Angioimmunoblastic T-cell lymphoma (AITL, sometimes misspelled AILT, formerly known as angioimmunoblastic lymphadenopathy with dysproteinemia ) is a rare form of non-Hodgkin lymphoma, which is a group of related malignancies (cancers) that affect the lymphatic system (lymphomas). It comprises innate immunity covered by NK cells and adaptive immunity by the B and T-cells. Non-Hodgkins lymphoma is the disorder of these immune cells. Lymphomas are the cancer of white blood cells (lymphocytes) and can be divided depending on the type of cells, B-lymphocytes (B-cells) or T-lymphocytes (T-cells), AITL is a T-cell lymphoma. 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.
PTCL is a group of rare, aggressive lymphomas. PTC is a subgroup of non-Hodgkin lymphoma (NHL). PTC are T-cell lymphomas that develop from malignant T-lymphocytes. PTC is generally classified as rapidly-growing (aggressive) lymphomas. 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.
AITL is characterized by the 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 the dysfunction of the immune system, which can lead to a variety of symptoms. Affected individuals 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.
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 people have developed the disorder following the administration of certain drugs such as antibiotics, after a viral infection, or after an allergic reaction. 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, these potential risk factors play in the development of the disorder.
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 the disorder. 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.
Researchers have also discovered that some people may have a genetic predisposition to developing AITL. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors. Researchers have shown that many people have specific altered genes including the DNMT3A, TET2, IDH2, and RhoA genes. The exact role these gene changes play in the development of AITL is not fully understood.
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 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.
The cause of the majority of T-cell Lymphoma remains unexplained. CTCL is considered to arise secondary to dysregulation of genes (cancer-testis genes and B lymphoid tyrosine kinase) and signaling pathways(Jak-3/STAT and NOTCH1). There have been reports suggesting an association between chronic cutaneous inflammation (e.g.: chronic urticaria, chemical exposure) and CTCL development. Infectious etiology has also been considered for both CTCL and PTCL, which include bacterial (staphylococcal enterotoxin) and viral association (retrovirus-like Human T-cell leukemia virus (HTLV)1 and HTLV2, HIV, EBV, CMV, HHV8), with a specific association of HTLV1 with adult T-cell lymphoma/leukemia and EBV with Natural-killer cell/T-cell lymphoma, and AITL.[rx] Enteropathy associated T-cell lymphoma(ETAL) is seen in association with celiac disease. T-cell activating autoimmune disease and family history of myeloma increases the risk of T-cell lymphoma.[rx]
Diagnosis
A diagnosis of AITL is made based upon the 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 and tonsil region, under the arms, on or near the elbows, and in the groin. They may also examine other regions to help determine whether there is an 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 diagnoses (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 examinations. 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), computed tomography (CT) scanning, and positron emission tomography (PET scan) 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. During a PET scan, three-dimensional images are produced to evaluate how healthy and functional certain tissues and organs are. This exam involves the use of a radioactive drug called a tracer. This drug is inhaled, injected, or swallowed by an individual, and will accumulate in areas where there are excess areas of chemical activity, which indicates disease. These areas will show up on the PET scan as brighter than the surrounding areas.
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 are first numbed with a 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. 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, PET scan). In addition, in some people, 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 (extra lymphatic 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 extra lymphatic organ or site and its regional lymph node region (with or without the 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 extra lymphatic organ or site.
- Stage IV – indicates widespread (disseminated) disease in which the malignancy is diffusely spread throughout one or more extra lymphatic 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 before diagnosis).
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.
Angioimmunoblastic T cell lymphoma
Initial evaluation, in addition to physical examination, should include complete blood count, comprehensive metabolic panel, LDH, HTLV-1, systemic imaging such as CT chest, abdomen, pelvis with contrast, or positron emission tomographic [PET-CT] scan, bone marrow evaluation, echocardiogram (before anthracycline therapy).[rx]
Diagnosis is based on clinical features, histopathologic features, immunophenotyping, and molecular studies.
Hematology
Some of the hematological abnormalities include polyclonal hypergammaglobulinemia, direct coombs positive autoimmune hemolytic anemia, and peripheral eosinophilia.[rx]
Histopathology
The cell of origin of AITL is the follicular T helper cell. There is dysregulation of T helper cells resulting in unchecked B cell activation and development of AITL. It is histologically characterized by effacement of normal lymphoid architecture, accompanied by a pleomorphic cellular infiltrate, resulting in loss of follicles and extensive intranodal revascularization. The cellular infiltrate includes B cells, plasma cells, histiocytes, and eosinophils. Some of the B cells are EBV+ reflecting the immunodeficient state.[rx][rx][rx]
Immunophenotyping and molecular studies
Immunophenotyping reveals that the malignant cells are CD3+, CD4+, and CD10+. CXCL13, uniformly expressed in neoplastic cells, is diagnostically significant, whereas CD30+, which is seen in about 20% of all AITLs, is therapeutically relevant.[rx][rx][rx] An abnormal karyotype is seen in AITL and frequently involves chromosomes 3 and 5. Clonal complexity is considered a negative prognostic factor.[rx][rx]
Laboratory findings
The classical laboratory finding is polyclonal hypergammaglobulinemia, and other immunoglobulin derangements are also seen, including hemolytic anemia with cold agglutinins, circulating immune complexes, anti-smooth muscle antibodies, and positive rheumatoid factor.[rx][rx]
Lymph node
The normal architecture of a lymph node is partially effaced by a polymorphous infiltrate and residual follicles are commonly seen. The polymorphous infiltrate consists of lymphocytes of moderate size with pale/clear cytoplasm and smaller reactive lymphocytes, eosinophils, histiocytes, plasma cells, and follicular dendritic cells. In addition, blast-like B-cells are occasionally seen. A classic morphological finding is the arborization and proliferation of high endothelial venules. Hyperplastic germinal centers and Reed-Sternberg-like cells can also be seen.[rx][rx]
Immunophenotype
AITL typically has the phenotype of a mixture of CD4+ and CD8+ T-cells, with a CD4:CD8 ratio greater than unity. Polyclonal plasma cells and CD21+ follicular dendritic cells are also seen.[rx]
Molecular findings
Clonal T-cell receptor gene rearrangements are detected in 75% of cases, and immunoglobin gene rearrangements are seen in 10% of cases, and these cases are believed to be due to expanded EBV-driven B-cell populations.[rx] Similarly, EBV-related sequences can be detected in most cases, usually in B-cells but occasionally in T-cells.[rx][rx] Trisomy 3, trisomy 5, and +X are the most frequent chromosomal abnormalities found in AITL cases.[rx][rx]
A diagnosis of diffuse large B-cell lymphoma may be uncovered concomitantly at the time of diagnosis of AITL or at relapse, warranting the need for re-biopsy if a relapse is suspected.
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 healthcare 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.
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 select individuals with no aggressive features of AITL, physicians may recommend waiting before implementing treatment until the disease leads to certain symptoms. In such instances, 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”.
The treatment options available for CTCL is palliative, not curative. Therapy can be divided into skin directed for early-stage disease and systemic therapy for later-stage disease (advanced nodal or visceral disease) and disease refractory to localized treatments. Topical therapy includes UV A with psoralen (PUVA), UV B, external beam radiation, total skin radiation, topical chemotherapy, and topical retinoids. Systemic therapy is achieved by Interferon-alpha, oral retinoids, targeted therapies, single or combination chemotherapy, and stem cell transplant. Corticosteroids are also used as both targeted and systemic therapy.[rx]
Retinoids help through antiproliferative and antiapoptotic properties. Commonly used topical regimens are bexarotene (FDA approved) and tazarotene. Severe hyperlipidemia and central hypothyroidism are side effects of bexarotene. Systemic retinoids include acitretin, isotretinoin, and bexarotene. Topical chemotherapy commonly used are mechlorethamine (nitrogen mustard), which is an alkylating agent, and carmustine. Systemic chemotherapy commonly used is methotrexate, pralatrexate, chlorambucil, gemcitabine, pegylated doxorubicin, and antimetabolite like fludarabine phosphate, 2-deoxycoformycin. PUVA inhibits DNA and RNA synthesis, but it will affect both normal and neoplastic cells, and thus the side effect profile is secondary malignancies of the skin. Histone deacetylase inhibitors (HDACi) are the newer group of therapeutic options available for the treatment of CTCL, which have both transcription-dependent and independent mechanisms of action for the expression of tumor suppressor genes. Vorinostat and romidepsin are FDA approved with an overall response rate of almost 50% with a tolerable side effect profile, the prominent one being cardiac arrhythmias from QTc prolongation. Targeted therapies include imiquimod (Toll-like receptor agonist), denileukin diftitox (recombinant fusion protein), alemtuzumab (a monoclonal antibody against CD52), and everolimus ( mTOR pathway target). Agents that are still undertrial are proteasome inhibitors like bortezomib. Allogenic stem cell transplant is used in advanced stages, usually appropriate for young patients with relapsing disease.[rx]
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.
Romidepsin is approved by the Food and Drug Administration for the treatment of individuals with peripheral T-cell lymphoma. The drug is a selective histone deacetylase (HDAC) inhibitor. Initial studies have shown the drug to be effective in individuals with AITL.
Investigational Therapies
Researchers are studying a variety of medications and procedures for the treatment of individuals with AITL. Of particular interest are drugs and other strategies to inhibit angiogenesis or to inhibit certain actions of the immune system. Standard chemotherapeutic agents to treat cancer in combination with therapies that affect the immune system (immunomodulators) to treat dysfunction of the immune system are also being studied.
Many different types of drugs have been used or are being studied to treat individuals with AITL including low dose methotrexate with corticosteroids, thalidomide, lenalidomide, bevacizumab, alemtuzumab, fludarabine, and 2-chlordeoxyadenosine. These drugs have had varying levels of success in inducing 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 analogs. One person described in the medical literature received effective treatment with the antibiotic, clarithromycin, and the corticosteroid, prednisolone.
The use of interferon alfa in association with or following chemotherapy is also under evaluation, such as for individuals who have had an 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 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 stem cells isolated earlier from circulating blood (peripheral blood) or bone marrow (autologous transplantation). These healthy stem cells are later re-infused into the bone marrow after the individual has been treated with chemotherapy. Initial results have demonstrated significant improvement in individuals with AITL treated by this procedure.
References
