MAST CELL DISEASE - pediagenosis
Article Update

Wednesday, July 8, 2020


Mast cell disease is an uncommon condition that has many clinical variants and subtypes. It can be seen as a solitary finding, as in the solitary mastocytoma, or it can result in widespread cutaneous disease, as in urticaria pigmentosa. Most mast cell disease is caused by an abnormality in the c-kit gene (KIT). There are many other forms of mast cell disease, most in the benign category; some affect the skin predominantly, and others are more systemic in nature. One systemic type is the rare mast cell leukemia. Other systemic forms have been reported, such as mast cell sarcoma, and carry a poor prognosis. It is important to recall that mast cells are derived from the bone marrow and share certain things in common with other hematopoietic cells. The World Health Organization (WHO) has developed a simplified classification system for mast cell disease (see box to right).

Clinical Findings: Solitary mastocytoma is one of the most common of all the mast cell disease types. It manifests in early childhood, often in the first few years of life. It appears as a yellowish to brownish macule, papule, or plaque. On rare occasions, a lesion develops a vesicle or bulla. Most lesions are asymptomatic until rubbed or scratched. When this takes place, a localized urticarial reaction occurs above the mastocytoma and extends into the surrounding skin. This sign, called Darier’s sign, can be used in any of the cutaneous mast cell diseases to help make the diagnosis. These solitary mast cell collections almost always spontaneously resolve with no sequelae.

Urticaria pigmentosa is a more diffuse affliction of the skin with mast cells; it has been reported to be the most common variant of mast cell disease. From a few to hundreds of slightly hyperpigmented macules and plaques occur across the surface of the skin. Some develop into vesicles and bullae. This most commonly occurs in early childhood but has also been reported to occur in adulthood. Most children are diagnosed on the basis of the clinical presentation and demonstration of a positive Darier’s sign. The condition typically runs a benign course in children, and most cases spontaneously remit over a few years and then disappear at about the time of puberty. Adult-onset urticaria pigmentosa is a more chronic disease that rarely remits. Special care should be taken to continually screen adult patients for the development of systemic mast cell involvement.
Telangiectasia macularis eruptiva perstans is a less commonly seen variant of mast cell disease. It occurs almost exclusively in the adult population. Patients often present with widespread telangiectases in unusual locations such as the back, chest, and abdomen. There can be a background erythema, and Darier’s sign may or may not be present. The most common symptom is pruritus. The appearance can be bothersome for some. It is most often limited to the skin, but the clinician should evaluate for systemic involvement.
Measurement of the serum tryptase level is the most accurate means of screening for systemic involvement with mastocytosis. Levels in the normal range indicate cutaneous disease only; levels greater than 20 ng/mL are indicative of systemic involvement, and further systemic workup is warranted. Urine histamine and histamine metabolites can also be assessed but seem to be less sensitive and less specific than the serum tryptase level. If systemic involvement is considered, further testing with a bone marrow biopsy may be indicated. Molecular genetic testing can be performed on the bone marrow sample to assess for the KIT gene mutation.
Histology: The histological features depend on the form of mast cell disease. Most biopsy specimens show an excessive number of mast cells, typically surrounding the cutaneous vasculature. These mast cells are best appreciated with special staining techniques. The Leder (chloracetate esterase) stain, the Giemsa stain, and the toluidine blue stain are the most commonly used special stains to help highlight the cutaneous mast cells. CD117 immunostaining also stains mast cells.
Pathogenesis: Darier’s sign is caused by direct release of histamine and other inflammatory mediators from the excessive collection of mast cells within the affected skin. On direct stimulation such as scratching or rubbing, the mast cells automatically release the contents of their granules. These granules contain histamine and other vasoactive substances that cause edema, redness, and pruritus.
Mast cell disease is caused by a mutation in the KIT gene. KIT is a protooncogene that encodes a protein called stem cell factor receptor (SCFR). SCFR is a transmembrane protein tyrosine kinase protein. This receptor is prominent in two skin cell types, mast cells and melanocytes. It is also present on a host of other primitive hematological cell types. Stem cell factor is also known by various other names, including KIT ligand, CD117, Steel factor, and mast cell growth factor. It is the molecule that binds to the transmembrane SCFR and acts to promote the reproduction of mast cells. The activating mutation of SCFR seen in mast cell disease causes an upregulation of signaling via this pathway and an uncontrolled proliferation of mast cells. The continuous activation of the stem cell factor allows for prolonged survival of mast cells, which also contributes to their increased number. Numerous mutations of KIT have been described, and it is believed that the different mutations play a role in the varied clinical expression of the disease. The most common mutation is a D816V mutation that is caused by replacement of the normal aspartic acid at the 816 position with a valine amino acid.

Treatment: Cutaneous mast cell disease in children is often self-limited and resolves spontaneously with time. Therapy with antihistamines may help decrease the pruritus and provide symptomatic relief until the condition resolves on its own. The most important aspect for children with cutaneous mast cell disease, especially urticaria pigmentosa, is to avoid agents or physical insults that may cause massive degranulation of mast cells. These triggers include medications such as anesthetics, narcotics, polymyxin B, and many others. Physical triggers include extremes of temperature, vigorous exercise, repeated rubbing of the involved skin, and many other stimuli that differ from individual to individual.
Antihistamines are the mainstay of therapy. The leukotriene inhibitors are also used as adjunctive therapy to the antihistamines. Cromolyn is a mast cell stabilizer that is not absorbed through the gastrointestinal tract. Its use is limited to treatment of coexisting diarrhea caused by mast cell disease of the gut. Telangiectasia macularis eruptiva perstans has been treated with the 585-nm pulsed dye laser to decrease the redness and telangiectases for cosmetic purposes. Some success has been achieved in treating systemic disease with the tyrosine kinase inhibitor, imatinib. Depending on the symptoms and the body systems involved, systemic chemotherapy may be warranted to decrease the mast cell load. These agents rarely put patients into long-term remission, and the response is transient. At this point, there is no cure for mast cell disease.

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