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Systemic Mastocytosis – Patient Information Sheet Systemic mastocytosis is a disorder which can present in many ways. The symptoms or signs are due to an abnormal growth of mast cells in various sites for example skin, bone marrow and internal organs (e.g. liver or spleen). Mast have granules that can cause symptoms when released. The bone marrow may be abnormal in some patients due to an additional blood problem and these patients are treated differently from those with systemic mastocytosis without an additional blood disorder. Mast cells contain packets (or granules) of chemicals, including histamine, which can be released outside the mast cell. This chemical release can lead to symptoms such as flushes, indigestion (dyspepsia), abdominal pain, muscle/bone pain or changes in blood pressure (usually a fall known as hypotension). The severity of the symptoms will depend on the site or organ affected and the extent to which the mast cells have built up in that organ. The clinical symptoms of mastocytosis have been recognised since the middle of the 19th century but most of our current knowledge on how to diagnose and classify the disease has developed over the last 10 years. Diagnosis of Systemic Mastocytosis Mastocytosis is diagnosed as systemic when the patient has involvement of another organ apart from skin. This disorder has recently been shown to be associated with an activating mutation in the c-kit gene in about 85% of patients. This c-kit gene is important in controlling the development and maturation of bone marrow cells. The common c-kit mutation (known as D816V) leads to an increased production of abnormal mast cells, which is usually slowly progressive. The diagnosis of systemic mastocytosis is not always straightforward several different investigations may be required. Systemic mastocytosis is classified by the combination of symptoms, which organs are involved and how badly. We are still not fully aware of what the classification means for each patient and the majority of patients with systemic mastocytosis have a chronic, slowly progressive disorder. Treatment is usually only necessary to control symptoms. Most patients who are considered for further investigation have a skin eruption either in the form of Urticaria Pigmentosa (UP) or, rarely, Telengectasia Macularis Eruptiva Perstans (TMEP) or a solitary lesion called a mastocytoma. This diagnosis will have been made by the Dermatologist. A skin biopsy is usually done to confirm it in adults but this is not always necessary, especially in children. Skin disease in children (especially those under 2 years) usually stays in the skin, in adults more widespread or systemic disease is more common. A number of tests are often done if systemic mastocytosis is suspected. full blood count blood tryptase level ultra sound scan of the abdomen DEXA scan of the spine and hip bone marrow biopsy genetic testing for the c-kit D816V mutation The full blood count is a good indicator of how well the bone marrow is working. A normal full blood count usually means that if there are mast cells in the bone marrow, they are scanty or not present in enough numbers to affect the bone marrow function. Blood tryptase levels are thought to reflect the quantity of mast cells that may be in the body and a level of greater than 20ng/ml is currently believed to be the level to suggest bone marrow involvement. Tryptase levels can rise after anaphylaxis. It is therefore important that the tryptase level is measured when the patient is at his/her baseline level of health and not during or soon after an anaphylactic reaction. It is important to remember a tryptase level of greater than 20ng/ml alone does not lead to a diagnosis of systemic mastocytosis. An ultra sound scan is a simple test carried out to document the size of the spleen and liver. Some patients can develop an enlarged spleen, as mast cells can increase in numbers in the spleen as well as other organs. Sometimes this enlargement can be felt during an examination of their abdomen but this is unusual. A DEXA Scan is a special type of x-ray which looks to see if there is any evidence of osteoporosis, or thinning of the bones. This can sometimes be caused by accumulation of mast cells. Osteoporosis is more common in women than men as a rule as women commonly develop osteoporosis due to hormonal changes. The scan is used as a baseline and if there is evidence of osteoporosis medication can be started to try and slow the speed at which it develops or reverse it. A Bone Marrow Biopsy is recommended when the baseline blood tryptase levels are greater than 20ng/ml in adults or there are other reasons for suspecting systemic mastocytosis. Once consent is obtained this is usually carried out as a day case under a local anaesthetic. The bone marrow histology can give us important information: firstly, it can confirm the diagnosis of systemic mastocytosis when abnormal numbers or types of mast cells are seen within the bone marrow. Secondly, as more bone marrows are being examined, a scheme has been developed to differentiate between characteristics of the less aggressive (indolent or benign) mast cells from the more aggressive type of mast cells. Bone marrow findings cannot be interpreted on their own to classify the type of systemic mastocytosis, the blood count, tryptase level and the presence of any organ damage should be taken into account. Occasionally bone marrow involvement with mast cells is because there is another underlying blood disorder which itself increases mast cell production as part of a process different from systemic mastocytosis.
Bone Marrow Biopsy showing mast cells which are highlighted with special Mast Cell Tryptase Stain on the left. Codon 816 c-kit mutation (also known as D816V) can be tested for in the bone marrow or any organ involved with large numbers of abnormal mast cells. It is present in about 85% of patients. As there are usually very few mast cells in the blood, in most cases bone marrow samples are needed to give useful results. This c-kit mutation leads to increased levels of a protein receptor on mast cells called KIT (a tyrosine kinase) which is involved in controlling mast cell growth and causes increased numbers of mast cells in the bone marrow and elsewhere. Testing for this D816V c-kit mutation is important as new drugs (called tyrosine kinase inhibitors) are being specifically developed to target its function and slow or even stop the production of mast cells. Also, some drugs (for example, one called Glivec) may not be effective in patients who are shown to have this mutation. Classification of Systemic Mastocytosis The World Health Organisation has developed criteria which help us classify patients with systemic mastocytosis into 3 broad groups based on the information obtained after examination and the tests discussed above. This classification does not include patients who have mast cell leukaemia (see other leaflet) or when mast cells are increased due to other blood conditions.
Treatment of Systemic Mastocytosis Treatment is tailored to individual patients depending upon the extent of their disease and symptoms Systemic mastocytosis is not currently curable. Indolent systemic mastocytosis. Most patients have the indolent form of systemic mastocytosis and will need treatment to control the symptoms that result from the release of chemicals (or mediators) from the mast cells. Commonly used medications are anti-histamines for itching, antacids or antihistamines that reduce acid production for symptoms of indigestion. Bisphosphonates and calcium supplements are used for osteoporosis. Adrenaline (also called epinephrine) are used in patients who suffer from anaphylactic reactions (or severe allergies). Sodium cromoglycate may be useful in patients who have gut symptoms. Occasionally, steroids have been used with limited benefit in patients with frequent anaphylactic reactions or severe gut symptoms. Psoralen ultraviolet A (PUVA) therapy or other forms of ultraviolet treatment can provide temporary relief for some patients with severe itching. In those with increasing numbers of skin lesions it can lead to some temporary cosmetic improvement. Chemotherapy has no recognised role in indolent mastocytosis. Associated haematological non-mast cell Disease Patients with systemic mastocytosis associated with a another haematological disorder need the appropriate treatment for that haematological disorder. Aggressive systemic mastocytosis. Here there is damage to the tissues due to mast cells and the aim of treatment is to try and reduce the mast cell numbers as well as suppressing symptoms as discussed above. Different types of treatment are used and these include steroids, interferon alpha (IFNα), cladrabine (2 CDA) and, more recently, the use of tyrosine kinase inhibitors such as imatinib (or Glivec). Patients with the D816V c-kit mutation do not usually respond to treatment with Imatinib and newer agents such as Nilotinib and PKC412 (Midostaurine) have been tried with some success. Very few bone marrow transplants have been carried out for systemic mastocytosis and usually for the very few patients with aggressive and very advanced disease. Systemic mastocytosis is a very rare disorder. A mixture of symptoms and tests are needed to make the diagnosis. The vast majority of patients have a disorder that is indolent (very slow growing). The prognosis for these patients is good. A small minority of patients can have a more aggressive form of the disorder and will need treatment to try and stop or reduce the number of mast cells produced by the bone marrow. The prognosis for this set of patients is poor but more novel treatments are being looked into as we are finding out more about this disorder. Dr Deepti Radia Haematology Consultant Dr Claire Harrison Haematology Consultant Yvonne Frances Clinical Nurse Specialist MPD's Dept of Haematology, Guy’s & St Thomas’ Hospital NS Foundation Trust 4th Floor North Wing St Thomas' Hospital Lambeth Palace Road London SE17EH September 2007
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