Systemic Mastocytosis

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Practice Essentials

Systemic mastocytosis, often termed systemic mast cell disease (SMCD), is a myeloproliferative neoplasm characterized by infiltration of clonally derived mast cells in different tissues, including bone marrow (see the image below), skin, the gastrointestinal tract, the liver, and the spleen.[1, 2, 3, 4] Median survival ranges from 198 months in patients with indolent systemic mastocytosis to 41 months in aggressive systemic mastocytosis and 2 months in mast cell leukemia.



View Image

Bone marrow aspirate, Romanowsky stain, high-definition magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cells. This is a bon....

Signs and symptoms

Manifestations of systemic mastocytosis may include the following:

Findings on physical examination may include the following:

See Presentation for more detail.

Diagnosis

Findings on blood studies may include the following:

Measurement of serum tryptase may reveal the following:

The following imaging studies may be necessary to identify the extent and stage of the disease:

Diagnostic procedures are as follows:

The major diagnostic criterion for systemic mastocytosis is the presence of dense infiltrates of mast cells in bone marrow or other extracutaneous tissues. Mast cells should be seen in aggregates of 15 or more.

Major criteria may be absent in early disease. In this situation, the minor criteria are used to make the pathologic diagnosis. Three of the following four minor criteria are required to make the diagnosis:

Types of systemic mastocytosis (World Health Organization criteria) are as follows:

See Workup for more detail.

Management

Therapy for systemic mastocytosis is primarily symptomatic; no therapy is curative. Treatment modalities include the management of the following:

Agents for symptomatic relief include the following:

Chemotherapy has not been particularly successful in the management of systemic mastocytosis, but the following regimens have been tried[9] :

See Treatment and Medication for more detail.

Background

Systemic mastocytosis, often termed systemic mast cell disease (SMCD), is a heterogeneous clonal disorder of the mast cell and its precursor cells. The clinical symptoms and signs of systemic mastocytosis result from the accumulation of these clonally derived mast cells in different tissues, including bone marrow, skin, the gastrointestinal (GI) tract, the liver, and the spleen.[1, 2, 12, 3, 4]

Systemic mastocytosis is characterized by mast cell infiltration of extracutaneous organs, which is in contrast to cutaneous mast cell disorders, which involve only the skin. Ehrlich first described mast cells in 1877 when he found cells that stained metachromatically with aniline dyes.[13] He called these cells "mast Zellen" because the cells were distended with granules (ie, the botanical definition of mast, which refers to an accumulation of nuts on the forest floor).

Cutaneous mastocytosis was identified in the late 19th century. Sangster first described urticaria pigmentosa, which is one of the cutaneous mast cell disorders, in 1878. In 1933, Touraine suggested that this disease could involve internal organs. In 1949, Ellis first established at autopsy that cutaneous mastocytosis can also involve internal organs. An autopsy of a 1-year-old infant revealed mast cell infiltration of the bone marrow, lymph nodes, spleen, kidneys, and pancreas.

For patient education information, see the Allergies Center, as well as Allergic Reaction and Severe Allergic Reaction (Anaphylactic Shock).

Pathophysiology

Systemic mastocytosis (systemic mast cell disease) is characterized by mast cell infiltration of extracutaneous organs. Mast cells typically infiltrate the bone marrow and consequently affect the peripheral blood and coagulation system.[14] Mast cells are derived from CD34+/ KIT+ pluripotent hematopoietic cells in the bone marrow.[15] The neoplastic clone of mast cells express abnormal cell surface markers CD25 and/or CD2.

Mueller et al reported that the adhesion molecule CD44 is expressed in systemic mastocytosis cell lines and correlates with the aggressiveness of the disorder. They found that serum levels of soluble CD44 were higher in advanced systemic mastocytosis compared with indolent systemic mastocytosis or cutaneous mastocytosis, and correlated with overall and progression-free survival.[16]

The marrow cellularity ranges from normocellular to markedly hypercellular changes. Erythropoiesis is usually normoblastic without any significant abnormalities. Eosinophilia is a common bone marrow histology finding (see Workup, Histologic Findings). Hypocellular bone marrow and myelofibrosis can be observed in late stages of systemic mastocytosis (systemic mast cell disease).

Ho et al evaluated the plasma level of pro–major basic protein (proMBP), a precursor of major basic protein that is contained in eosinophil cytoplasmic granules, in eosinophilic and chronic myeloproliferative disorders.[17] They found that the plasma proMBP level was significantly higher in patients with systemic mastocytosis with eosinophilia, idiopathic eosinophilia, and myeloproliferative disorders with eosinophilia than in healthy controls. In addition, the median proMBP level of patients with postpolycythemic myeloid metaplasia and those with postthrombocythemic myeloid metaplasia was significantly higher than in those with polycythemia vera and essential thrombocythemia.[17]

Ho et al also reported that the presence and size of splenomegaly was correlated with proMBP levels in certain conditions. In patients with idiopathic eosinophilia, the presence of splenomegaly was significantly associated with elevated proMBP.[17] In 76 patients with de novo myelofibrosis, the proMBP level was correlated with spleen size and the presence of hypercatabolic symptoms. All of these find ings led the investigators to conclude that "significantly elevated levels of proMBP in myelofibrosis patients implies that proMBP could be an important stromal cytokine in bone marrow fibrosis."[17]

Focal mast cell lesions in the bone marrow are found in approximately 90% of adult patients with systemic mastocytosis. A typical mast cell has a spindle-shaped nucleus and fine eosinophilic granules, which can be visualized at high magnification. These cells are likely to return positive findings upon Giemsa staining. Peripheral blood can show anemia, leukopenia, thrombocytopenia, and lymphopenia. The most common abnormality found in the peripheral blood is anemia. In some patients, eosinophilia, leukocytosis, basophilia, thrombocytosis, and monocytosis can be observed.

Spleen and lymphoid tissue involvement is a significant manifestation of systemic mastocytosis. Mast cell infiltrates in the spleen can cause nodular areas that could be confused with lymphomas. A biopsy specimen from the spleen can reveal findings similar to a myeloproliferative disorder or hairy cell leukemia. Histopathology studies of the spleen can reveal two types of involvement: (1) diffuse infiltration of the red pulp and sinuses and (2) focal infiltration of the white pulp. Lymph node biopsy can show mast cell infiltrates, particularly in the paracortex. Follicles and medullary involvement can be observed in some cases.

The immune system is affected as a consequence of the previously mentioned pathology. Mast cell products, such as interleukin 4 (IL-4) and interleukin 3 (IL-3), may induce immunoglobulin E (IgE) synthesis and augment T-cell differentiation toward an allergic phenotype. Mast cells also release histamine, which results in inhibition of interleukin 2 (IL-2).

GI involvement includes microscopic infiltration of the liver, pancreas, and intestines by mast cells.[18, 19] Abdominal pain has been attributed to peptic ulcer disease, involvement of the GI tract by mast cells, mediators released by mast cells, and motility disorders. GI involvement includes esophageal involvement (eg, esophagitis, stricture, varices), gastric involvement (eg, peptic ulcer disease, mucosal lesions), small intestine involvement (eg, dilatated small bowel, malabsorption), colon and rectal involvement (eg, multiple polyposis, diverticulitis), and liver involvement (eg, hepatomegaly and portal hypertension, ascites, sclerosing cholangitis, Budd-Chiari syndrome).

Osteoporosis is a common manifestations of systemic mastocytosis, particularly in adults, and can result in vertebral fractures. The mechanism of bone loss is not yet fully elucidated, but stimulation of osteoclast activity through RANK-RANKL signaling appears to be most important. Histamine and other cytokines also play significant roles.[20]

Systemic mastocytosis has many features common to myeloproliferative disorders. However, the 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia no longer lists mastocytosis under the broad heading of  myeloproliferative neoplasms (MPNs), and instead assigns it to a separate category.[21]

Systemic mastocytosis is almost always associated with the KIT D816V mutation. This gain of function KIT receptor mutation is detected by polymerase chain reaction (PCR) techniques in 68% of bone marrow specimens in patients with systemic mastocytosis.[7] Additional molecular markers being tested include mutations of JAK2, MPL, and TET2. The association between JAK2 V617F and systemic mastocytosis is weak and was noted in just 4% of patients with systemic mastocytosis (all had associated non–mast cell hematological disease).[7] The incidence of TET2 mutations (reportedly as high as 29% in KIT+ systemic mastocytosis) seems to influence the phenotype without affecting the prognosis.[22]

Epidemiology

Frequency

United States

Systemic mastocytosis is an extremely rare disorder; the specific incidence has not been reported.

International

Epidemiologic data on the incidence of systemic mastocytosis are lacking. Some studies in Great Britain showed two cases per year from a study population of 300,000.

Mortality/Morbidity

Systemic mastocytosis is a progressive neoplastic disorder that has no known curative therapy. Survival in patients with indolent systemic mastocytosis (ISM), with a median survival of 198 months, is not significantly different from the general population. However, median survival with aggressive systemic mastocytosis (ASM) is 41 months and that with SM-AHNMD (associated hematological non– mast cell disorder) is 24 months. Mast cell leukemia (MCL) has the poorest prognosis with a median survival of 2 months.

Early evolution into acute leukemia may occur in as many as 32% of patients with aggressive mastocytosis.[12] Leukemic transformation is rare with indolent systemic mastocytosis.[7]

 

Sex- and Age-related Demographics

A slight male preponderance in the incidence of mastocytosis is noted.[7] Mastocytosis is more common in children than in adults, and it is usually transient and self-limited in children compared with the adult version. Onset in those younger than 2 years is noted in 55% of patients, and, in an additional 10% of patients, the onset is between the ages of 2 and 15 years.

Progression of pediatric cutaneous mastocytosis is uncommon, but not so in adults, where it frequently progresses to systemic disease.[3]

The median age at diagnosis of systemic mastocytosis in adults is 55 years. Patients with indolent systemic mastocytosis were younger and symptomatic for a longer duration of time as compared with patients with aggressive systemic mastocytosis or SM-AHNMD (with other hematological disorders).[7]

History

Patients with systemic mastocytosis (systemic mast cell disease) can have symptoms related to involvement of the hematopoietic system, the gastrointestinal (GI) tract, the skin, and the immune system. Patients can also have symptoms related to additional coexistent hematologic manifestations.

Systemic mastocytosis is known to be associated with a number of other hematologic diseases, including the following:

The incidence of various symptoms reported in one of the largest case series of systemic mastocytosis is as follows[7] :

Many GI symptoms are observed in patients with systemic mastocytosis. Abdominal pain is the most common GI symptom, followed, by diarrhea, nausea, and vomiting. Symptoms and signs of gastroesophageal reflux disease (GERD) are noted in some patients.

Some studies show that GI symptoms are precipitated by agents such as penicillin, narcotics, cocaine, aspirin,[23] nonsteroidal anti-inflammatory drugs (NSAIDs), and dipyridamole (Persantine). These drugs can also provoke anaphylaxis, vascular collapse, or syncope.

GI symptoms seem to be as common as pruritus in patients with systemic mastocytosis. Patients may present with pruritus and flushing if their mastocytosis is associated with cutaneous abnormalities.

While the risk of recurrent anaphylactoid reaction is well known, it appears that the association with Hymenoptera (eg, bee, wasp) stings is stronger than the association with other food- and drug-induced systemic reactions.[5]

Caution during anesthesia in the endoscopic and surgical suites is advised. Rare anaphylactoid reactions to intravenous contrast have been reported.[6]

Anemia and coagulopathy (eg, acquired von Willebrand syndrome[24] ) may be observed.

Physical

Physical examination findings in patients with systemic mastocytosis (systemic mast cell disease) may include the following:

Causes

Studies have shown that mutations of the c-kit proto-oncogene may cause some forms of mastocytosis.[25, 26, 19] Mutations of c-kit in mast cell tumor lines and the ability of c-kit to cause mast cell proliferation and transformation suggest that these mutations are necessary in most forms of mastocytosis. Several types of mutations in c-kit have been demonstrated to cause mastocytosis. One of the common mutations found in systemic mastocytosis is a D816V KIT receptor mutation. Most, if not all, adult patients with systemic mastocytosis carry this mutation.[27]

Laboratory Studies

The peripheral blood picture can show anemia, thrombocytopenia, and leukocytosis. The most common abnormality found in the peripheral blood is anemia (45%). In some patients with systemic mastocytosis, the following abnormalities can be observed in peripheral blood:

Total serum tryptase levels of 20 ng/mL or higher in a baseline serum sample that is associated with a ratio of total–to–beta-tryptase ratio greater than 20:1 is suggestive of systemic mastocytosis.[8] More than 50% of patients reveal a high tryptase level using the cut-off value of 11.5 ng/mL. However, a normal serum tryptase level does not exclude the diagnosis of systemic mastocytosis.[28]

Measurements of urinary N-methyl imidazole are useful in some patients with systemic mastocytosis.

Lueke et al developed an assay for measurement of urinary leukotriene E4 (LTE4) and confirmed that median urine LTE4 concentrations were significantly higher in patients with systemic mastocytosis (median 97 pg per mg creatinine versus 50 pg/mg cr.; P< 0.01), with 48% sensitivity and 84% specificity for the disorder. These authors incorporated LTE4 into a panel of urinary biomarkers to provide a screening tool for systemic mastocytosis.[29] Additional biomarker results and accuracy were as follows:

 

 

Imaging Studies

Some imaging studies may be necessary in patients with systemic mastocytosis in order to identify the extent and stage of the disease, as follows:

Other Tests

Cytogenetic data indicate that about 20% of patients with systemic mastocytosis have an abnormal karyotype. These include trisomy 8; monosomy 7; del (13q); del(5q); trisomy 10, 6, and 19; del(20q); and trisomy X. Cytogenetic abnormalities are more often seen with aggressive systemic mastocytosis (ASM) and systemic mastocytosis with associated hematological non–mast cell disorder (SM-AHNMD) than with indolent systemic mastocytosis.[7]

Molecular testing for KIT D816V mutation is universally positive, whereas JAK2 V617F is rarely positive (4%).

The mast cell clone is CD117 positive and CD25 and/or CD2 positive.

Bone marrow mast cells reveal 54% CD2 positivity and 93% CD25 positivity on flow cytometry, whereas on immunohistochemistry CD2 positivity is 17% and CD25 positivity is 100%.[7]

Expression of CD25 on mast cells is seen in systemic mastocytosis but is not noted in reactive states of mast cell hyperplasia.[30]

Procedures

The following procedures may be indicated in patients with systemic mastocytosis:

Histologic Findings

Marrow cellularity ranges from normocellular to markedly hypercellular changes. Erythropoiesis is usually complete without any significant changes. Eosinophilia is a common finding from bone marrow histology. Hypocellular bone marrow and myelofibrosis are usually observed in late stages of systemic mastocytosis. Focal mast cell lesions in the bone marrow are found in approximately 90% of affected adult patients. A bone marrow smear is shown below.



View Image

Bone marrow aspirate, Romanowsky stain, high-definition magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cells. This is a bon....

A typical mast cell has a spindle-shaped nucleus and fine eosinophilic granules visualized at high magnification. These cells are likely to return positive findings upon Giemsa staining. Other stains used to identify mast cells are toluidine blue, chloroacetate esterase, aminocaproate esterase, and tartrate-resistant acid phosphatase. Examples are shown in the images below.



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Bone marrow aspirate, toluidine stain, low magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cells. This is a toluidine blue s....



View Image

Bone marrow biopsy, toluidine stain, low magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cell infiltrate. This is a toluidin....

The peripheral blood picture can show anemia, leukopenia, thrombocytopenia, and lymphopenia. The most common abnormality found in the peripheral blood is anemia. Eosinophilia, leukocytosis, basophilia, thrombocytosis, and monocytosis can be observed in some patients.

Spleen and lymphoid tissue involvement is an important manifestation in systemic mastocytosis. Mast cell infiltrates in the spleen can cause nodular areas that could be confused with lymphomas. A biopsy sample from the spleen can reveal findings similar to a myeloproliferative disorder or hairy cell leukemia. Histopathology of the spleen can show two types of involvement: (1) diffuse infiltration of the red pulp and sinuses and (2) focal infiltration of the white pulp.

Lymph node biopsy can show mast cell infiltrates, particularly in the paracortex. Follicles and medullary involvement can be observed in some cases. Lymph node biopsy samples are shown below.



View Image

Lymph node biopsy. Diagnosis is mastocytosis, morphology is mast cell infiltrate, and the organ is the lymph nodes. This is a lymph node biopsy from a....



View Image

Lymph node biopsy, chloroacetate esterase stain. Diagnosis is mastocytosis, and morphology is mast cell infiltrate. This is a portion of a lymph node ....

Diagnostic criteria

Major diagnostic criteria for systemic mastocytosis are as follows:

Major criteria may be absent in early disease. In this situation, the minor criteria are used to make the pathological diagnosis. Three of the following four minor criteria are required to make the diagnosis:

Types of mastocytosis

The World Health Organization classifies mastocytosis as cutaneous or systemic.[21] Types of systemic mastocytosis are as follows:

Staging

A classification for mastocytosis provided by Metcalfe in 1991 includes four categories.[31]

Category I is indolent mastocytosis, with the following subcategories:

Category II is associated with a hematopoietic disorder, as follows:

Category III is associated with mast cell leukemia.

Category IV is associated with lymphadenopathic mastocytosis with eosinophilia (aggressive mastocytosis).

Bone Marrow Biopsy

Bone marrow aspiration and biopsy is essential for the diagnosis of systemic mastocytosis.[32] Histologic findings provide both major and minor diagnostic criteria.

Medical Care

Therapy for systemic mastocytosis (systemic mast cell disease) is primarily symptomatic; no therapy is curative. Treatment modalities include the management of (1) anaphylaxis and related symptoms, (2) pruritus and flushing, and (3) intestinal malabsorption. The principles of treatment include control of symptoms with measures to decrease mast cell activation.[33]

Treatment of Anaphylaxis and Other Symptoms

Epinephrine is used in acute anaphylaxis. H1 and H2 receptor blockers are used to control anaphylactic symptoms. Acute anaphylaxis can be treated with 0.3 mL of a 1:1000 dilution of epinephrine. In children, the dose is 0.01 mL/kg (up to 0.3 mL) administered every 10-15 minutes as needed.

Corticosteroids have been used to control malabsorption, ascites, and bone pain and to prevent anaphylaxis. Oral prednisone (40-60 mg/d) for 10-20 days has been used in the treatment of malabsorption. Cromolyn is also helpful for decreasing bone pain and headaches and for improving skin symptoms. Patients with osteopenia that does not respond to therapy may receive a trial of interferon alfa-2b.

Classic H1 antagonists, such as diphenhydramine and hydroxyzine, have been used to treat pruritus and flushing. Mast cell stabilizers, such as ketotifen, have also been used to treat pruritus and whealing. Aspirin can be used in conditions in which H1 and H2 receptor blockers do not prevent vascular collapse. Leukotriene antagonists, such as zafirlukast and montelukast, have also been used in the treatment of systemic mastocytosis.

H2 receptor blockers have been used to treat gastric hypersecretion and peptic ulcer disease associated with systemic mastocytosis. Proton pump inhibitors are also useful.

Psoralen ultraviolet A therapy may provide transient relief of pruritus and may cause fading of skin lesions in some patients.

Anticholinergics have been used in the treatment of diarrhea. Disodium cromolyn has been used in the treatment of abdominal cramping and diarrhea.

Osteoporotic fractures are common in patients with mastocytosis. Unlike the general population, males are heavily affected. The risk of osteoporotic fractures increases with age, as in the general population, but starts at younger ages. Monitoring for osteoporosis should be applied to mastocytosis patients.[34]

Antiresorptive treatment with bisphosphonates is a rational treatment for osteoporosis in patients with systemic mastocytosis. A few small studies support this approach, most of which have used zoledronic acid.[20]

Treatment of Primary Disease

Various chemotherapy regimens have been used in the treatment of category II-IV systemic mastocytosis. Chemotherapy has not been particularly successful in the management of this disease.[9]

In April 2017, the FDA approved midostaurin (Rydapt) for aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL), collectively referred to as advanced systemic mastocytosis.

Approval of midostaurin was based on an open-label study in 89 patients with mastocytosis-related organ damage. Of these, 16 had ASM, 57 had SM-AHN, and 16 had MCL. The overall response rate was 60% (95% confidence interval [CI], 49 to 70); 45% of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage. Response rates were similar regardless of the subtype of advanced systemic mastocytosis, KIT mutation status, or exposure to previous therapy. The median best percentage changes in bone marrow mast-cell burden and serum tryptase level were −59% and −58%, respectively. The median overall survival was 28.7 months, and the median progression-free survival was 14.1 months. Among the 16 patients with mast-cell leukemia, the median overall survival was 9.4 months (95% CI, 7.5 to not estimated). Dose reduction owing to toxic effects occurred in 56% of the patients; re-escalation to the starting dose was feasible in 32% of those patients.[11]

Interferon-alfa benefits some patients, especially those with disease in the aggressive systemic mastocytosis category. In a retrospective analysis, 57% had treatment responses but only 21% had a major response. Other published studies show no response to interferon-alfa. It is perhaps not indicated in patients with indolent disease.

2-Chlorodeoxyadenosine (Cladribine) was reported to have yielded a major response in one patient. Responses may be transient. 2-Chlorodeoxyadenosine has myelosuppressive properties and, at this time, is not recommended for patients with indolent disease.[35]

There have been anecdotal reports of thalidomide use in advanced systemic mastocytosis.

Allogenic bone marrow transplantation is considered experimental and is being pursued in clinical trials at the US National Institutes of Health (NIH).

The tyrosine kinase inhibitor imatinib mesylate (Gleevec) may be useful in those types of systemic mastocytosis that do not have mutations of the codon 816 on the c-kit gene and carry the wild-type kit. Imatinib mesylate may also be useful in a subtype of systemic mastocytosis that carries the FIP1L1-PDGFRA rearrangement.[10] Knowledge of the types of systemic mastocytosis that respond to tyrosine kinase inhibition continues to evolve.

Dowse et al reported that treatment with the JAK 1/2 inhibitor ruxolitinib objectively improved symptom burden and splenomegaly in a patient with systemic mastocytosis and associated clonal hematological non–mast cell lineage disease. Mutation analyses demonstrated no evidence of JAK2, kit, MPL, or CALR mutations.After 4 months of treatment, ruxolitinib was tapered over a 10-day period with no symptom flare. These authors note that many of the inflammatory cytokines produced by mast cells utilize the JAK1/JAK2-STAT pathway for signalling, and that reduction in cytokine levels could explain the abatement of systemic symptoms seen in this case.[36]

Surgical Care

Some surgical procedures, such as laparoscopy and bone marrow biopsy (and sometimes endoscopy), can precipitate anaphylaxis, and patients undergoing these procedures should be closely monitored.[37]

Administration of beta-blockers is contraindicated in patients with systemic mastocytosis who are undergoing surgery, because these agents may interfere with endogenous epinephrine and may precipitate anaphylaxis. Also avoid alpha-blockers and cholinergic antagonists.

Consultations

Patients thought to have severe systemic mastocytosis that requires chemotherapy may need consultation with hematologists, dermatologists, and immunologists. A bone marrow biopsy is necessary in such cases, and supervision by a hematology/oncology specialist may be needed.

Patients with severe GI symptoms may need endoscopic procedures and biopsies to exclude other causes of malabsorption. Consultation with a gastroenterologist is helpful in such situations.

Activity

Insect stings can precipitate anaphylaxis; therefore, patients with systemic mastocytosis should exercise great care in avoiding stings when engaging in outdoor activities.

Patients should carry an epinephrine autoinjector at all times and should be taught to use the device in case of emergency.

Medication Summary

Tyrosine kinase inhibitors (eg, midostaurin, imatinib) have been approved by the FDA for various forms of mastocytosis.[10, 11]

The tyrosine kinase inhibitors midostaurin and imatinib have each been approved by the FDA for various types of mastocytosis.[10, 38] A case report of ruxolitinib, a Janus Associated Kinase (JAK) inhibitor, was shown to improve symptoms and quality of life a patient with systemic mastocytosis.[39]

Midostaurin (Rydapt)

Clinical Context:  Midostaurin has demonstrated the ability to inhibit KIT signaling, cell proliferation, and histamine release and induce apoptosis in mast cells. It is indicated for adults with advanced mastocytosis which includes aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

Imatinib (Gleevec)

Clinical Context:  Imatinib is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase. It is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF-and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-kit mutation. It is indicated for adults with aggressive systemic mastocytosis without the D816V c-Kit mutation as determined with an FDA-approved test.

Class Summary

The tyrosine kinase inhibitors midostaurin and imatinib have each been approved by the FDA for various types of mastocytosis. A case report of ruxolitinib, a Janus Associated Kinase (JAK) inhibitor, was shown to improve symptoms and quality of life a patient with systemic mastocytosis.

Epinephrine (Adrenalin, Bronitin, EpiPen)

Clinical Context:  Drug of choice for treating anaphylactoid reactions. Has alpha-agonist effects that include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. Beta-agonist effects of epinephrine include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects.

Class Summary

Sympathomimetic agents are used in the treatment of anaphylaxis.

Cromolyn sodium (Intal, NasalCrom)

Clinical Context:  Inhibits degranulation of sensitized mast cells following their exposure to specific antigens.

Class Summary

Mast cell stabilizers prevent release of mediators from mast cells, which cause airway inflammation and bronchospasm.

Prednisone (Deltasone, Orasone, Meticorten)

Clinical Context:  Immunosuppressant for the treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil activity.

Class Summary

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify body's immune response to diverse stimuli.

Complications

See Clinical.

Prognosis

The prognosis of systemic mastocytosis (systemic mast cell disease) is variable.[40] Young children and patients who present with primarily cutaneous and flushing manifestations tend to have little or no progression of the disease over a considerable length of time. However, older patients and those with more extensive systemic disease involving organ systems other than the skin have a poorer prognosis.[41] Although their median duration of survival is not known, it appears to be a few years.

On laboratory studies, elevated lactate dehydrogenase levels, are a poor prognostic sign.[41] On multivariate analysis, the following findings have also been shown to portend poor prognosis[7] :

 

 

Patient Education

Patients should carry epinephrine-filled syringes at all times and should be taught to administer epinephrine in cases of emergency.

How is systemic mastocytosis characterized?What are the signs and symptoms of systemic mastocytosis?Which studies are performed in the diagnostic workup of systemic mastocytosis?How is systemic mastocytosis diagnosed?What is included in symptom management of systemic mastocytosis?Which medications are used in the treatment of systemic mastocytosis?What is systemic mastocytosis?What is the pathophysiology of systemic mastocytosis?How is systemic mastocytosis related to myeloproliferative disorders?What is the role of genetics in the pathophysiology of systemic mastocytosis?What is the prevalence of systemic mastocytosis in the US?What is the global prevalence of systemic mastocytosis?What is the mortality and morbidity associated with systemic mastocytosis?Which patient groups have the highest prevalence of systemic mastocytosis?Which systems may be symptomatic in systematic mastocytosis?Which hematologic diseases are associated with systematic mastocytosis?Which clinical history findings are characteristic of systematic mastocytosis?Which GI findings are characteristic of systematic mastocytosis?What causes recurrent anaphylactoid reaction in systematic mastocytosis?Which hematologic findings may be present in systematic mastocytosis?Which physical findings are characteristic of systemic mastocytosis?What causes systemic mastocytosis?Which conditions are included in the differential diagnoses of systemic mastocytosis?Which conditions are included in the differential diagnoses of systemic mastocytosis with bone marrow involvement?What are the differential diagnoses for Systemic Mastocytosis?What is the role of lab tests in the workup of systemic mastocytosis?What is the role of imaging studies in the workup of systemic mastocytosis?What is the role of genetic testing in the workup of systemic mastocytosis?When is biopsy indicated in the workup of systemic mastocytosis?Which GI procedures are included in the workup of systemic mastocytosis?Which histologic findings are characteristic of systemic mastocytosis?What are the diagnostic criteria for systemic mastocytosis?How is systemic mastocytosis classified?How is systemic mastocytosis staged?What is the role of bone marrow aspiration in the diagnosis of systemic mastocytosis?How are the symptoms of systemic mastocytosis treated?How is systemic mastocytosis-related anaphylaxis treated?How is systemic mastocytosis treated?What precautions should be taken for patients with systemic mastocytosis undergoing surgical procedures?Which specialist consultations are beneficial to patients with systemic mastocytosis?Which activity modifications are used in the treatment of systemic mastocytosis?What is the role of medications in the treatment of systemic mastocytosis?Which medications in the drug class Corticosteroids are used in the treatment of Systemic Mastocytosis?Which medications in the drug class Mast Cell Stabilizers are used in the treatment of Systemic Mastocytosis?Which medications in the drug class Sympathomimetics are used in the treatment of Systemic Mastocytosis?Which medications in the drug class Antineoplastics, Tyrosine Kinase Inhibitor are used in the treatment of Systemic Mastocytosis?What is the prognosis of systemic mastocytosis?What is included in patient education about systemic mastocytosis?

Author

Koyamangalath Krishnan, MD, FRCP, FACP, Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine, James H Quillen College of Medicine at East Tennessee State University

Disclosure: Nothing to disclose.

Coauthor(s)

Devapiran Jaishankar, MBBS, Associate Professor, Division of Oncology, East Tennessee State University, James H Quillen College of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MBBCh, FRCPC, DTM&H, Professor of Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Additional Contributors

Thomas H Davis, MD, FACP, Associate Professor, Fellowship Program Director, Department of Internal Medicine, Section of Hematology/Oncology, Geisel School of Medicine at Dartmouth

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Stephen J Smith, MD, Harsha G Vardhana, MD, and Guha Krishnaswamy, MD, to the development and writing of this article.

References

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Bone marrow aspirate, Romanowsky stain, high-definition magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cells. This is a bone marrow smear from a patient with systemic mastocytosis. Several mast cells are present in this photograph. These mast cells are larger than normal mast cells and have more irregularly shaped nuclear outlines and less densely packed mast cell granules. Courtesy of the American Society of Hematology Slide Bank. Used with permission.

Bone marrow aspirate, Romanowsky stain, high-definition magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cells. This is a bone marrow smear from a patient with systemic mastocytosis. Several mast cells are present in this photograph. These mast cells are larger than normal mast cells and have more irregularly shaped nuclear outlines and less densely packed mast cell granules. Courtesy of the American Society of Hematology Slide Bank. Used with permission.

Bone marrow aspirate, toluidine stain, low magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cells. This is a toluidine blue stain of a bone marrow smear from a patient with marrow involvement by systemic mastocytosis. Five mast cells are present in this field. The mast cell granules are metachromatic with the toluidine blue reaction. Courtesy of the American Society of Hematology Slide Bank. Used with permission.

Bone marrow biopsy, toluidine stain, low magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cell infiltrate. This is a toluidine blue stain of a bone marrow biopsy from a patient with systemic mastocytosis. The mast cells are metachromatic with toluidine blue and contain numerous purple granules. Courtesy of the American Society of Hematology Slide Bank. Used with permission.

Lymph node biopsy. Diagnosis is mastocytosis, morphology is mast cell infiltrate, and the organ is the lymph nodes. This is a lymph node biopsy from a person with systemic mastocytosis. The mast cells have a characteristic perifollicular distribution. Courtesy of the American Society of Hematology Slide Bank. Used with permission.

Lymph node biopsy, chloroacetate esterase stain. Diagnosis is mastocytosis, and morphology is mast cell infiltrate. This is a portion of a lymph node biopsy from a patient with systemic mastocytosis. The mast cells are chloroacetate esterase positive, which is characterized by an orange granular appearance. Courtesy of the American Society of Hematology Slide Bank. Used with permission.

Bone marrow aspirate, Romanowsky stain, high-definition magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cells. This is a bone marrow smear from a patient with systemic mastocytosis. Several mast cells are present in this photograph. These mast cells are larger than normal mast cells and have more irregularly shaped nuclear outlines and less densely packed mast cell granules. Courtesy of the American Society of Hematology Slide Bank. Used with permission.

Bone marrow aspirate, toluidine stain, low magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cells. This is a toluidine blue stain of a bone marrow smear from a patient with marrow involvement by systemic mastocytosis. Five mast cells are present in this field. The mast cell granules are metachromatic with the toluidine blue reaction. Courtesy of the American Society of Hematology Slide Bank. Used with permission.

Bone marrow biopsy, toluidine stain, low magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cell infiltrate. This is a toluidine blue stain of a bone marrow biopsy from a patient with systemic mastocytosis. The mast cells are metachromatic with toluidine blue and contain numerous purple granules. Courtesy of the American Society of Hematology Slide Bank. Used with permission.

Lymph node biopsy. Diagnosis is mastocytosis, morphology is mast cell infiltrate, and the organ is the lymph nodes. This is a lymph node biopsy from a person with systemic mastocytosis. The mast cells have a characteristic perifollicular distribution. Courtesy of the American Society of Hematology Slide Bank. Used with permission.

Lymph node biopsy, chloroacetate esterase stain. Diagnosis is mastocytosis, and morphology is mast cell infiltrate. This is a portion of a lymph node biopsy from a patient with systemic mastocytosis. The mast cells are chloroacetate esterase positive, which is characterized by an orange granular appearance. Courtesy of the American Society of Hematology Slide Bank. Used with permission.