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

Non-Hodgkin lymphoma may develop in any organ associated with the lymphatic system (e.g. spleen, lymph nodes, or tonsils). Most cases start with infiltration of lymph nodes, but some subtypes may be restricted to other lymphatic organs.

 The diagnosis of non-Hodgkin lymphoma requires a biopsy of involved tissue. The numerous subtypes of non-Hodgkin lymphoma are typically grouped into three distinct categories based on their aggressiveness, or histologic grade. These categories are indolent (or low-grade), aggressive (or intermediate-grade), and highly aggressive (or high-grade). The treatment of indolent or low-grade lymphoma may initially involve a period of observation, while aggressive or highly aggressive non-Hodgkin lymphoma is typically treated with chemotherapy and/or radiation therapy.

  

Symptoms

 The most common symptom of non-Hodgkin's lymphoma is a painless swelling of the lymph nodes in the neck, underarm (axilla), or groin.

 Other symptoms may include the following: 

    * Unexplained fever

    * Unexplained weight loss and anorexia (poor appetite)

    * Constant fatigue

    * Itchy skin

    * Reddened patches on the skin

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

 

Diagnosis

 If 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

 

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 commonly used

     * 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 of lymphoma once the presence of the disease has been confirmed. PET scans have supplanted gallium scans for evaluation and follow up of NHL.

 

  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 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 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.

 

  Types of non-Hodgkin's lymphoma

 Over the years, doctors have used a variety of terms to classify the many different types of non-Hodgkin's lymphoma . 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 non-Hodgkin's lymphoma is that the indolent lymphomas generally cannot be cured by chemotherapy, while in a significant number of cases aggressive lymphomas can be.

     * Diffuse vs. follicular: Follicular lymphoma tends to be indolent, and diffuse lymphoma tends to be aggressive.

     * T-cell lymphoma vs. B-cell lymphoma

          o Gluten-sensitive enteropathy associated T-cell lymphoma or EATL

     * Large cell lymphoma (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.

 

  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 lymphoma are associated with Epstein-Barr virus. Adult T-cell lymphoma/leukemia, endemic in parts of Japan and the Caribbean, is caused by the HTLV-1 virus. Lymphoma of the stomach (extranodal marginal zone B-cell lymphoma) is often caused by the Helicobacter bacteria.

 The incidence of non-Hodgkin's lymphoma 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's lymphoma.

 Doctors can seldom explain why one person gets 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" 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 lymphoma than in those who do not. However, most people with these risk factors do not get non-Hodgkin's lymphoma, 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/sex. The likelihood of getting non-Hodgkin's lymphoma increases with age and is more common in men than in women.

    * Weakened immune system (AIDS-related lymphoma). Non-Hodgkin's lymphoma is 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)

    * Viruses. Human T-lymphotropic virus type I (HTLV-1) and Epstein-Barr virus are two infectious agents that increase the chance of developing 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 non-Hodgkin's lymphoma.

 Staging

 If 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.

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

     * 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 lymphoma. 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.

   Stages of NHL

 The various stages of NHL (the Ann Arbor staging classification, developed for Hodgkin's lymphoma) 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 lymphoma

   Prognosis

The most significant factor in overall prognosis is the grade, or aggressiveness, of the lymphoma. Indolent (low-grade) non-Hodgkin's lymphoma is 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.

International Prognostic Index

The International Prognostic Index, or IPI, is the most widely used prognostic system for non-Hodgkin's lymphoma. 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.

  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.

 

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