scans have supplanted gallium scans for evaluation and follow up of NHL.

[edit] Types of non-Hodgkin's lymphomas

Over the years, doctors have used a variety of terms to classify the many different types of non-Hodgkin's lymphomas. Most often, they are grouped by how the cancer cells look under a microscope and how quickly they are likely to grow and spread. Current lymphoma classification is complex.

MeSH includes four different criteria for classifying NHL. (It is possible to be classified under more than one.)

* High-grade vs. intermediate vs. low-grade: Aggressive lymphomas, also known as intermediate and high-grade lymphomas, tend to grow and spread quickly and cause severe symptoms. Indolent lymphomas, also referred to as low-grade lymphomas, tend to grow quite slowly and cause fewer symptoms. One of the paradoxes of the non-Hodgkin's lymphomas is that the indolent lymphomas generally cannot be permanently cured by chemotherapy, while in a significant number of cases aggressive lymphomas can be.

* Diffuse vs. follicular: Follicular lymphomas tend to be indolent, and diffuse lymphomas tend to be aggressive.

* T-cell lymphomas vs. B-cell lymphomas
o Gluten-sensitive enteropathy associated T-cell lymphoma or EATL

* Large cell lymphomas (such as anaplastic large cell lymphoma) vs. Small cell lymphoma vs. Mixed cell lymphoma)

Details of the most popular classifications of lymphoma can be found in the lymphoma page.

[edit] Causes

The etiology, or cause, of most lymphomas is not known. Some types of lymphomas are associated with viruses. Burkitt's lymphoma, extranodal NK/T cell lymphoma, classical Hodgkin's disease and most AIDS-related lymphomas are associated with Epstein-Barr virus. Adult T-cell lymphoma/leukemia, which are endemic in parts of Japan and the Caribbean, is caused by the HTLV-1 virus. Lymphomas of the stomach (extranodal marginal zone B-cell lymphoma) is often caused by the Helicobacter bacteria.

The incidence of non-Hodgkin lymphomas has increased dramatically over the last couple of decades. This disease has gone from being relatively rare to being the fifth most common cancer in the United States. At this time, little is known about the reasons for this increase or about exactly what causes non-Hodgkin lymphomas.

Doctors can seldom explain why one person gets a non-Hodgkin's lymphoma and another does not. It is clear, however, that cancer is not caused by an injury, and is not contagious; no one can "catch" a non-Hodgkin's lymphoma from another person.

By studying patterns of cancer in the population, researchers have found certain risk factors that are more common in people who get non-Hodgkin's lymphomas than in those who do not. However, most people with these risk factors do not get non-Hodgkin lymphomas, and many who do get this disease have none of the known risk factors.

The following are some of the risk factors associated with this disease:

* Age and sex. The likelihood of getting a non-Hodgkin's lymphoma increases with age and is more common in men than in women.
* Weak immune system. Non-Hodgkin's lymphomas are more common among people with inherited immune deficiencies, autoimmune diseases, or HIV/AIDS, and among people taking immunosuppressant drugs following organ transplants. See post-transplant lymphoproliferative disorder and AIDS-related lymphomas.
* Viruses. Human T-lymphotropic virus type I (HTLV-1) and Epstein-Barr virus are two infectious agents that increase the chance of developing a non-Hodgkin's lymphoma.
* Environment. People who work extensively with or are otherwise exposed to certain chemicals, such as pesticides, solvents, or fertilizers, have a greater chance of developing a non-Hodgkin's lymphoma.

There is no clear connection between alcohol consumption and NHL. For further information, see the alcohol and cancer article.

[edit] Staging

If a non-Hodgkin's lymphoma is diagnosed, the doctor needs to learn the stage, or extent, of the disease. Staging is a careful attempt to find out whether the cancer has spread and, if so, what parts of the body are affected. Treatment decisions depend on these findings.[1]

The doctor considers the following to determine the stage of non-Hodgkin's lymphomas:

* The number and location of affected lymph nodes;
* Whether the affected lymph nodes are above, below, or on 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 to organs outside the lymphatic system, such as the liver and the testes;
* Whether B symptoms (systemic symptoms) such as fever, chills, night sweats, or weight loss are present.

In staging, the doctor may use some of the same tests used for the diagnosis of non-Hodgkin's lymphomas. Other staging procedures may include additional biopsies of lymph nodes, the liver, bone marrow, or other tissue. A bone marrow biopsy involves removing a sample of bone marrow through a needle inserted into the hip or another large bone. A pathologist examines the sample under a microscope to check for cancer cells.

[edit] Stages of NHL

The various stages of NHL (the Ann Arbor staging classification, developed for Hodgkin's lymphomas) are based on how far the cancer has spread throughout and beyond the lymphatic system, and whether constitutional symptoms (fever, night sweats, or weight loss) are present.

Stage I
"Stage I" indicates that the cancer is located in a single region, usually one lymph node and the surrounding area. Stage I often will not have outward symptoms.
Stage II
"Stage II" indicates that the cancer is located in two separate regions, an affected lymph node or organ within the lymphatic system and a second affected area, and that both affected areas are confined to one side of the diaphragm - that is, both are above the diaphragm, or both are below the diaphragm.
Stage III
"Stage III" indicates that the cancer has spread to both sides of the diaphragm, including one organ or area near the lymph nodes or the spleen.
Stage IV
"Stage IV" indicates that the cancer has spread beyond the lymphatic system and involves one or more major organs, possibly including the bone marrow or skin.

The absence of constitutional symptoms is denoted by adding an "A" to the stage; the presence is denoted by adding a "B" to the stage (hence the name B symptoms).

Staging in non-Hodgkin's lymphomas is far less significant in determining therapy than it is in Hodgkin's disease.

[edit] Prognosis

See also: International Prognostic Index

The most significant factor in overall prognosis is the grade, or aggressiveness, of the lymphoma. Indolent (low-grade) non-Hodgkin's lymphomas are generally not curable, but is typically slowly progressive and responds temporarily to therapy. Aggressive and highly aggressive (intermediate- and high-grade) NHL's are potentially curable with combination chemotherapy. Long-term survival or cure rates for these diseases vary with a number of prognostic factors.

[edit] International Prognostic Index

The International Prognostic Index, or IPI, is the most widely used prognostic system for non-Hodgkin's lymphomas. This system uses 5 factors:

* Age
* Lactate dehydrogenase level (a blood test)
* Performance status
* Clinical stage
* Sites of extranodal disease

However, it should be noted that the IPI was developed prior to the introduction of rituximab. As rituximab has become a standard part of therapy for B-cell NHL's, the impact on the prognostic value of the IPI is unclear.

[edit] FLIPI

For the subtype of NHL known as follicular lymphoma, a modified version of the IPI called the FLIPI (follicular lymphoma international prognostic index) has been developed. The factors which figure into the FLIPI are age, clinical stage, lactate dehydrogenase level, hemoglobin level, and number of nodal sites involved. As with the IPI, the FLIPI was developed and validated prior to the widespread use of rituximab, so the same caveats apply as were mentioned with the IPI above.

[edit] Treatment

The doctor develops a treatment plan to fit each patient's needs. Treatment for non-Hodgkin's lymphomas depend on the stage of the disease, the type of cells involved, whether they are indolent or aggressive, and the age and general health of the patient.

Non-Hodgkin's lymphomas are often treated by a team of specialists that may include a hematologist, medical oncologist, and/or radiation oncologist. Non-Hodgkin's lymphomas are usually treated with chemotherapy and/or radiation therapy. In some cases, bone marrow transplantation, biological therapies, or surgery may be options. For indolent lymphomas, the doctor may decide to wait until the disease causes symptoms before starting treatment. Often, this approach is called "watchful waiting."

Taking part in a clinical trial (research study) to evaluate promising new ways to treat non-Hodgkin's lymphomas is an important option for many people with this disease.

[edit] Chemotherapy and radiation therapy

Chemotherapy and radiation therapy are the most common treatments for non-Hodgkin's lymphomas, although bone marrow transplantation, biological therapies, or surgery are sometimes used. CHOP, with rituximab added in certain circumstances, is the most commonly used combination of chemotherapy.

Rituximab is an antibody-based therapy. Ibritumomab tiuxetan (commonly known as Zevalin) and Tositumomab (Bexxar) are FDA-approved options, requiring a Nuclear Medicine facility, but only two short infusions one week apart. There is mounting evidence that more patients have long-term remission if they use radioimmunotherapy first.

Radiation therapy (also called radiotherapy) is the use of high-energy rays to kill cancer cells. Treatment with radiation may be given alone or with chemotherapy. Radiation therapy is local treatment; it affects cancer cells only in the treated area. Radiation therapy for Non Hodgkin's lymphomas comes from a machine that aims the high-energy rays at a specific area of the body. There is no radioactivity in the body when the treatment is over.

Sometimes patients are given chemotherapy and/or radiation therapy to kill undetected cancer cells that may be present in the central nervous system (CNS). In this treatment, called central nervous system prophylaxis, the doctor injects anticancer drugs directly into the cerebrospinal fluid.

[edit] Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT), or Bone marrow transplantation (BMT) may also be a treatment option, especially for patients whose non-Hodgkin's lymphoma has recurred (come back). BMT provides the patient with healthy stem cells (very immature cells, found in the marrow, that produce blood cells), the function of which is to replace white blood cells that are damaged or destroyed by treatment with very high doses of chemotherapy and/or radiation therapy. The healthy bone marrow may come from a donor, or it may be "autologous" (marrow that was removed from the patient, stored, and then given back to the person following the high-dose treatment). Autologous transplants are preferred, as the recipient is less likely to reject the cells, the origins of which were the same entity. However, in order for an autologous transplant to be performed, certain physiological conditions must be optimal within the patient. If these conditions are not present, transplanted stem cells can come from other donors. Until the transplanted bone marrow begins to produce enough white blood cells, patients have to be carefully protected from infection due to the virtual elimination of the immune system resulting from the high-intensity treatment. Without the introduction of the stem cells following the high dose treatment, the patient will not survive as the body will be unable to produce infection-fighting white blood cells. Patients usually stay in the hospital for several weeks and will be monitored for transplant rejection and overall health.

[edit] Immunotherapy

Biological therapy (also called immunotherapy) is a form of treatment that uses the body's immune system, either directly or indirectly, to fight cancer or to lessen the side effects that can be caused by some cancer treatments. It uses materials made by the body or made in a laboratory to boost, direct, or restore the body's natural defenses against disease. This approach is under close investigation. Biological therapy is sometimes also called biological response modifier therapy.

[edit] Measuring response to treatment

After treatment for a non-Hodgkin's lymphoma, the response is classified as follows:

* Complete Response (CR). This indicates the disappearance of all detectable disease.
* Partial Response (PR). A reduction in the bulk of disease by at least 50%, but with some remaining disease.
* Stable Disease. Less than a partial remission, but no progression of disease and no new sites of disease.
* Progressive Disease. Growth in bulk of disease by >50%, or the appearance of new sites of disease.

If a complete remission is achieved, the patient is watched closely for any evidence of recurrent disease. Standard guidelines dictate that a patient be monitored for relapse every three months in the first year following a complete remission, every six months in the second year, and finally once annually in the third and later years. Diffuse large B-cell lymphoma is the most common type of lymphoma that is considered curable. Currently, if a patient maintains a complete remission for 3 years, the patient is considered cured. Generally most relapses of diffuse large B-cell lymphoma occur within the first year after a complete remission is obtained. Reoccurrences after 3 years are rare but they do occur. The effect of Rituximab on relapse rates for diffuse large B-cell lymphoma is still largely unknown, though initial relapse rates since 2003 have been much lower than expected.

Patients with follicular lymphomas are generally not considered cured. Instead, they are categorized as in ongoing complete remission. Relapses occur steadily over time. Relapse rates are estimated to be 33%, 66%, and 100% for follicular lymphomas in Grades I, II, and III respectively.

Research has indicated that relapse rates can be lowered on patients with follicular lymphomas by giving supplemental radiation therapy, however, it is known that this additional therapy increases the chances of a second malignancy of unknown type later in life.

If the response to treatment falls short of a complete response, more treatment may be administered (using a different chemotherapy regimen), or watchful waiting may be utilized, depending on the goals of treatment.

[edit] Nutrition during treatment

Eating well during cancer treatment means getting enough food energy and protein to help prevent weight loss and regain strength. Good nutrition often helps people feel better and have more energy.

Some people with cancer find it hard to eat a balanced diet because they may lose their appetite. In addition, common side effects of treatment, such as nausea, vomiting, or mouth sores, can make eating difficult. Often, foods may taste or smell different. Also, people being treated for cancer may not feel like eating when they are uncomfortable or tired.

Doctors, nurses, and dietitians can offer advice on how to get enough food energy and protein during cancer treatment. Patients and their families also may want to read the National Cancer Institute (USA) booklet Eating Hints for Cancer Patients, which contains many useful suggestions.[2]

[edit] Followup care

People who have had a non-Hodgkin's lymphoma should have regular follow-up examinations after their treatment is over. Follow-up care is an important part of the overall treatment plan, and people should not hesitate to discuss it with their health care provider. Regular follow-up care ensures that patients are carefully monitored, any changes in health are discussed, and new or recurrent cancer can be detected and treated as soon as possible. Between followup appointments, people who have had a non-Hodgkin's lymphoma should report any health problems as soon as they appear.