Mast cell leukemia (MCL) is a very rare form of systemic mastocytosis. Patients typically present with symptoms of mast cell activation, involvement of liver, spleen and lymph nodes. Diagnostic criteria have been published by the World Health Organization and comprise those for systemic mastocytosis and the presence of at least 20% of mast cells in a bone marrow aspirate smear. Due to the rarity of the disease, therapeutic guidelines have not yet been established. Patients are usually treated with tyrosine kinase inhibitors, cytoreductive therapy, or allogeneic stem cell transplantation. Despite all efforts, mortality remains high and survival times are short.
Upon activation, mast cells release a wide variety of mediators, such as tryptase and histamine . MCL patients often present with symptoms of mast cell activation, i.e., with symptoms resulting from the effects of mast cell mediators on distinct tissues and organs. In this regard, fever, asthenia, malaise, headache, flushing, tachycardia and diarrhea are commonly reported. Furthermore, MCL patients tend to lose their appetite and may consequently lose weight. The latter may be due to gastroduodenal ulcers, or because of hepatomegaly and splenomegaly, which are common findings in those suffering from MCL. An involvement of liver and spleen is observed in about two thirds of all patients . Some also suffer from ascites. Less frequently, lymph node involvement can be demonstrated. MCL patients may occasionally present with urticaria pigmentosa, but skin changes are not characteristic of the disease  . While other organ systems, namely the cardiovascular system, the respiratory and genitourinary tracts may be involved in MCL, such findings a rare. Organ involvement may be assessed by means of diagnostic imaging and histological examinations of tissue samples .
It is important to remember that MCL may occasionally be associated with diseases like chronic myelomonocytic leukemia, chronic eosinophilic leukemia and other myeloproliferative neoplasms as well as myelodysplastic syndromes  . It cannot be ruled out that such comorbidities may affect clinical and laboratory findings.
MCL is a rare form of systemic mastocytosis. Consequently, the diagnosis of MCL can be made when general criteria required for systemic mastocytosis and specific criteria for MCL are met . With regards to the former, systemic mastocytosis may be diagnosed in patients who present with multifocal, dense infiltrates of mast cells in sections of bone marrow and/or other extracutaneous organs, and one of the following signs and symptoms:
Of note, infiltrates are considered dense if there are at least 15 mast cells in aggregates. Furthermore, systemic mastocytosis may be diagnosed if the major criterion of multifocal mast cell infiltrates isn't met but three out of four minor criteria are.
In MCL, the histological examination of bone marrow biopsy samples also reveals a diffuse infiltration by immature, atypical mast cells. Accordingly, the proportion of normal hematopoietic precursors and fat is reduced. Common features of atypical mast cells are hypogranular cytoplasm and irregularly shaped nuclei. In bone marrow aspirate smears, more than 20% of all nucleated cells are mast cells. It is highly recommended to realize cytological analyses of bone marrow aspirates and to not rely on estimates regarding the proportion of mast cells derived from biopsy sample examinations. In case of typical MCL, mast cells account for more than 10% of peripheral white blood cells. This is not to be expected in case of atypical, aleukemic MCL. Contrary to what may be assumed, this atypical form of MCL may account for the majority of cases . Aleukemic MCL may progress to leukemic MCL .
There is no standard therapy for MCL. Due to the rarity of the disease, there is limited experience with distinct therapeutic regimens, the patients' response and survival. Several strategies have been followed:
The overall risk of transformation of systemic mastocytosis to MCL has been estimated to 6%. Those individuals suffering from systemic mastocytosis with associated clonal hematological non–mast cell-lineage disease or aggressive systemic mastocytosis are at higher risks of developing MCL than those diagnosed with other forms of mastocytosis . In any case, it should be noted that MCL may develop de novo, irrespective of previously diagnosed mast cell disorders. Unfortunately, MCL is usually refractory to therapy. Mean survival times have been calculated repeatedly, to about six months   or two years  - all authors coincide in that MCL is associated with a poor prognosis, though.
MCL is associated with acquired, gain-of-function mutations of the gene encoding for the receptor tyrosine kinase c-Kit . The KIT gene is located on chromosome 4 and is considered a proto-oncogene. c-Kit locates to the membrane of hematopoietic stem cells and functions as a receptor for the cytokine mast cell growth factor. The latter is also known as stem cell factor and is involved in cell cycle regulation, proliferation and differentiation. In case of activating mutations, mast cell survival and proliferation are enhanced. Additionally, the threshold for the activation of mast cells by other stimuli is lowered.
While mutation D816V is most frequently detected in patients suffering from MCL, other mutations of the same codon or mutations of other codons may also account for the disease. Additional mutations affecting genes like SRSF2, TET2, ASXL1, N/KRAS, CBL, IDH1/2, and RUNX1 may be identified in the majority of MCL patients if comprehensive analyses are carried out. It has been postulated that such additional mutations are acquired prior to KIT mutations, but a causal relation has not yet been established between both events .
Of note, activating KIT mutations play major roles in the pathogenesis of other diseases, too. Besides other hematopoietic neoplasms, non-hematopoietic tumors like gastrointestinal stromal tumors and melanomas have also been related to such mutations.
The incidence of mastocytosis has been estimated to less than 10 per 1,000,000 inhabitants. Both European and North American studies concluded that the prevalence of mastocytosis is about 1 in 60,000 persons . Presumably, less than 1% of all these cases correspond to MCL .
MCL is most commonly diagnosed in patients in their fifth to seventh decade of life, but isolated case reports of MCL in children and young adults are available in literature   . Females seem to be affected more frequently than males  .
According to current knowledge, the main pathophysiological event leading to systemic mastocytosis and MCL is the acquisition of a gain-of-function mutation of KIT. Under physiological conditions, tyrosine kinase c-Kit is activated only upon binding of its ligand, mast cell growth factor or stem cell factor. Subsequently, autophosphorylation and dimerization of c-Kit take place. Activated c-Kit then intervenes in several signaling cascades involved in the regulation of cell cycle, proliferation and differentiation. Signaling pathways affected comprise phosphoinositide 3-kinase signaling, JAK/STAT and mitogen-activated protein kinase cascades. As a consequence of activating KIT mutations, c-Kit remains constitutively active. Its regulating effect on mast cell proliferation and survival is no longer exerted. These cells start to proliferate in an uncontrolled manner, while at the same time, their rate of apoptosis is reduced .
Little is known about the events determining if an individual carrying activating KIT mutations develops MCL or other forms of mastocytosis. It may be speculated that additional mutations of other genes play major roles in this regard, but evidence cannot currently provided.
No recommendations can be given to prevent MCL.
MCL is a very rare form of systemic mastocytosis and accounts for less than 0.5% of all cases of mastocytosis. MCL may develop secondary to other forms of mastocytosis or appear de novo. Despite its designation as leukemia, it rather resembles systemic mastocytosis with regards to clinical features . The clinical picture is characterized by symptoms of mast cell activation, particularly by those related to increased levels of histamine. Liver, spleen, and lymph nodes are usually involved in the disease, while skin changes are less frequently observed.
The diagnosis of MCL relies on clear-cut criteria defined by experts of the World Health Organization. Since MCL is a form of systemic mastocytosis, the diagnosis of MCL first of all requires that criteria for systemic mastocytosis are met. Additionally, mast cells have to account for more than 20% of all nucleated cells observed in bone marrow aspirate smears. Depending on the subtype of MCL - a typical, leukemic subtype is distinguished from an atypical, aleukemic one - the proportion of mast cells in circulating white blood cells may or may not exceed 10%.
Therapeutic guidelines have not yet been established. Due to the low prevalence of the disease, it is difficult to conduct conclusive clinical studies to assess the efficacy of determined treatment regimens. To date, the application of tyrosine kinase inhibitors or cytostatic drugs as well as the transplantation of stem cells all represent possible therapeutic measures. Unfortunately though, neither has yielded satisfactory results and survival times remain short. Most MCL patients die within a year after diagnosis.
Mast cells are white blood cells and part of the immune system. They fulfill a variety of functions and in order to do so, they secrete mediators like tryptase and histamine. Mast cells develop in the bone marrow, are eventually released into the peripheral blood and infiltrate distinct organs. Under physiological conditions, proliferation and differentiation of mast cell precursors are tightly regulated and the numbers of mast cells in bone marrow and blood are low. However, DNA sequence anomalies may be acquired that interfere with the aforementioned processes and that facilitate the proliferation of mast cells. Such events may trigger neoplastic mast cell disorders like systemic mastocytosis, a disease that may follow a benign or an aggressive course. Mast cell leukemia (MCL) is a form of aggressive systemic mastocytosis.
In patients suffering from systemic mastocytosis, mast cells accumulate within the bone marrow or other organs, but rarely within the skin. Liver, spleen, and lymph nodes are most commonly involved in case of MCL. Contrary to less aggressive forms of the disease, MCL also involves an increase of circulating mast cells. This is why it is called "leukemia" instead of "mastocytosis". Abundant mast cells release abundant mediators and these will have negative effects on several organ systems. Consequently, MCL patients suffer from fever, malaise, headaches, flushing, tachycardia and diarrhea. They are prone to develop peptic ulcers and tend to lose their appetite and weight.
Unfortunately, treatment options are limited. Most patients are given tyrosine kinase inhibitors, drugs that may limit the uncontrolled proliferation of mast cells. Chemotherapeutic regimens that have been proven effective in other types of leukemia may also be followed. Finally, MCL patients may be considered for stem cell transplantation. Despite all efforts, most individuals diagnosed with MCL die within a year after receiving the diagnosis.