eMedicine Specialties > Hematology > Immune System and Disorders

Mastocytosis, Systemic

Author: Koyamangalath Krishnan, MD, FRCP, FACP, Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University
Coauthor(s): Stephen J Smith, MD, Assistant Professor of Medicine, Department of Internal Medicine, Division of Hematology/Oncology, East Tennessee State University, James H. Quillen College of Medicine; Harsha G Vardhana, MD, Chief Fellow, Medical Oncology, Department of Internal Medicine, James H Quillen College of Medicine at East Tennessee State University
Contributor Information and Disclosures

Updated: Oct 4, 2009

Introduction

Background

Systemic mastocytosis, often termed systemic mast cell disease (SMCD), is a clonal disorder of the mast cell and its precursor cells. The clinical symptoms and signs of systemic mastocytosis (systemic mast cell disease) are due to the accumulation of these clonally derived mast cells in different tissues, including bone marrow, skin, the gastrointestinal (GI) tract, the liver, and the spleen.^1,2,3,4,5

Systemic mastocytosis (systemic mast cell disease) 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.⁶ 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 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 excellent patient education resources, visit eMedicine's Allergic Reaction and Anaphylactic Shock Center. Also, see eMedicine's patient education articles 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.⁷ 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.⁸ They found that the plasma proMBP level was significantly higher in patients with systemic mastocytosis (systemic mast cell disease) 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.⁸

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.⁸ In 76 de novo myelofibrosis patients, the proMBP level was correlated with spleen size and the presence of hypercatabolic symptoms. All of these findings 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."⁸

Focal mast cell lesions in the bone marrow are found in approximately 90% of adult patients with systemic mastocytosis (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 mastocytosis (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 (Ig) 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.^9,10 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 (systemic mast cell disease) is an extremely rare disorder; the specific incidence has not been reported.

International

Epidemiologic data on the incidence of systemic mastocytosis (systemic mast cell disease) are lacking. Some studies in Great Britain showed 2 cases per year from a study population of 300,000.

Mortality/Morbidity

Systemic mastocytosis (systemic mast cell disease) 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. Mastocytosis (mast cell disease) is more common in children than adults, and it is usually more transient and self-limited in children than in adults.

Clinical

History

Patients with systemic mastocytosis (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 mastocytosis (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 mastocytosis (systemic mast cell disease).

• Anemia and coagulopathy may be observed.
• Many GI symptoms are observed in patients with systemic mastocytosis (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 (GERD) are noted in some patients. Of 7 case series reported since 1985, GI symptoms seem to be as common as pruritus in patients with systemic mastocytosis (systemic mast cell disease).
• Patients may present with symptoms of pruritus and flushing if their mastocytosis (mast cell disease) is associated with cutaneous abnormalities.

Physical

• Signs of anemia, such as pallor, can be noted in some patients with systemic mastocytosis (systemic mast cell disease).
• 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,¹¹ nonsteroidal anti-inflammatory drugs (NSAIDs), and dipyridamole (Persantine). These drugs can provoke anaphylaxis, vascular collapse, or syncope.
• Thrombocytopenia caused by splenomegaly, hypersplenism, and a rise in portal pressure; heparin release from mucosal mast cells; and vitamin K malabsorption resulting from mast cell involvement can all contribute to GI bleeding in patients with systemic mastocytosis (systemic mast cell disease).
• Patients may have signs of urticaria if the mastocytosis (mast cell disease) is associated with cutaneous involvement. In these situations, flushing can be noted upon physical examination.

Causes

Some studies have shown that mutations of the c-kit proto-oncogene may cause some forms of mastocytosis (mast cell disease).^12,13,10 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 mastocytosis (systemic mast cell disease) is a codon-816 c-kit mutation.

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