Manifestation of SM strongly depends on the affected organ system. In this context, symptoms pointing at disturbances of the hematopoietic and immune system are most frequently seen, but symptoms regarding skin and gastrointestinal tract are also very common and still observed in more than half of all SM patients [7].

SM patients are more prone to anaphylactoid reactions because otherwise innocuous compounds may trigger mediator release. Presumably, the risk associated with bee or wasp stings is particularly high [8]. Food and drugs less frequently trigger such reactions, but risk awareness is of utmost importance since anaphylactoid reactions have been described after application of penicillin, non-steroidal anti-inflammatory drugs, narcotics and intravenous contrast agents [9] [10].

Urticaria pigmentosa, the most common symptom of cutaneous mastocytosis, is experienced by approximately 40% of SM patients. Pruritus and flushing can often be detected. With regards to the gastrointestinal tract, unspecific symptoms such as abdominal pain, nausea, vomitus and diarrhea are generally associated with SM. Due to increased histamine release, stomach acid production augments and some patients may report heartburn as an indicator of gastroesophageal reflux.

Musculoskeletal symptoms as well as those indicating anemia and coagulopathy may also be related to SM.

Of note, patients suffering from mastocytosis and other hematologic disorders may present additional symptoms that are not directly associated with SM. Myeloproliferative disorders such as the polycythemia vera, hypereosinophilic syndrome, different non-Hodgkin lymphoma and essential thrombocythemia have been related with SM.

Medical history and clinical picture should prompt laboratory analyses of blood samples. Complete blood counts and blood chemistry should be realized. The most common findings are anemia, leukocytosis and thrombocytopenia. Almost half of all SM patients present with anemia. Eosinophil, basophil and monocytic cell counts are often elevated. However, as has been indicated above, leukopenia and thrombocytosis have also been detected in cases of SM and should therefore not be considered exclusion criteria. Serum levels of mast cell mediator tryptase are often increased in SM patients. Total serum tryptase levels > 20 ng/ml and a ratio of total-to-beta tryptase > 20 are suggestive of SM [11].

Elevated urinary levels of the histamine metabolite N-methyl imidazole may further support the diagnosis.

Upon tentative diagnosis of SM, bone marrow fine-needle aspiration and biopsy need to be performed and analyzed.

Molecular biological tests may reveal further evidence for SM. The vast majority of SM patients tests positive for KIT gene mutation D816V. The degenerated mast cell clone is CD-117 positive and most likely CD-25 and/or CD-2 positive. Positivity for CD-25 has been proposed as a distinctive feature in relation to reactive mast cell hyperplasia [12]. Of note, cytogenetic abnormalities, particularly pathological karyotypes such as monosomy and trisomy, are seen in about 20% of SM patients.  The share of positive patients is higher among subgroups suffering from aggressive mastocytosis or mastocytosis associated with other hematologic disorders.

Imaging techniques may be helpful to assess the extend of organ damage. While liver, spleen and gastrointestinal tract will best be visualized by X-ray, ultrasonography or endoscopy, bone and joint involvement may be evaluated with computed tomography images. Biopsies may be required for further analysis.

Treatment is symptomatic and is based on preventing mast cell degranulation and inhibiting the effects of mast cell mediators.

In this context, H1- and H2-antihistaminika help to reduce allergic reactions and protect the gastrointestinal tract. Effectivity is not guaranteed for all H1- and H2-antihistaminika [13]. Cromoglicic acid should be administered to prevent mast cell degranulation (200 mg po qid in adults; 100 mg po qid in children aged 2 to 12 years, maximum 40 mg per kg body weight and day). Although acetylsalicylic acid controls flushing, it may aggravate other symptoms triggered by mast cell mediators and is therefore not recommended.

Immunomodulatory therapy is indicated in patients suffering from more aggressive forms of SM. Corticosteroids may be administered (e.g., prednisone, up to 60 mg po qd for up to 3 weeks). IFN-α may be administered in a dose of up to 3 million units per day to treat bone lesions [14].

Cytostatics may be required to treat mast cell leukemia. There is little data regarding the effectivity of determined compounds. Tyrosine kinase receptor inhibitors may slow down mast cell proliferation, but imatinib is ineffective in patients with KIT gene D816V mutation. Midostaurin is currently under study. Daunomycin, etoposide and 6-mercaptopurine may be applied.

Some patients may benefit from splenectomy. In order to prepare SM patients for surgery, special guidelines should be followed [10].

Prognosis is strongly dependent on the subtype of SM. A good prognosis is associated with indolent SM. For this kind of disease, a median survival time of about 18 years has been calculated. Considering the average age of patients at the moment of diagnosis, this is not significantly different from the general population. The median survival time for patients suffering from aggressive SM is considerably lower and has been estimated to range between 3 and 4 years. If SM is diagnosed in patients that simultaneously suffer from other hematological disorders, the median survival time reduces to 2 years. Mast cell leukemia is associated with a poor prognosis and a median survival time of only two months. While there is not always a clearly defined transition from one subtype to another, it is unlikely for an indolent SM to transform into mast cell leukemia [6].

Additional parameters have been defined to allow for a more specific prognosis. In this context, old age, hepatosplenomegaly, ascites, weight loss in the course of the disease, anemia (hemoglobin < 10.0 mg/dl), excess bone marrow blasts (> 5%), thrombocytopenia (platelet count < 150,000/μl), hypoalbuminemia (albumin < 3.5 g/dl), elevated levels of alkaline phosphatase and lactate dehydrogenase are considered unfavorable prognostic parameters.

Most cases of SM may be ascribed to mutations of the KIT gene that encodes for the proto-oncogene c-kit [3] [4]. Nearly 70% of all SM patients present the KIT D816V mutation. The KIT gene is mainly expressed on hematopoietic stem cells. c-kit is a member of the tyrosine kinase family and forms a cell surface receptor that binds cytokines. It stimulates growth and proliferation promoting intracellular pathways upon activation. In this context, any mutation enhancing cytokine binding or tyrosine kinase activity, any mutation interfering with ligand dissociation or receptor deactivation may trigger uncontrolled growth and proliferation. In fact, KIT mutations related to SM are gain-of-function mutations and yield excessive numbers of mast cells that subsequently infiltrate different organs.

Reliable data regarding SM incidence can only be provided for specific regions. In this line, a study realized in Great Britain determined SM incidence to be about 7 per 1,000,000 inhabitants.

While SM may be detected in children, the majority of cases occurs in adults.

In patients suffering from SM, increased numbers of mast cells can be found in several organs. The skin may or may not be involved in the disease process.

Mast cells derive from hematopoietic cells in the bone marrow. If for any as of yet unknown reason mutations affect the KIT gene expressed by those cells, mast cells start to proliferate in an uncontrolled manner. Clones of the degenerated mast cell may subsequently spread through the cardiovascular system and will easily reach liver, spleen, lymph nodes, the gastrointestinal tract, particularly stomach, small intestine and pancreas, as well as other organ systems [5].

The vast majority of adult SM patients presents focal mast cell lesions in their bone marrow. Bone marrow and blood cell counts, however, have to be interpreted with caution. Excess mast cell proliferation in the bone marrow does usually not affect erythropoiesis. Numbers of eosinophil granulocytes, which also originate from myeloid precursor cells, may even be increased. Despite the augmented mast cell proliferation, the overall number of cells as visible in bone marrow samples is not necessarily enhanced. This apparent contradiction may possibly be explained with general shifts in blood cell counts. Lymphocyte counts, for instance, are usually diminished. Of note, these parameters may only serve for rough orientation since there are significant shares of patients who present with anemia, leukopenia or leukocytosis, thrombocytopenia or thrombocytosis. Finally, hypocellular bone marrow indicates advanced stages of the disease and is associated with a poor prognosis.

Furthermore, mast cell infiltrates may be detected in the above mentioned organs and may interfere with their respective function. With regards to the spleen, some patients show diffusion infiltration of the red pulp, while others depict focal infiltration of the white pulp. Mast cell infiltration in lymph nodes is most often seen in the paracortical area, but sometimes follicles and medullary sinus are also affected.

The immune system of SM patients is weakened for two reasons. On the one hand, mast cells infiltrate immune organs and impede their correct function. On the other hand, mast cells themselves release cytokines such as interleukin 4 that promotes T helper cell differentiation towards type 2. Immunoglobulin E synthesis and histamine release are also stimulated. Indeed, SM patients have a higher risk for peptic ulcers due to elevated histamine levels and excess stomach acid.

No preventive measures can be recommended.

Mastocytosis refers to a condition of elevated numbers of mast cells. While the majority of mastocytosis cases is limited to the skin, systemic mastocytosis (SM) affects several other organ systems. SM is characterized by mast cell infiltration in skin, lymph nodes, liver, spleen, gastrointestinal tract, bones and joints [1] [2].

SM is usually triggered by acquired gene mutations and typically diagnosed in adults. Inheritable forms of the disease exist, may affect several members of one family, but are less common.

A patient does not necessarily show increased numbers of mast cells in all the above mentioned organs. Therefore, symptoms may differ widely between individual patients. They are mainly determined by the organ systems that are compromised. In general, four types of SM are distinguished:

• An indolent mastocytosis will be diagnosed if mast cell proliferation does not interfere with organ function. Its prognosis is good.
• In contrast, aggressive mastocytosis is associated with more severe symptoms and a less favorable prognosis because it does impair the functionality of the organs affected.
• In some cases, mastocytosis and other hematologic disorders, e.g., myeloproliferative disorders and lymphoma, will be diagnosed in the same patient.
• An unfavorable prognosis is associated with mast cell leukemia. This condition is defined as a bone marrow mast cell content that exceeds 20%. While there are typically no skin lesions, patients may die from multi organ failure.

Mast cells pertain to the immune system. They fulfill important function in immune defense, wound healing and other processes. If mast cells proliferate in an uncontrolled manner and infiltrate several organs throughout the body, this condition is called systemic mastocytosis (SM).

Causes

Most cases of SM result from acquired mutations of the KIT gene. This gene is expressed by hematopoietic stem cells in the bone marrow and encodes for a cell surface receptor that controls cell growth and proliferation. The mutation that accounts for the majority of SM cases renders this receptor constantly active. The consequence is excess mast cell proliferation and spread throughout the body.

Symptoms

Mast cells may infiltrate skin, lymph nodes, liver, spleen, gastrointestinal tract, bones and joints. Thus, symptoms vary widely and may include flushing and pruritus, abdominal pain, nausea, heartburn, vomiting, diarrhea, bone and joint paint, among others.

Diagnosis

Symptoms are rather unspecific and only allow for a tentative diagnosis of SM. Laboratory analyses of blood samples may reveal anemia, high counts of white blood cells and lack of platelets and thus support the above mentioned diagnosis. However, analyses of bone marrow aspirates and biopsies are essential to confirm diagnosis of SM and to specify which subtype the patient suffers from.

Imaging techniques may be applied to assess the damage to internal organs.

Treatment

Only symptomatic treatment can be provided. Therapy aims at avoiding mast cell degranulation and inhibiting mast cell mediator effects. This may be realized with mast cell stabilizers and antihistamines. However, mast cell proliferation can hardly be reduced. In severe cases, cytostatics will probably be administered, but their effectivity is not guaranteed.

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