Mastocytosis, Systemic 

Systemic mastocytosis, often termed systemic mast cell disease (SMCD), is a heterogeneous clonal disorder of the mast cell and its precursor cells. It is now classified as a myeloproliferative neoplasm (MPN) as per the 2008 revision of the WHO classification of myeloid neoplasms.^[1] 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.^{[2, 3, 4, 5, 6]}

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.^[7] 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.

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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.^[8] Mast cells are derived from CD34⁺/ KIT⁺ pluripotent hematopoietic cells in the bone marrow.^[9] The neoplastic clone of mast cells express abnormal cell surface markers CD25 and/or CD2. 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.^[10] 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.^[10]

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.^[10] 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."^[10]

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 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.^{[11, 12]} 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).

Systemic mastocytosis has many features common to myeloproliferative disorders and is now included under the umbrella of myeloproliferative neoplasm (MPN).^[1] 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.^[13] 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).^[13] The incidence of TET2 mutations (reportedly as high as 29% in KIT⁺ systemic mastocytosis) seems to influence the phenotype without affecting the prognosis.^[14]

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. 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. Leukemic transformation is rare with indolent systemic mastocytosis.^[13]

Sex

A slight male preponderance in incidence is noted.^[13]

Age

Mastocytosis (mast cell disease) 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.^[5]

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).^[13]