AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Systemic mastocytosis is a clonal disorder of the mast cell and its precursor cells. The clinical symptoms and signs of systemic mastocytosis are due to the accumulation of these clonally derived mast cells in different tissues, including bone marrow, skin, the GI tract, the liver, and the spleen.

Systemic mastocytosis, often termed systemic mast cell disease (SMCD), 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. He called these cells mast Zellen because the cells were distended with granules.

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 this condition can also involve internal organs. An autopsy of a 1-year-old infant revealed mast cell infiltration of bone marrow, lymph nodes, spleen, kidneys, and pancreas.

Pathophysiology

Systemic mastocytosis 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. 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. Hypocellular bone marrow and myelofibrosis can be observed in late stages of the disease.

Focal mast cell lesions in the bone marrow are found in approximately 90% of adult patients with systemic mast cell disease. 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 mast cell disease. 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 2 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 (IL)–4 and IL-3, may induce immunoglobulin E synthesis and augment T cell differentiation toward an allergic phenotype. Mast cells also release histamine, which results in inhibition of IL-2.

GI involvement includes microscopic infiltration of the liver, pancreas, and intestines by mast cells. 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).

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 2 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.

Age

The onset of mastocytosis occurs in children younger than 2 years in 55% of patients and in children aged 2-15 years in 10% of patients. Mast cell disease is more common in children than adults and is usually more transient and self-limited in children than in adults.

CLINICAL

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History

Patients with systemic mast cell disease can have symptoms related to involvement of the hematopoietic system, the GI system, the skin, and the immune system. Also, patients can have symptoms related to additional coexistent hematologic manifestations. Systemic mast cell disease is known to be associated with a number of other hematologic diseases, including hypereosinophilic syndrome, Castleman disease, monoclonal gammopathy, and hairy cell leukemia. Non-Hodgkin lymphoma, polycythemia vera, and primary thrombocythemia are also known to occur in conjunction with systemic mast cell disease.

• Anemia and coagulopathy may be observed.
• Many GI symptoms are observed in patients with systemic mast cell disease. Abdominal pain is the most common GI symptom, followed respectively by diarrhea, nausea, and vomiting. Symptoms and signs of gastroesophageal reflux disease are noted in some patients. Of 7 series reported since 1985, GI symptoms seem to be as common as pruritus in patients with systemic mast cell disease.
• Patients may present with symptoms of pruritus and flushing if their mast cell disease is associated with cutaneous abnormalities.

Physical

• Signs of anemia, such as pallor, can be noted in some patients.
• Hepatomegaly, splenomegaly, and lymphadenopathy can be found in patients with the respective organ involvement.
• Some studies show that GI symptoms are precipitated by agents such as penicillin, narcotics, cocaine, aspirin, nonsteroidal anti-inflammatory drugs, and dipyridamole (Persantine). These drugs can provoke anaphylaxis, vascular collapse, or syncope.
• Patients may have signs of urticaria if the mast cell disease is associated with cutaneous involvement. In these situations, flushing can be noted upon physical examination.

Causes

Some recent studies have shown that mutations of the c-kit proto-oncogene may cause some forms of mastocytosis. 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 some forms of mastocytosis. Several types of mutations in c-kit have been demonstrated to cause mastocytosis. One of the common mutations found in systemic mast cell disease is a codon-816 c-kit mutation.

DIFFERENTIALS

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Other Problems to be Considered

The 3 most important differential diagnoses are carcinoid syndrome, VIPoma, and Zollinger-Ellison syndrome. Similar to systemic mast cell disease, each of these conditions causes diarrhea, abdominal pain, and some degree of malabsorption. Urticaria pigmentosa can help in distinguishing systemic mast cell disease from the other disorders. Plasma hormone measurements can also help in identifying these disorders. Gastrin levels can be elevated in persons with Zollinger-Ellison syndrome, and serotonin levels can be elevated in persons with carcinoid syndrome. Other malabsorption syndromes, such as celiac sprue, are also in the differential diagnosis.

Bone marrow involvement can have differential diagnoses such as leukemias, hairy cell leukemia, and other myeloproliferative disorders. Distinguish lymph node involvement from the wide variety of lymphomas. Systemic mastocytosis can coexist with other primary hematologic disorders.

WORKUP

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Lab Studies

• The peripheral blood picture 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.
• Measurements of urinary N-methyl imidazole are useful in some patients with systemic mast cell disease.
• Total serum tryptase levels of 20 ng/mL or higher in a baseline serum sample associated with a ratio of total to beta-tryptase greater than 20:1 is suggestive of systemic mast cell disease.

Imaging Studies

• Some imaging studies may be necessary in patients with systemic mast cell disease in order to identify the extent and stage of the disease.
• • For patients with abdominal pain, GI radiography, ultrasonography, and liver-spleen CT scanning may be necessary.
  • Skeletal surveys and bone CT scanning may be necessary in patients with suspected bone involvement.

Procedures

• Bone marrow aspiration and biopsy are essential in a patient who may have systemic mast cell disease.
• When GI symptoms are present, perform GI procedures (eg, barium studies, endoscopy) to help confirm the diagnosis.
• Patients with hepatomegaly can show evidence of mast cell infiltration on liver biopsy specimens.
• Skin biopsy may be warranted in patients with skin manifestations.

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 the disease. Focal mast cell lesions in the bone marrow are found in approximately 90% of adult patients with systemic mast cell disease.

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. 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 mast cell disease. 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 2 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.

Diagnostic criteria for systemic mastocytosis are as follows:

• Major criteria: Dense infiltrates of mast cells can be seen in bone marrow or other extracutaneous tissues. Mast cells should be seen in aggregates of 15 or more. Tryptase immunohistochemistry or metachromatic staining (eg, Giemsa, toluidine blue) should be used to confirm the presence of mast cells. Immunohistochemical staining for mast cells is more reliable than metachromatic staining.
• Minor criteria: Major criteria may be absent in early disease. In this situation, the minor criteria are used to make the pathological diagnosis. Three of the 4 minor criteria are required to make the diagnosis and include the following:
• • Atypical mast cell morphology
  • Aberrant mast cell phenotype
  • Serum/plasma tryptase levels greater than 20 ng/mL
  • A codon-816 c-kit mutation in peripheral blood, bone marrow, or involved tissue

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

• Cutaneous mastocytosis
• Indolent systemic mastocytosis
• Systemic mastocytosis with associated clonal hematologic non–mast cell lineage disease
• Aggressive systemic mastocytosis
• Mast cell leukemia
• Mast cell sarcoma
• Extracutaneous mastocytoma

Staging

This is a classification for mastocytosis provided by Metcalfe in 1991.

• Category I is indolent mastocytosis in which skin involvement is IA and systemic involvement with or without skin involvement is IB.
• Category II is associated with a hematopoietic disorder.
• • Category IIA is a dysmyelopoietic disorder.
  • Category IIB encompasses myeloproliferative disorders.
  • Category IIC is acute nonlymphocytic leukemia.
  • Category IID is malignant lymphoma.
  • Category IIE is chronic neutropenia.
• Category III is associated with mast cell leukemia.
• Category IV is associated with lymphadenopathic mastocytosis with eosinophilia (aggressive mastocytosis).

TREATMENT

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Medical Care

Therapy 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.

• 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.
• Treatment of peptic ulcer disease: H2 receptor blockers have been used to treat gastric hypersecretion and peptic ulcer disease associated with systemic mast cell disease. Proton pump inhibitors are also useful in the treatment of systemic mast cell disease.
• Treatment of pruritus: Psoralen ultraviolet A therapy may provide transient relief of pruritus and may cause fading of skin lesions in some patients.
• Treatment of diarrhea: Anticholinergics have been used in the treatment of diarrhea. Disodium cromolyn has been used in the treatment of abdominal cramping and diarrhea.
• Treatment of primary disease: Various chemotherapy regimens have been used in the treatment of category II-IV systemic mast cell disease. Chemotherapy has not been particularly successful in the management of this disease.
• • Interferon-alfa benefits some patients, especially those with disease in the aggressive systemic mastocytosis category. In a retrospective analysis, 57% had responses but only 21% had a major response. Other studies have been published that 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.
  • Allogenic bone marrow transplantation is considered experimental and is being pursued in clinical trials at the US National Institutes of Health.
  • 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. Knowledge of the types of systemic mastocytosis that respond to tyrosine kinase inhibition continues to evolve.

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.
• Administration of beta-blockers is contraindicated in patients with systemic mast cell disease who are undergoing surgery because these agents may interfere with endogenous epinephrine and may precipitate anaphylaxis.
• Avoid alpha-blockers and cholinergic antagonists.

Consultations

• Patients thought to have severe disease 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 should exercise great care in avoiding stings when engaging in outdoor activities.
• Patients should carry epinephrine-filled syringes at all times and should be taught to administer epinephrine in cases of emergency.

MEDICATION

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Therapy is primarily symptomatic; no therapy is curative.

Drug Category: Sympathomimetics

For treatment of anaphylaxis.

Drug Category: Mast cell stabilizers

Prevent release of mediators from mast cells, which cause airway inflammation and bronchospasm.

Drug Category: Corticosteroids

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

FOLLOW-UP

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Complications

• See Clinical.

Prognosis

• The prognosis is variable. 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, patients with more extensive systemic disease involving organ systems other than the skin have a poorer prognosis. Although their median duration of survival is not known, it appears to be a few years. Other poor prognostic factors include older age at diagnosis, anemia, leukopenia and/or thrombocytopenia, elevated lactate dehydrogenase levels, and a myeloproliferativelike disorder.

Patient Education

• Patients should carry epinephrine-filled syringes at all times and should be taught to administer epinephrine in cases of emergency.
• For excellent patient education materials related to anaphylaxis, see the eMedicine article Allergic Reaction.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to warn patients diagnosed with this disease about possible anaphylaxis when undergoing surgery or receiving preoperative medications

MULTIMEDIA

Section 10 of 11  

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Media file 1:  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.
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Media type:  Photo

Media file 2:  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.
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Media type:  Photo

Media file 3:  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.
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Media type:  Photo

Media file 4:  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.
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Media type:  Photo

Media file 5:  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.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
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• Differentials
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• Akin C, Schwartz LB, Kitoh T, et al. Soluble stem cell factor receptor (CD117) and IL-2 receptor alpha chain (CD25) levels in the plasma of patients with mastocytosis: relationships to disease severity and bone marrow pathology. Blood. Aug 15 2000;96(4):1267-73. [Medline].
• Akin C, Metcalfe DD. Systemic mastocytosis. Annu Rev Med. 2004;55:419-32. [Medline].
• Bain BJ. Systemic mastocytosis and other mast cell neoplasms. Br J Haematol. Jul 1999;106(1):9-17. [Medline].
• Jensen RT. Gastrointestinal abnormalities and involvement in systemic mastocytosis. Hematol Oncol Clin North Am. Jun 2000;14(3):579-623. [Medline].
• Karnam U, Rogers A. Systemic mastocytosis. Dig Dis. 1999;17(5-6):299-307. [Medline].
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• Letterman G, Schurter M. Inframammary-based dermofat flaps in mammary reconstruction following a subcutaneous mastectomy. Plast Reconstr Surg. Feb 1975;55(2):156-9. [Medline].
• Longley BJ, Metcalfe DD. A proposed classification of mastocytosis incorporating molecular genetics. Hematol Oncol Clin North Am. Jun 2000;14(3):697-701, viii. [Medline].
• Ma Y, Zeng S, Metcalfe DD, et al. The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood. Mar 1 2002;99(5):1741-4. [Medline].
• Pardanani A, Elliott M, Reeder T, et al. Imatinib for systemic mast-cell disease. Lancet. Aug 16 2003;362(9383):535-6. [Medline].
• Pardanani A, Ketterling RP, Brockman SR, et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood. Nov 1 2003;102(9):3093-6. [Medline].
• Parker RI. Hematologic aspects of systemic mastocytosis. Hematol Oncol Clin North Am. Jun 2000;14(3):557-68. [Medline].
• Pauls JD, Brems J, Pockros PJ, et al. Mastocytosis: diverse presentations and outcomes. Arch Intern Med. Feb 22 1999;159(4):401-5. [Medline].
• Schwartz LB, Irani AM. Serum tryptase and the laboratory diagnosis of systemic mastocytosis. Hematol Oncol Clin North Am. Jun 2000;14(3):641-57. [Medline].
• Soter NA. Mastocytosis and the skin. Hematol Oncol Clin North Am. Jun 2000;14(3):537-55, vi. [Medline].
• Swolin B, Rodjer S, Roupe G. Cytogenetic studies in patients with mastocytosis. Cancer Genet Cytogenet. Jul 15 2000;120(2):131-5. [Medline].
• Tefferi A, Li CY, Butterfield JH, Hoagland HC. Treatment of systemic mast-cell disease with cladribine. N Engl J Med. Jan 25 2001;344(4):307-9. [Medline].
• Worobec AS. Treatment of systemic mast cell disorders. Hematol Oncol Clin North Am. Jun 2000;14(3):659-87, vii. [Medline].

Article Last Updated: Dec 18, 2006