Aggressive systemic mastocytosis (ASM) is a rare form of systemic mastocytosis. Affected individuals may present with symptoms due to organopathies caused by mast cell infiltration, bone marrow failure and subsequent cytopenias, and symptoms of mast cell activation - clinical presentations are heterogeneous. Diagnosis of ASM relies on diagnostic criteria as published by the World Health Organization and require bone marrow biopsies and aspirations. Curative treatment is not available. Patients are treated with tyrosine kinase inhibitors, cytoreductive chemotherapeutics, and stem cell transplantation, but response rates vary largely and mean survival times don't exceed seven years.
ASM patients may present with symptoms resulting from enhanced mast cell activation and release of mediators like histamine or with organopathies due to mast cell infiltration .
With regards to organopathies, almost any organ can be affected. Bone marrow, skeleton, liver, spleen, and gastrointestinal tract are most frequently involved. In fact, bone marrow failure is associated with cytopenias and patients suffering from anemia, leukopenia, or thrombocytopenia may present with pallor, weakness, and fatigue, increased susceptibility to infectious diseases, or hemorrhagic diathesis. While osteolytic lesions may not be recognizable unless diagnostic imaging is applied, they predispose for pathological fractures, whereby vertebral fractures are most frequently reported  . Hepatic and splenic mast cell infiltration cause palpable hepatomegaly and splenomegaly and may ensue loss of appetite, aszites, and portal hypertension as well as hypersplenism. However, loss of appetite due to hepatomegaly is not the only condition that causes ASM patients to lose weight: Mast cells also infiltrate the intestinal walls, which causes malabsorption. ASM patients may present with maculopapular skin lesions , although skin changes are not characteristic of this form of mastocytosis .
As has been mentioned above, excessive mast cell activation may be associated with considerable histamine release. Histamine exerts its effects on a wide variety of target structures and increased histamine levels may provoke flushing, skin itching, nausea, vomiting, diarrhea, and anaphylaxis.
The disease may follow a slowly progressive or rapid course. Patients with rapidly progressive ASM are considered at particularly high risks of transformation to systemic mastocytosis with associated clonal hematological non–mast cell-lineage disease and mast cell leukemia .
The World Health Organization has published diagnostic criteria for variants of systemic mastocytosis . There are general criteria to be met before making a diagnose of systemic mastocytosis, and there are specific criteria that apply for certain subtypes like ASM. With regards to the general criteria for systemic mastocytosis, one major criterion and four minor criteria have been defined. Systemic mastocytosis can be diagnosed if the major criterion and one minor criterion, or three minor criteria are met:
The World Health Organization has defined a number of so-called B findings and C findings, which are characteristic of certain subtypes of systemic mastocytosis. As per definition, the diagnosis of ASM requires one or more of the following C findings:
Additionally, there should be no evidence of mast cell leukemia. The latter is characterized by a diffuse infiltration of the bone marrow by immature, atypical mast cells. Additionally, more than 20% of all nucleated cells visible in bone marrow aspirate smears are identified as mast cells. Consequently, if these criteria apply, the diagnosis of ASM should be reconsidered. It should be recalled that ASM may progress to mast cell leukemia .
Although several therapeutic approaches have been proposed - and are taken in clinical practice - effective treatment is not available.
Because curative treatment is not available, the goal of therapy is to reduce the systemic mast cell burden, to alleviate symptoms and to maintain life quality as high as possible. Thus, ASM treatment should be understood as palliative therapy. Mean survival times have been estimated to less than 4  and 6 to 7 years .
Gain-of-function mutations of the KIT gene have long since been assumed to be the single cause of proliferative mast cell disease, but comprehensive genetic analyses have revealed that the vast majority of ASM patients carries additional mutations affecting other genes. Those additional mutations may serve as an explanation as to why certain KIT mutations may result in different forms of mastocytosis:
All mutations described are somatic, acquired mutations.
ASM is a rare form of systemic mastocytosis and accounts for less than 2% of all cases. In Denmark, the incidence of ASM has been estimated to 1 in 10,000,000 inhabitants per year and the prevalence of the disease was calculated to be 9 per 10,000,000 people .
ASM is generally diagnosed in adult patients. Their mean age at the time of diagnosis is 60 years, with the majority of individuals being diagnosed in their sixth or seventh decade of life . In children, mastocytosis typically involves the skin and follows a benign, often self-limiting course. Nevertheless, ASM has occasionally been described in young patients, even in neonates . Most studies reveal a slight predilection for females .
Mast cell proliferation and differentiation is largely regulated by their main growth factor, namely mast cell growth factor or stem cell factor. This growth factor binds to tyrosine kinase c-Kit, a protein expressed in the membrane of hematopoietic stem cells. Ligand binding triggers tyrosine kinase phosphorylation and dimerization and ultimately activation. Through a variety of signaling cascades, c-Kit activation finally translates into an enhancement of mast cell proliferation. However, in the absence of its ligand, c-Kit remains inactive and doesn't stimulate mast cell propagation. This regulatory mechanism is invalidated in patients suffering from ASM. They present with gain-of-function mutations of the KIT gene, which encodes for receptor tyrosine kinase c-Kit. Such mutations are associated with constitutive activity of c-Kit, uncontrolled mast cell proliferation and reduced apoptosis rates.
The role of genes TET2, SRSF2, ASXL1, RUNX1, JAK2, and RAS in ASM pathogenesis is less clear. Most of them presumably affect the cell cycle, survival and death. In detail, TET2 has been related to an "increased self-renewal capacity of hematopoietic stem cells", while mutations of SRSF2 result in alterations of the spliceosome machinery and mutations of ASXL1 affect chromatin remodeling .
No recommendations can be given to prevent ASM.
It becomes apparent from the list that there are several forms of systemic mastocytosis, with indolent systemic mastocytosis being the most benign variant of the disease and mast cell leukemia being the one with the poorest prognosis. Still, and as the name already suggests, ASM follows an aggressive course and affected individuals have mean survival times of less than 7 years .
Of note, the term advanced systemic mastocytosis refers to systemic mastocytosis with associated clonal hematological non–mast cell-lineage disease, ASM, and mast cell leukemia .
Mast cells are part of the immune system. They are white blood cells but may also be found in different tissues outside the bloodstream. Under physiological conditions, they account for a minor proportion of blood cells and immune cells to be found in distinct organs. Their proliferation is tightly regulated.
In patients suffering from aggressive systemic mastocytosis (ASM), those regulatory mechanisms are invalidated due to an acquired mutation of a gene called KIT. This gene encodes for c-Kit, a protein able to bind mast cell growth factor and undergo subsequent activation. ASM-associated mutations of the KIT gene may result in permanent activity of c-Kit, which provokes enhanced mast cell proliferation.
Consequently, abundant mast cells may be detected in the bone marrow - mast cells develop from hematopoietic stem cells in the bone marrow - and in virtually any organ that becomes infiltrated with mast cells. Degenerated mast cells interfere with organ function and therefore, ASM patients may develop bone marrow failure with subsequent anemia, susceptibility to infections, and bleeding diathesis, bone pain and pathological fractures, and dysfunction of liver, spleen, and intestines. The latter usually leads to significant weight loss. Because mast cells release histamine, ASM is also associated with histamine-mediated symptoms like flushing, skin itching, nausea, vomiting, diarrhea, and anaphylaxis.
ASM may be treated by means of pharmacotherapy or stem cell transplantation, but curative therapy is not yet available. Mean survival times are 3 to 7 years.