A new review article provides an overview of recent developments concerning the physiology and pathobiology of mast cells and discusses current diagnostic and therapeutic approaches to mast-cell disorders, with an emphasis on mastocytosis.
Pathologic conditions involving mast cells appear to be more common than once thought. The diagnosis and treatment of such disorders are challenging, given protean symptoms and the presence of coexisting conditions. In patients with severe symptoms or those with allergies to hymenoptera venom, the investigation of mast-cell monoclonality may provide the diagnosis. Most symptoms can be managed with histamine-receptor antagonists or other drugs that interfere with mast-cell mediators, along with blockers of mast-cell activation.
• Describe the variants of mastocytosis and the associated clinical features.
The most common form of mastocytosis in children, cutaneous mastocytosis, is diagnosed in the first years of life. It is commonly characterized by multiple hyperpigmented macular or maculopapular lesions that become urticarial when rubbed or scratched (Darier’s sign). In most children with cutaneous mastocytosis, the condition resolves or improves by puberty. The categories of systemic mastocytosis, which is characterized by mast-cell infiltration of various internal organs (most commonly bone marrow), are indolent mastocytosis, aggressive mastocytosis, mastocytosis associated with a hematologic non-mast-cell-lineage disease, and mast-cell leukemia. Among patients with indolent systemic mastocytosis, which is the most common variant, life expectancy is similar to that in the general population. Aggressive systemic mastocytosis, which is characterized by specific tissue damage associated with mast cells, is most commonly identified in the bone marrow, liver, gastrointestinal tract, and cortical bone. Portal hypertension and ascites, malabsorption, cytopenias, and large osteolytic lesions with pathologic fractures may ultimately develop in these patients. Patients with systemic mastocytosis and associated hematologic disease often have evidence of an additional myeloproliferative or myelodysplastic syndrome.
• What mutation is seen in a majority of patients with mastocytosis?
Almost all patients with indolent systemic mastocytosis and approximately 80% of all patients with systemic mastocytosis have a somatic “gain-of-function” mutation in KIT, most commonly in codon 816 (D816V), where a valine is substituted for an aspartate.
Cutaneous mastocytosis is associated with gain-of-function KIT mutations in approximately 60 to 80% of cases.
Morning Report Questions
Q: What are the diagnostic criteria for mastocytosis?
A: The diagnosis of systemic mastocytosis is based on the presence of one major and one minor criterion or three minor criteria established by the World Health Organization. The major criterion is multifocal clustering of mast cells (>15 mast cells per cluster) identified by means of tryptase immunohistochemical analysis, KIT immunohistochemical analysis, or both in an extracutaneous organ, commonly the bone marrow. Minor criteria include abnormal morphologic features of mast cells (e.g., spindle shapes with cytoplasmic projections and sometimes bilobed and multilobed nuclei), the presence of the KIT D816V mutation, expression of CD2 or CD25 on mast cells, and an increased basal serum tryptase level (greater than or equal to 20 ng per milliliter).
Q: What laboratory findings suggest mast-cell activation in patients in whom mast-cell counts are normal?
A: Patients with increased numbers of mast cells, as is the case in systemic mastocytosis, may not always have symptoms of mast-cell activation. Conversely, mast-cell activation is often seen in patients in whom the mast-cell burden is normal, as in patients with allergic rhinitis or those presenting with anaphylaxis in whom serum tryptase levels reportedly increase during the attack but later return to normal values. However, mast-cell activation and severe anaphylactic reactions are more common in patients with systemic mastocytosis than in healthy controls. The symptoms may be subtle in a patient who has a less severe form of mast-cell activation. Serum tryptase levels that increase by 20% above the baseline level plus an additional 2 ng per milliliter if measured within 4 hours after the onset of the acute event suggest mast-cell involvement. In some patients with primary severe mast-cell activation, there is evidence of mast-cell clonality (a KIT mutation or CD25+ mast cells) that may fulfill the diagnostic criteria for systemic mastocytosis. In other patients, there is evidence of clonal mast-cell expansion, but the criteria for systemic mastocytosis are not met and these patients are known to have monoclonal mast-cell activation, which is increasingly recognized in patients with hymenoptera-induced or idiopathic anaphylaxis.