What is T-Cell Lymphoma?
The lymphoid system forms the backbone of our body’s immune response. It’s made up of NK cells that provide innate (natural) immunity and B and T cells that offer adaptive (acquired) immunity. A disease of these immune cells is known as Non-Hodgkin lymphoma (NHL). Understanding these cells, from their formation to maturation, is essential for diagnosing and managing this range of diseases.
T-cell lymphomas are a large group of rare diseases that can either be slow-growing or aggressive, making up 12% of all NHL cases. Since NK cells are closely related to T-cells, their cancers are also included in this group. In 2016, the World Health Organization updated their classification for lymphoma, separating T-cell/NK-cell lymphomas into ‘precursor’ and ‘mature’ subcategories, with the mature group further categorized into leukemic, nodal, extranodal, and skin-related diseases.
NHL can also be separated into slow-growing or aggressive diseases. Slow-growing lymphomas often have a prolonged disease course and are usually resistant to standard chemotherapy. In contrast, aggressive diseases often involves sudden onset of symptoms and quick progression. Cutaneous T-cell lymphoma (CTCL) is considered slow-growing, whereas peripheral mature lymphomas—encompassing all the other types—are seen as aggressive. Most of the CTCL cases are made up of diseases called mycosis fungoides (MF) and Sezary syndrome (SS). Among the peripheral mature lymphomas, unspecified types (PTCL-NOS) are the most common, followed by anaplastic large cell lymphoma (ALCL) and angioimmunoblastic T-cell lymphoma (AITL).
What Causes T-Cell Lymphoma?
The exact cause of most T-cell Lymphoma, a type of blood cancer, isn’t fully known. Cutaneous T-cell Lymphoma (CTCL), one type of T-cell Lymphoma, is thought to occur as a result of certain genes and cellular communication pathways not functioning correctly.
There are also suggestions pointing to the connection between long-lasting skin inflammation (like chronic hives and exposure to certain chemicals) and the development of CTCL.
The role of certain bacteria and viruses in the development of CTCL and Peripheral T-cell Lymphoma (PTCL), another type of T-cell Lymphoma, is also considered. For example, specific bacteria and viruses like Human T-cell leukemia virus (HTLV) 1 and 2, HIV, Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), and Human Herpes Virus 8 (HHV8) have shown possible associations. HTLV1 is specifically related to adult T-cell lymphoma/leukemia while EBV has been associated with Natural-killer cell/T-cell lymphoma and Angioimmunoblastic T-cell Lymphoma (AITL).
It’s also important to mention that a type of T-cell lymphoma called Enteropathy Associated T-cell lymphoma (ETAL) has been associated with celiac disease, a condition that impairs digestion. Lastly, having a T-cell activating autoimmune disease or a family history of myeloma, another type of blood cancer, can heighten the risk of developing T-cell lymphoma.
Risk Factors and Frequency for T-Cell Lymphoma
The occurrence of T-cell lymphoma, a type of cancer that affects a certain kind of white blood cell, increases as people get older. Where a person lives and their ethnic background can affect how likely they are to be diagnosed with this disease. People between the ages of 55 and 74 are most commonly diagnosed with PTCL, a particular type of T-cell lymphoma, and it is more frequently found in men. The exact type of T-cell lymphoma can also vary based on location – PTCL-NOS is more common in North America, while EBV-associated lymphomas are found mostly in Asia and Central and South America.
Adult T-cell lymphoma is more common in Japan and the Caribbean islands. ETAL, another subtype of the disease, is associated with HLA DQ2 and DQ8 – proteins that are also linked to celiac disease. Younger individuals can commonly be diagnosed with ALK-positive ALCL and hepatosplenic T-cell lymphoma. MF and SS, two different types of the disease, are slightly more common in the African-American population and less common in Asia.
Signs and Symptoms of T-Cell Lymphoma
When it comes to diseases like Cutaneous T-cell Lymphoma (CTCL) and Peripheral T-cell Lymphoma (PTCL), the early signs and symptoms can be hard to identify, and thus these conditions often go unrecognized until they’re in advanced stages. That’s because the initial symptoms usually resemble non-threatening conditions.
CTCL typically starts as skin lesions, appearing as patches or spots in the early stages, primarily on parts of the body that don’t get much sun exposure. But as the disease advances, these lesions can turn into plaques, tumors, or nodules and may spread to other body parts. It could even progress to Sézary syndrome, which is a more aggressive form of CTCL characterized by an extensive red rash, enlarged lymph nodes, and abnormal white blood cells observed in the blood, skin, and lymph nodes.
PTCL, on the other hand, can affect various parts of the body including the lymph nodes, liver, and spleen, and can also present as skin involvement. It’s not uncommon for patients to experience symptoms like fever, night sweats, and weight loss. There are also several paraneoplastic syndromes, or disorders triggered by an abnormal immune response to a cancerous tumor, that can be associated with PTCL, such as excessive white blood cells, hemophagocytic syndrome, and autoimmune-related phenomena. One rare type of PTCL, known as subcutaneous panniculitis-like T-cell lymphoma, can present as painless nodules or skin plaques and is often misdiagnosed as an infection or inflammation.
NK/T-cell lymphomas, another subtype of PTCLs, tend to affect the breathing and digestion routes, particularly the nose, causing nasal obstruction, nosebleeds, and bone decay. Some types of T-cell lymphoma, like adult T-cell lymphoma and hepatosplenic T-cell lymphoma, can manifest in both skin-related and other symptoms, like high levels of calcium in blood and destructive lesions in bones.
Noticing these symptoms early and seeking medical help can make treatment more effective, leading to better outcomes.
Testing for T-Cell Lymphoma
Diagnosing Cutaneous T-cell Lymphoma (CTCL) can be a long process, taking around six years from the time symptoms first appear. This is because early CTCL symptoms often look similar to benign (non-cancerous) skin conditions. To help solve this, your doctor may suggest several tests.
One will likely be a peripheral smear examination, where they test a sample of your blood, and a bone marrow aspirate, where they take a small sample of your bone marrow. Both these tests can help doctors spot signs of CTCL or other similar conditions. They may also do tests called immunophenotyping and molecular cytogenetics, to understand more about the disease. These tests help identify the specific types of cells involved and whether they are normal or abnormal.
If the results are not clear, your doctor might suggest additional tests, such as analyzing a sample of your peripheral blood (blood circulating in your body) for malignant (cancerous) T-cells, a type of white blood cell. A biopsy, a procedure to get a small sample of tissue from a lymph node or other area, can also provide valuable information for diagnosing CTCL.
Specific markers on the cells, known as antigens, can also be helpful in identifying the type of lymphoma. Specifically, cells in some types of T-cell lymphoma, known as ATCL and AITL, are usually marked as CD4+/CD8-. Identifying which markers are present helps doctors get a more accurate diagnosis.
As the disease advances, more tell-tale signs might start appearing. Doctors will look for the presence of the proteins Ki67, CD34, and AgNORs, which typically show up as the disease progresses. The presence of something known as the soluble IL-2 receptor – a molecule that is only released during certain immune responses – could signal the severity of the disease and help determine the prognosis. Other diagnostic markers may include miRNA profiling, TOX gene, EPHA4, and ALCL cells that are CD30+.
Note that the loss or overexpression of certain markers like CD26, CD27, CD7, CD164, CD10, CD56+, and CD30 + can also be indicators of certain types of lymphomas. Getting these tests done can be critical in determining the most effective treatment plan.
Treatment Options for T-Cell Lymphoma
The first step in managing lymphoma is to correctly identify the type it is. This is done by taking a biopsy; a small sample of tissue from the affected area. Doctors will then analyze this sample to determine what type of lymphoma is present and how far it has spread.
To see the extent of the disease, doctors often use computed tomography (CT) scans and FDG PET/CT scans, which are more sensitive than traditional CT scans. They can also use Magnetic Resonance Imaging (MRI), especially when lymphoma has spread to soft tissues.
Regarding the treatment of Cutaneous T-Cell Lymphoma (CTCL), the treatments available are generally aimed at relieving symptoms rather than curing the disease. The type of treatment chosen depends on the stage of the disease. For early-stage disease, treatments focus on the skin; this could include ultraviolet light therapies, radiation, topical chemotherapy, and topical forms of drug treatments called retinoids. For later-stage disease or disease that does not respond to localized treatments, doctors use systemic therapy, which involves using medication that travels through the bloodstream to reach cells throughout the body. Systemic therapy can include several types of medications, including interferon-alpha, oral retinoids, targeted therapies, single or combination chemotherapy drugs, and may also involve a stem cell transplant.
Three retinoids are typically used: bexarotene, acitretin, and isotretinoin. Their job is to slow down the growth of the cancer cells, but they may have some side effects such as hyperlipidemia (too many fats in the blood) and central hypothyroidism (your thyroid doesn’t produce enough hormones).
There’s also a new class of drug treatments, called histone deacetylase inhibitors (HDACi), which have been shown to be another effective treatment for CTCL, but it can cause heart rhythm abnormalities. Other targeted therapies are also being used, with some still being tested.
In the treatment of Peripheral T-Cell Lymphomas (PTCL), the regimens are chosen based on small-scale studies as there are not enough larger clinical trials due to the rarity of the disease. The standard chemotherapy regimen for PTCL involves a combination of different drugs, including cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (known as CHOP). A few variants of this regimen also exist. Some additional therapies are being tested, including brentuximab vedotin and romidepsin, with these currently being in phase III of clinical trials.
In cases of lymphoma localized to one place, a chemoradiotherapy using various medications is used, whereas for advanced disease, a different regimen exists. In very severe cases, the best treatment modality is unclear and such patients should be enrolled in a clinical trial.
Finally, in cases where the disease has come back or does not respond to other treatments, autologous stem cell transplantation (ASCT), where stem cells are removed before treatment and then returned afterward, may be an option if the patient is a candidate. If a patient is not eligible for transplant, other chemotherapy regimens can be more tolerable.
What else can T-Cell Lymphoma be?
When a healthcare professional is considering a diagnosis of Cutaneous T-Cell Lymphoma (CTCL), the following conditions might also be considered due to their similar appearances:
- Atopic/contact dermatitis (skin inflammation caused by contact with certain substances)
- Drug eruptions (skin reactions due to certain medications)
- Erythrodermic psoriasis (a severe form of psoriasis that leads to redness and shedding of the skin)
- Lichen planus (a skin rash caused by an immune response)
- Cutaneous B-cell lymphoma (a type of skin cancer)
- Subcutaneous panniculitis t-cell lymphoma (a type of lymphoma that affects the fatty layer of skin)
Meanwhile, for Peripheral T-Cell Lymphoma (PTCL), the following conditions might be differential diagnoses due to their similar symptoms:
- Other subtypes of T-cell lymphoma (various types of cancer affecting white blood cells)
- B-cell lymphoma (a type of lymphoma that starts in white blood cells)
- Granulomatous histiocytosis (a rare disease that causes inflammation of certain immune cells)
- Paracortical hyperplasia (an abnormal growth of cells in lymph nodes)
It’s crucial to highlight that correct diagnosis in both CTCL and PTCL cases is essential to make sure the patient receives proper treatment.
What to expect with T-Cell Lymphoma
At the initial stages, cutaneous T-cell lymphoma (CTCL – a type of cancer that begins in the white blood cells and attacks the skin) does not shorten the life expectancy compared to healthy adults. However, as the disease worsens and spreads, it can have a negative impact on life expectancy. Mycosis fungoides (MF – a common type of CTCL) is a disease that lasts a lifetime, and it can return even after treatment. Many patients who have a long-term history with MF eventually pass away from a disease other than MF. Sézary syndrome (SS – a more aggressive type of CTCL) has a lower survival rate, with most people living between 3 to 4 years after diagnosis.
Peripheral T-cell lymphoma (PTCL – another type of cancer that affects the lymphatic system) has a less favorable outlook compared to a similar cancer that affects B-cells (white blood cells that help protect the body against infections). The international prognostic Index is a tool doctors use to predict the course of the disease. It uses factors like age, overall health status, stage of cancer, and areas of the body affected to determine the outlook. Even if someone has a lower score on this index, PTCL is still typically considered to carry a worse prognosis. Certain markers or proteins, like p53 or BCL-2, can indicate a poorer prognosis, while others like AKL or TCR BF1 suggest a better prognosis.
Possible Complications When Diagnosed with T-Cell Lymphoma
Patients with weakened immune systems and higher rates of secondary cancers, particularly lymphomas, are at a greater risk of infection. Acute T-cell lymphoma/leukemia is often associated with high calcium levels in the blood and damage to the bones. Damage to the bones can also occur in a type of lymphoma that affects the nose and other non-lymphatic organs, called Extranodal Nk/T-cell lymphoma, nasal type. This type of cancer can additionally affect the skin, digestive tract, lungs, and adrenal glands.
In Cutaneous T-cell Lymphoma (CTCL), a kind of lymphoma that starts in the skin, the cancer cells may change into more aggressive forms, a process known as large cell transformation. Another type of cancer called Precursor T-cell lymphoblastic lymphoma can cause a condition called superior vena cava syndrome, cause blockage in the windpipe, and lead to fluid accumulation around the lungs or heart. In Mycosis Fungoides (MF), a type of CTCL, the lesion can ulcerate, or break open.
- Greater risk of infection in patients with weakened immune systems and secondary cancers
- High blood calcium levels and bone damage in Acute T-cell lymphoma/leukemia
- Bone damage and impact on nose, skin, digestive tract, lungs, and adrenal glands in Extranodal Nk/T-cell lymphoma, nasal type
- Large cell transformation in CTCL
- Superior vena cava syndrome, windpipe blockage, and fluid accumulation around the lungs or heart in Precursor T-cell lymphoblastic lymphoma
- Ulceration in Mycosis Fungoides
Preventing T-Cell Lymphoma
Patients need to understand the origin, progression, and likely outcomes of their condition. Research shows reversible factors, like long-term chemical exposure/pesticides and HTLV-1 infection, which can be transmitted. It’s crucial for patients to stop being exposed to these chemicals, stay safe when handling body fluids, and practice safe sex.
