The Lymphatic System
In order to understand ATL better, it is useful to understand the lymphatic system. The lymphatic system is part of the body’s immune system which includes
• Lymph nodes – there are groups of lymph nodes throughout the body including in the neck, armpits, groin, chest and abdomen. They are connected by a network of fine tubes called lymphatic vessels. Lymph nodes filter bacteria and viruses and often swell up when they are fighting infection (“swollen glands”).
• Lymphocytes – the lymph nodes contain lots of infection-fighting white blood cells known as lymphocytes. There are two main types of lymphocyte known as B-cells and T-cells. ATL is a cancer of the T-cells.
• Lymphatic organs – such as bone marrow (where blood cells are made), lymph nodes, tonsils, thymus, testicles, spleen
What is ATL and how does it develop?
ATL is a rare type of blood cancer and only seen in people infected with HTLV-1. There are approximately 10- 20 new cases per year in the UK. ATL may cause either a lymphoma, which is a cancer white blood cells in the lymphatic system, or a leukaemia which is a cancer of the white blood cells in the blood. The type of leukaemia may be acute (faster growing) or chronic (slower growing). ATL is a type of non-Hodgkin lymphoma.
During HTLV-1 infection, the virus lives inside T-cell lymphocytes that circulate in the blood and lymph nodes. HTLV-1 may live silently within the T-cells without causing any problems and the amount of infected T-cells is controlled by the immune system. Like all cells in the body, they are replaced as they get older or damaged. This happens by a process called cell division- when a cell divides and makes two new cells. This is usually a carefully controlled process, but if the process gets out of control for whatever reason, too many cells can be made too quickly, which are often unhealthy cells, and a cancer develops.
In ATL, the HTLV-1 infected T-cells become abnormal and keep dividing, growing out of control and cannot be controlled by the immune system. They are then called leukaemic cells or lymphoma cells. Over time, the number of lymphoma cells increases and they form lumps called tumours. The most common place for these lumps to occur is in a lymph gland, but because lymphatic vessels are all over the body, the tumours can occur almost anywhere in the body including stomach, skin, tonsils and brain.
Because the lymphocytes travel around the body, ATL can spread from where it first started through the lymphatic system from lymph nodes in one part of the body to another. Lymphoma cells can also travel in the bloodstream to organs such as the bone marrow, skin, liver or lungs and form new tumours at these sites.
Who gets ATL?
Less than 5% of HTLV-1 carriers will develop the disease during their lifetime. In the UK, the average age of first presentation of a patient with ATL is 53 years. It is not yet known exactly what causes an HTLV-1 carrier to develop ATL, but risk factors include:-
• Being infected with HTLV-1 as a baby - when the virus lives in the body for many decades, there are more opportunities for damage to lymphocytes and development of cancer.
• HTLV-1 carriers with high proviral loads (the amount of virus in the body) which suggests the immune system is less able to control the virus.
• Males with HTLV-1 are at increased risk of ATL compared with female carriers (see also the section on mother to child transmission and ATL).
There are no known environmental risk factors, such as radiation or exposure toxic chemicals.
Types of ATL
ATL is grouped (classified) into four subtypes according to certain characteristics. This classification is known as the Shimoyama classification.
• Acute The symptoms develop rapidly, and quite quickly ATL becomes life-threatening if not treated. Common symptoms include tiredness, skin rash, lymph node swelling, fevers and infections. Examination and scans may also reveal enlargement of the liver and spleen. Blood tests show a raised white blood count containing abnormal cells and high levels of calcium in the blood. Scans may also show evidence of bone damage.
• Lymphoma The symptoms develop rapidly, and quite quickly ATL becomes life-threatening if not treated. The commonest symptom is of lymph node swelling. The blood counts will be completely normal. For unknown reasons all the cancerous lymphocytes stick inside the lymph nodes and do not circulate in the blood.
• Chronic This is a more slow growing type of ATL compared with acute or lymphoma subtypes. The common symptoms include skin rash and tiredness but many patients are completely well and the condition is detected on a routine blood test due to the increased number of white blood cells. Approximately half of these patients will later develop acute or lymphoma type ATL. Blood tests can show some favourable or unfavourable factors which can help guide treatment.
• Smoldering This is a slower growing type of ATL compared with acute or lymphoma subtypes. The commonest symptom is skin rash or abnormal lumps growing on the skin. The blood counts are normal but by looking at the blood under the microscope and with specialised molecular tests there may be evidence of slow growing ATL within the blood. Individuals with smoldering ATL may later develop chronic, acute or lymphoma type ATL.
What are the symptoms of ATL?
The symptoms of ATL will vary, but it’s often a painless swelling of lymph glands in the neck, armpit or groin. Lymph nodes in several different areas of the body are frequently involved. Skin rashes often occur and it may affect other organs of the body such as liver, spleen, stomach or bowel causing symptoms. Some patients experience loss of appetite and tiredness. Other symptoms may include night sweats, high fevers and weight loss (together known as B-symptoms).
How is ATL diagnosed?
Usually the diagnosis can be made by looking at blood counts, examining the blood cells under the microscope and undertaking specialised tests to distinguish ATL from other types of cancer and to confirm the presence of HTLV-1 infection. Frequently a sample of an enlarged lymph node is required (a biopsy). A biopsy is usually a small procedure performed under local or general anaesthetic to remove a piece of the tumour for further analysis. Biopsies may be required from other parts of the body such as skin or bone marrow. Sometimes a lumbar puncture is required to look for evidence of spread to the brain. A lumbar puncture is a usually painless procedure under local anaesthetic in which a fine hollow needle is inserted carefully between the bones of the lower back and into the fluid below the lower part of the spinal cord. The fluid (cerebrospinal fluid) is collected for analysis.
Other tests include scans such as a PET or CT scan which are undertaken to get more information about the type of lymphoma and how far it has spread in the body. This information is used to help decide which treatment is most appropriate.
Staging and grading
Grading: for practical purposes ATL can be considered in two groups, low-grade and high-grade. The low grades (chronic and smoldering subtypes) are generally, but not always, slow-growing. The high grade (acute and lymphoma subtypes) tend to grow more quickly and usually need prompt treatment.
Staging: only lymphoma subtypes require staging. This describes how many groups of lymph nodes are affected, where they are in the body and whether any other organs such as the bone marrow or liver are affected.
• Stage 1: the lymphoma is only in one group of lymph nodes, in one area of the body
• Stage 2: more than one group of lymph nodes are affected, but in the same half of the body (the body is split in half by the diaphragm muscle which sits below the lungs).
• Stage 3: the lymphoma is present in lymph nodes in both halves of the body (above and below the diaphragm).
• Stage 4: the lymphoma has spread beyond the lymph nodes to other lymphatic organs e.g. the bone marrow, liver or lungs
The stage usually includes the letter A or B, which describes whether B symptoms are present (e.g. stage 2B) or not (e.g. stage 2A). Sometimes a lymphoma can start in areas outside the lymph nodes, and this is represented by the letter E, which stands for extranodal (e.g. stage 3AE).
How can ATL be treated?
The high grade subtypes (acute or lymphoma), usually require prompt and strong treatment whereas the low grade subtypes (chronic or smouldering) can often be treated with less-intensive therapies, unless they start behaving more aggressively, in which case they are treated similarly to the high grade subtypes.
Not all patients with smoldering type ATL will require immediate treatment, and some patients may be kept under ‘active monitoring’ where the skin and blood tests are closely monitored. In some cases a dermatologist may recommend skin-only therapies (topical treatments).
Other treatments used in ATL include “anti-viral” based therapy (zidovudine and interferon-α, ZDV/IFN-α) chemotherapy, immunotherapy and bone marrow transplants. Radiotherapy may occasionally be used to treat early stage lymphoma or for symptom control. Sometimes skin-only treatments (topical treatments) are used to treat isolated skin disease. The main principle of each therapy is described.
Chemotherapy uses anti-cancer (cytotoxic) drugs to destroy cancer cells. Chemotherapy is required to treat the lymphoma subtype of ATL, and to treat chronic/acute subtypes of ATL that do not respond to ZDV/IFN-α.
Usually a combination of different chemotherapy drugs is used, but the optimal combination is not known. If available patients with ATL are invited to participate in a clinical trial that’s trying to find out which drugs work best. The standard ATL therapy is called CHOP. It includes the chemotherapy drugs vincristine, doxorubicin, cyclophosphamide and the steroid prednisolone. CHOP may be given in combination with other drugs such as etoposide. In some cases of ATL, low doses of antivirals may be given alongside the chemotherapy.
If the lymphoma does not respond sufficiently to CHOP-based treatments, other therapies may be considered including high dose chemotherapy which may include drugs such as gemcitabine or etoposide.
Zidovudine/Interferon-alpha (ZDV/IFN-α) is sometimes referred to as anti-viral therapy. This is a more effective treatment in patients with leukaemic types of ATL who have minimal lymph nodes involved (usually chronic subtype and some acute subtypes). This type of treatment is often continued indefinitely. It involves daily tablets and injections under skin, which many patients learn to give themselves. The frequency of injections varies from once daily to once weekly.
Side-effects which are usually worse at first and lessen over time include flu-like symptoms, tiredness, loss of appetite, nausea, susceptibility to infections, depression. Simple treatments such as paracetamol and anti-sickness tablets can help prevent these side-effects.
Monoclonal antibodies Monoclonal antibodies are artificial antibodies against a particular target on the tumour cell. Monoclonal antibodies are now widely used in cancer treatments and several have been used in ATL. The optimal target in ATL and the best antibody are still not known. It is also unknown where in the course of treatment antibodies should be incorporated. Patients with ATL may be invited to participate in a clinical trial that’s trying to find out which monoclonal antibodies should be used in ATL.
Allogeneic (donor) stem cell transplantation is the replacement of a patient's bone marrow and immune system with that of a donor's. This gives the patient a new, healthy bone marrow and immune system that can fight any remaining cancer cells. At present, this is the only completely curative treatment method for ATL but even with transplantation cures is not guaranteed. Donor transplants are specialised and complicated treatments, with significant risks, and only a small proportion of patients with ATL are be able to receive a stem cell transplantation.
ATL research in the UK and worldwide
Since its discovery in the early 1980's, HTLV-I and its related diseases have been a focus of research by scientists and doctors around the world.
The aim of research into ATL is to find ways to prevent disease development and to design more effective treatments including approaches to enhance the patient’s own immune response to the virus.
There is a clinical need to enrol patients with ATL into clinical trials to improve cancer care and survival. The aim of clinical trials is to test new treatments, such as chemotherapy drugs or new targeted therapies; to look at new combinations of existing drugs or to reduce their side effects; and to find out how they work. Clinical trials provide the evidence that doctors and patients need, so treatments offered are the safest and most effective.
ATL is a cancer of white blood cells called T-cells exclusively affecting people infected with HTLV-I. In the UK the majority of infected people are descendants from the West Indies or West Africa. Only 1 in 20 HTLV-1 infected persons will develop ATL.
There are factors that make one person to be more susceptible to the disease than another. These include time of the infection (at birth or later in life), the amount of virus the person carries, the ability of person's immune system to respond to the infection.
ATL varies in its forms from acute aggressive to milder less aggressive subtypes.
Aggressive forms are difficult to treat and survival has been measured in months rather than years. The only treatment that potentially offers cure is a donor stem cell transplant, but this treatment has a high early death rate due to the procedure.
Useful UK charities providing information and support on lymphoma/blood cancer care
Macmillan Care www.macmillan.org.uk
The Lymphoma Association www.lymphomas.org.uk
Leukaemia Care www.leukaemiacare.org.uk
The National Centre for Human Retrovirology Clinic Imperial College Healthcare NHS Trust, Ground Floor, Winston Churchill Wing, St Mary's Hospital, Praed Street, London W2 1NY