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Angioimmunoblastic T-Cell Lymphoma

NORD is very grateful to John Sweetenham, MD, Professor of Medicine, Vice-Chair for Clinical Research, Taussig Cancer Institute, Cleveland Clinic, for assistance in the preparation of this report.

Synonyms of Angioimmunoblastic T-Cell Lymphoma

  • AILD
  • AITL
  • angioimmunoblastic lymphadenopathy with dysproteinemia
  • immunoblastic lymphadenopathy
  • lymphogranulomatosis X

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Angioimmunoblastic T-cell lymphoma (AITL) is a rare form of non-Hodgkin lymphoma, which is a group of related malignancies (cancers) that affect the lymphatic system (lymphomas). The lymphatic system functions as part of the immune system and helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream.

Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes. As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. Lymphocytes are stored within lymph nodes and may also be found in other lymphatic tissues. In addition to the lymph nodes, the lymphatic system includes the spleen, which filters worn-out red blood cells and produces lymphocytes, and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue or circulating lymphocytes may also be located in other regions of the body. There are two main types of lymphocytes: B-lymphocytes (B-cells), which may produce specific antibodies to "neutralize" certain invading microorganisms, and T-lymphocytes (T-cells), which may directly destroy microorganisms or assist in the activities of other lymphocytes.

AITL results from errors in the production of a T-cell or transformation of a T-cell into a malignant cell. Abnormal, uncontrolled growth and multiplication (proliferation) of malignant T-cells may lead to enlargement of a specific lymph node region or regions; involvement of other lymphatic tissues, such as the spleen and bone marrow; and spread to other bodily tissues and organs. A key and differentiating aspect of AITL is dysfunction of the immune system, which can lead to a variety of symptoms. Individuals with AITL may develop a rash, persistent fever, unintended weight loss, tissue swelling due to the accumulation of fluid (edema) and additional symptoms. The exact, underlying cause of AITL is not fully understood.

Symptoms

The specific symptoms and physical findings of AITL may vary from case to case, depending upon the extent and region(s) of involvement and other factors. The progression is often aggressive, but spontaneous remission has occurred in some cases. All organ systems can potentially be affected. Researchers believe that many of the symptoms associated with AITL result from dysfunction of the immune system rather than from complications relating to tumor growth or spread.

It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

The initial symptoms of AITL are often vague and have a tendency to come and go. Some affected individuals develop certain generalized (systemic) symptoms known as "B symptoms". Such symptoms include persistent or repeated fever, unexplained weight loss (i.e., loss of at least 10 percent of normal body weight), and/or sweating, particularly at night (known as "night sweats"). Another common finding associated with AITL is the mild-to-moderate enlargement of various lymph nodes in the body (generalized lymphadenopathy). Lymph nodes in the neck, armpit and groin are most often affected.

Another prominent symptom associated with AITL is the development of a distinctive skin rash that may or may not be itchy (pruritic). Affected individuals may have a history of chronic skin rashes. Generally, the skin rash resembles the rash associated with measles (morbilliform) and may be reddened (erythematous) with small spots or bumps (maculopapular).

Individuals with AITL may also experience fatigue, a general feeling of poor health (malaise), inflammation of multiple joints (polyarthritis), fluid accumulation around the lungs (pleural effusion) and ascites, which is the excess fluid accumulation between the space lining the abdomen and the abdominal organs (peritoneal cavity). Abnormal enlargement of the liver (hepatomegaly) and/or the spleen (splenomegaly) may also occur. Bone pain has also been reported in individuals with AITL.

Bone marrow involvement may occur in some cases and can contribute to low levels of circulating red blood cells (anemia). Less often, low levels of white blood cells and low levels of platelets (thrombocytopenia) may occur.

Individuals with AITL may also develop symptoms directly associated with immune dysfunction including autoimmune hemolytic anemia, rheumatoid arthritis, vasculitis and autoimmune thyroid disease. Autoimmune hemolytic anemia is caused by the premature destruction of red blood cells and may result in fatigue, pale skin color, dark urine, shortness of breath and a rapid heartbeat. Rheumatoid arthritis is characterized by chronic pain and swelling of the joints. Vasculitis is a general term for inflammation of the blood vessels. The symptoms of vasculitis vary based upon the specific blood vessels and organ systems involved. Autoimmune thyroid disease occurs when the immune system attacks and damages the thyroid.

Less often, individuals with AITL may develop neurological and gastrointestinal abnormalities. Neurological abnormalities may include confusion, apathy, ringing in the ears (tinnitus), inflammation of the peripheral nerves (polyneuritis), swelling of the optic disc (papilledema) and hearing or visual impairment. Gastrointestinal abnormalities may include mucosal ulcers, diarrhea, GI bleeding, the development of multiple polyps in the GI tract (lymphomatous polyposis) and inflammation, hardening and destruction of the bile ducts (sclerosing cholangitis).

Affected individuals may also be prone to developing certain infections because of disease-related suppression of the immune system. Such infections can potentially cause severe, life-threatening complications.

Causes

The exact, underlying cause of AITL is unknown. It is believed that a dysfunctional immune system response to an unknown antigen ultimately leads to the development of the disorder. An antigen is any substance that causes the immune system to produce antibodies. The process through which a dysfunctional or abnormal immune system response ultimately progresses to lymphoma is not fully understood.

No specific risk factors have been confirmed to be associated with AITL. Many cases have developed following the administration of certain drugs such as antibiotics or after a viral infection. Suspected risk factors include several viruses including the Epstein-Barr virus, cytomegalovirus, hepatitis C virus, human herpes viruses 6 and 8, and the human immunodeficiency virus. Certain infectious agents including tuberculosis and Cryptococcus have also been linked to AITL. It is not known what role, if any, that these potential risk factors play in the development of AITL.

The Epstein-Barr virus, in particular, has been found in more than 90 percent of individuals with AITL. However, the virus is found in B-cells and not the cancerous T-cells. Consequently, some researchers have suggested that the virus most likely does not play a primary role in the development of AITL. However, EBV positive B cells are found very early in the disease process and other researchers suggest that the virus may play a more significant role in the development of AITL than previously thought.

Another substance that may play a role in the development of AITL is vascular endothelial growth factor A (VEGF-A). This substance is critical in tumor angiogenesis, which is the process by which tumors create a network of blood vessels in order to receive nutrients and oxygen and remove waste. Researchers believe that therapies targeted at VEGF-A can disrupt tumor angiogenesis and prevent tumors from growing.

More research is necessary to determine the exact underlying mechanisms that ultimately cause AITL.

Affected Populations

The incidence of AITL in the general population is unknown. It is estimated to account for 1-2 percent of all cases of non-Hodgkin lymphoma. Some reports state the AITL occurs slightly more often in men than women, but others state the ratio is 1:1. Most cases of AITL occur in people in their 60s and 70s. The disorder can occur in younger adults and, although rarely, has also been reported in children.

The disorder was first reported in the medical literature in 1974 by Frizzera et al. and called angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). AITL is subclassified as a peripheral T-cell lymphoma (PTCL). PTCLs account for approximately 10-15 percent of all cases of non-Hodgkin lymphoma. AITL is the second most common type of PTCL.

Related Disorders

Symptoms of the following disorders can be similar to those of AITL. Comparisons may be useful for a differential diagnosis.

PTCL is a group of rare, aggressive lymphomas. PTCLs are a subgroup of non-Hodgkin lymphoma (NHL). NHL may be broadly classified into lymphomas that arise from abnormal B-lymphocytes (B-cell lymphomas) and those derived from abnormal T-lymphocytes (T-cell lymphomas). PTCLs are T-cell lymphomas that develop from malignant T-lymphocytes. NHLs may also be categorized based upon certain characteristics of the cancer cells as seen under a microscope and how quickly they may tend to grow and spread. For example, NHLs may be characterized as "low-grade" (or indolent) lymphomas, which tend to grow slowly and result in few associated symptoms, or "intermediate" or "high-grade" (aggressive) lymphomas, which typically grow rapidly, requiring prompt treatment. PTCLs are generally classified as rapidly-growing (aggressive) lymphomas. Approximately 13 different subtypes of PTCL have been identified. Because of their rarity, PTCLs are poorly understood. However, new techniques to distinguish the various subtypes of PTCL have recently been developed and it is hoped that standards for the best treatment will be established soon as well.

Hodgkin disease (Hodgkin lymphoma) a type of cancer affects the lymphatic system (lymphoma). In contrast to NHL, Hodgkin disease is typically characterized by the presence of a specific type of cancer cell known as a Reed-Sternberg cell that has more than one nucleus. The disease is categorized into several subtypes according to certain features of affected lymphatic tissue as seen under a microscope (microscopic examination), such as relative number of Reed-Sternberg cells, proportion of other types of white blood cells, certain tissue changes, etc. The disease is also classified into one of four major stages based upon the number and location of lymph node regions affected, spread to other tissues and organs, and the presence or absence of certain symptoms. In individuals with Hodgkin disease, the malignancy often develops within lymph nodes in one area of the body and eventually spreads in a relatively predictable pattern throughout the lymphatic system. With disease progression, the malignancy may infiltrate the bone marrow and spread to involve other organs, such as the liver, lungs, and/or other tissues. A common finding associated with Hodgkin disease is painless swelling of lymph nodes, particularly in the neck region, under the arms (axillae), or, in some cases, other regions, such as the groin. Certain symptoms are also commonly present, such as unexplained fever, weight loss, and night sweats (so-called "B symptoms"); persistent fatigue; lack of energy; severe itching of the skin; coughing; and/or shortness of breath. Additional associated symptoms and findings may vary, depending upon the stage of the disease, the site(s) of involvement, and other factors. The specific treatments recommended may include radiation therapy, certain combinations of anticancer drugs (chemotherapy), and/or other measures, based upon the specific subtype of Hodgkin disease, stage, and other factors (e.g., patient age, general health, how much tumor is present [tumor bulk], whether the disease has returned following apparent recovery [relapse], etc.). For further information, choose "Hodgkin" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
A diagnosis of AITL is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a biopsy of an affected lymph node or other affected areas such as the skin or bone marrow.

During a complete physical examination, physicians may feel (i.e., palpate) the lymph nodes in certain regions to detect any swelling, including in the neck, tonsil, and adenoidal region; under the arms; and in the groin. They may also examine other regions to help determine whether there is enlargement of certain internal organs, particularly the spleen and liver, and to detect swelling and abnormal fluid accumulation that may be associated with disease of the lymphatic system.

Biopsies typically involve the removal and microscopic (i.e., histologic) examination of small samples of tissue cells from a lymph node--or, in some instances, removal of an entire, enlarged lymph node--that is suspected of being cancerous. Biopsy samples are examined by physicians who specialize in analyzing cells and tissues to help obtain accurate diagnosis (pathologists).

Additional various diagnostic tests may be recommended to assess the extent of AITL. These tests may include blood tests, specialized imaging tests and bone marrow examination. For example, blood tests may include studies to evaluate the number and appearance of white blood cells, red blood cells, and platelets; liver enzyme studies; tests to measure levels of the enzyme lactate dehydrogenase (LDH); and/or other studies. (High elevations of LDH may suggest that the lymphoma may have rapid progression, potentially requiring more intensive therapies.)

Specialized imaging techniques may include magnetic resonance imaging (MRI) and computed tomography (CT) scanning may aid in the diagnosis of AITL. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of certain organs and tissues. CT scanning and MRIs may be used to help detect enlargement of certain lymph nodes or the spread of malignancy to certain organs.

A procedure known as a bone marrow biopsy may also be recommended to help determine whether the malignancy involves the bone marrow. During this procedure, a sample of bone marrow is obtained, usually from the hipbone (iliac crest). Skin and tissue over the bone is first numbed with local anesthetic, and a needle is inserted into the bone through which a bone marrow sample is withdrawn. The sample is then examined under a microscope by a pathologist. Because a bone marrow biopsy may be painful, a mild, calming (sedative) medication may be offered before the procedure is conducted.

Staging
When an individual is diagnosed with a non-Hodgkin lymphoma (NHL) such as AITL, assessment is also required to determine the extent or "stage" of the disease. As is the case with NHL grading, staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests may be used in staging NHL (e.g., blood tests, CT scanning, bone marrow biopsy). In addition, in some cases, additional biopsies may be obtained to assist in lymphoma staging.

The specific stage of NHL may be based upon the number of lymph node regions involved; whether such lymph nodes are located above, below, or on both sides of the diaphragm*; and/or whether the malignancy has infiltrated other lymphatic tissues, such as the spleen or bone marrow, or spread to involve other organs outside the lymphatic system, such as the liver. (*The diaphragm is the dome-shaped muscle that separates the chest from the abdomen and plays an essential role in breathing.)

Although various staging systems have been described, a system commonly used for adult NHL is the Ann Arbor staging system, which includes the following stages:

Stage I - indicates early, localized disease in which the malignancy is limited to a single lymph node region or in a single organ or region outside the lymph node (extralymphatic organ or site).

Stage II - indicates locally advanced disease in which the malignancy involves more than one lymph node region on one side of the diaphragm or is found within one extralymphatic organ or site and its regional lymph node region (with or without involvement of other lymph nodes on the same side of the diaphragm).

Stage III - indicates advanced disease in which the lymphoma involves lymph node regions on both sides of (i.e., above and below) the diaphragm and may involve the spleen. There may also be localized involvement of an extralymphatic organ or site.

Stage IV - indicates widespread (disseminated) disease in which the malignancy is diffusely spread throughout one or more extralymphatic organs or sites with or without associated lymph node involvement.

Each stage of NHL may be further divided into categories A or B, based upon whether or not affected individuals have symptoms. More specifically:

A indicates that no generalized (systemic) symptoms are present upon diagnosis.

B indicates that an affected individual has experienced drenching night sweats, unexplained fever (above 38 degrees Celsius), and/or unexplained weight loss (i.e., loss of at least 10 percent of total body weight in the six months prior to diagnosis). Thus, individuals with such features may be said to have "B symptoms."

In addition, category E may indicate that the malignancy affects a single organ outside the lymphatic system or has spread from a lymph node to an organ.

Various additional elements may be considered as physicians determine the stage of NHL, potential disease course, and appropriate treatment options. Such factors may include patient age and general health, tumor size, levels of the enzyme lactate dehydrogenase, extranodal site involvement, and other factors.

Treatment
The diagnosis and therapeutic management of AITL may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other professionals.

Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage (see "Stages" above); tumor size; the presence or absence of certain symptoms; an individual's age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. Therapies used to treat individuals with AITL include corticosteroids, watch and wait, single-agent chemotherapy and multiagent chemotherapy.

Corticosteroids, such as prednisone, are used to treat the symptoms of AITL that result from dysfunction of the immune system. Prednisone may be used alone or in conjunction with chemotherapy regimens.

In selected individuals with low-grade (indolent) lymphoma without apparent symptoms, physicians may recommend waiting before implementing treatment until the disease leads to certain symptoms. In such cases, thorough, frequent checkups are required to ensure that appropriate therapies are begun when the disease course accelerates. This approach to disease management is often called "watch and wait".

However, as discussed above, AITL is typically considered an aggressive form of lymphoma. Therefore, physicians may recommend combination therapy with multiple anticancer (chemotherapeutic) drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying. For example, recommended treatment may include cyclophosphamide, doxorubicin or hydroxydaunorubicin (Adriamycin or Rubex), vincristine (Oncovin), and prednisone, known as the "CHOP" regimen.

The initial response to CHOP is often good, but the overall effectiveness of CHOP and other chemotherapy regimens has largely been inadequate. Although many individuals initially experience a remission, most will eventually experience a relapse.

Investigational Therapies

Researchers are studying a variety of medications and procedures for the treatment of individuals with AITL. Of particular interesting are drugs and other strategies to inhibit anigogenesis or to inhibit certain actions of the immune system. Standard chemotherapeutic agents to treat cancer in combination with therapies that have an effect on the immune system (immunomodulators) to treat dysfunction of the immune system are also being studied. High-dose chemotherapy along with autologous stem cell transplantation may have a role in treating AITL in some cases.

Many different types of drugs have been used or are being studied to treat individuals with AITL including low dose methotexate with corticosteroids, thalidomide, lenalidomide, bevacizumab, alemtuzumab, fludarabine and 2-chlordeoxyadenosine. These drugs have had varying levels of success in inducing a remission in affected individuals. Some drugs being studied for individuals with AITL have reportedly achieved complete remissions in some patients. Such drugs include interferon alfa, cyclosporine A and a class of drugs known as purine analogues.

The use of interferon alfa in association with or following chemotherapy is also under evaluation, such as for individuals who have had insufficient response to standard therapies. Interferons are proteins that are naturally produced by the body in response to certain infections, the presence of cancer cells, or other stimuli. Interferon alfa may also be produced artificially in the laboratory for the purposes of immunotherapy.

Cyclosporine, as a single agent, has shown promise in treating individuals with AITL. Cyclosporine may be able to help treat the immune system dysfunction that characterizes AITL.

One promising therapy for the treatment of AITL is the use of high-dose chemotherapy followed by autologous stem cell transplantation. Researchers are evaluating the safety and effectiveness (efficacy) of high-dose therapy with certain chemotherapeutic drugs, possibly in combination with radiation therapy and/or other treatments, followed by stem cell/bone marrow transplantation to help restore healthy bone marrow. The latter usually consists of transplantation using the affected individual's own stem cells isolated earlier from circulating blood (peripheral blood) or bone marrow (autologous transplantation). Initial results have demonstrated significant improvement in individuals with AITL treated by this procedure.

Monoclonal antibodies such as zanolimumab are also being evaluated in clinical trials at the moment. Monoclonal antibodies are antibodies artificially produced in a laboratory. Monoclonal antibodies bind to a specific substance (antigen) on cancer cells allowing for targeted therapy that spares surrounding tissue and cells.

More research is necessary to determiner the long-term safety and effectiveness of the above-mentioned therapies as potential treatments for individuals with AITL.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Contact for additional information about Angioimmunoblastic T-Cell Lymphoma:

John Sweetenham, MD
Professor of Medicine
Vice-Chair for Clinical Research
Taussig Cancer Institute
Cleveland Clinic
9500 Euclid Ave.
Cleveland, OH 44195
(216) 445-6707
sweetej@ccf.org

Organizations related to Angioimmunoblastic T-Cell Lymphoma

References

TEXTBOOKS
Sweetenham JW. Angioimmunoblastic Lymphadenopathy - Type T-Cell Lymphoma. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:398.

JOURNAL ARTICLES
Zaiden R, Ohman T, House J, Villas B, Rana F. Angioimmunoblastic T-cell lymphoma presenting as extensive psoriasis: a case report and discussion. Commun Oncol. 2010;7:90-92.

Reimer P, Rudiger T, Geissinger E, et al. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol. 2009;27:106-113.

De Leval L, Gisselbrecht C, Gaulard P. Advances in the understanding and management of angioimmunoblastic T-cell lymphoma. Br J Haematol. 2009;148:673-689.

Cho YU, Chi HS, Park CJ, et al. Distinct features of angioimmunoblastic T-cell lymphoma with bone marrow involvement. Am J Clin Pathol. 2009;131:640-646.

Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program. 2009;523-531.

Dunleavy K. Angioimmunoblastic T-cell lymphoma (AITL): a unique clinical and pathological entity. Onkologie. 2008;31:509-510.

Mourad N, Mounier N, Briere J, et al. Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials. Blood. 2008;111:4463-4470.

Kyriakou C, Canals C, Goldstone A, et al. High-dose therapy and autologous stem-cell transplantation in angioimmunoblastic lymphoma: complete remission at transplantation is the major determinant of outcome - Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2008;26:218-224.

Lachenal F, Berger F, Ghesquieres H, et al. Angioimmunoblastic T-cell lymphoma: clinical and laboratory features at diagnosis in 77 patients. Medicine (Baltimore). 2007;86:282-292.

Advani R, Horwitz S, Zelenetz A, Horning SJ. Angioimmunoblastic T cell lymphoma: treatment experience with cyclosporine. Leuk Lymphoma. 2007;48:521-525.

Zettl A, Lee SS, Rudiger T, et al. Epstein-Barr virus-associated B-cell lymphoproliferative disorders in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified. Am J Clin Pathol. 2002;117:368-379.

FROM THE INTERNET
Scheinfeld NS. Angioimmunoblastic Lymphoma. Emedicine Journal, August 13 2010. Available at: http://emedicine.medscape.com/article/1099386-overview Accessed January 10, 2011.

Peripheral T-Cell Lymphoma Facts. Leukemia & Lymphoma Society. November 2010. Available at: http://www.leukemia-lymphoma.org/attachments/National/br_1289923500.pdf Accessed January 10, 2011

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2011/02/16 00:00:00 GMT+0

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