Mastocytosis

Genetics

Mast cells are derived from hematopoietic progenitors ( Chapter 137 ). Systemic mastocytosis is associated with somatic gain-of-function point mutations in the KIT (formerly c-kit ) gene of the mast cell progenitor, thereby leading to a clonal neoplastic expansion of mast cells. KIT encodes a transmembrane receptor (Kit) whose intracellular portion functions as a tyrosine kinase enzyme. The extracellular portion of Kit binds the cytokine stem cell factor. The interaction between the stem cell factor and Kit provides the single most important growth and differentiation stimulus for mast cells from their progenitors. Under physiologic conditions, homodimeric stem cell factor binds and cross-links two Kit receptor molecules, thereby leading to autophosphorylation of the tyrosine amino acids of the intracellular portion of the Kit molecule. Phosphorylated tyrosine residues in turn act as docking sites for downstream adaptor and signal transduction molecules that regulate the differentiation, proliferation, chemotaxis, and functional activation of mast cells.

The most common mutation in mastocytosis involves codon 816 in KIT (located in exon 17), where replacement of an aspartic acid by a valine residue (D816V) in the Kit protein leads to ligand-independent autophosphorylation. This D816V mutation is present in the skin or bone marrow tissue of more than 90% of adults and approximately 40% of pediatric patients with mastocytosis. Another 40% of pediatric patients carry KIT mutations in other exons, most commonly in exons 8 and 9. KIT mutations can be demonstrated in non–mast cell hematopoietic lineages in advanced variants of systemic mastocytosis, similar to the multilineage involvement observed in myeloproliferative neoplasms ( Chapter 152 ). The sensitivity of detecting the mutation is much higher when a lesional tissue such as bone marrow or skin is analyzed compared with peripheral blood and when a sensitive technique such as allele specific polymerase chain reaction (PCR) testing is used.

Other pathogenetic factors also appear to be responsible for the final disease phenotype because the presence of the D816V KIT mutation alone does not explain the remarkable heterogeneity in the clinical presentation and prognosis of the disease. Molecular aberrations in TET2 , SRSF2 , ASXL1 , CBL , RUNX1 , and DNMT3A are the most frequently identified other mutations in advanced forms of systemic mastocytosis. In advanced systemic mastocytosis, most patients carry three or more mutations.

Mast cells are rich sources of cytokines. Activation of mast cells results in the release of various preformed mediators that are stored in mast cell granules, de novo synthesis of sulfidopeptide leukotrienes such as leukotriene C ₄ and prostaglandins (mostly prostaglandin D ₂ ) from membrane lipids, and synthesis of cytokines. Preformed mediators stored in mast cell granules include histamine; proteases such as tryptase, chymase, and carboxypeptidase A; and proteoglycans such as heparin and chondroitin sulfate.

Mature tryptase enzyme is a serine protease that is stored in mast cell granules and is transiently elevated in serum or plasma after mast cell degranulation episodes, such as anaphylaxis. In contrast, tryptase precursor proenzymes (α and ß protryptases) are constitutively secreted outside the cell, and their serum levels at baseline correlate with mast cell burden.

Symptoms

Mastocytosis is a disease with protean clinical manifestations. In general, patients with mastocytosis belong to one of two broad categories: patients who have cutaneous disease alone, and patients who have systemic disease with or without skin involvement. Although some patients may complain only about the cosmetic appearance of urticaria pigmentosa lesions ( Fig. 235-1 ), other patients suffer from frequent episodes of vascular instability or have life-threatening hematologic disease.

The symptoms of mastocytosis are primarily related to the release of vasoactive mast cell mediators (e.g., histamine, leukotriene C ₄ , and prostaglandin D ₂ ), which cause vasodilation that may lead to flushing, tachycardia, hypotension, presyncope, and syncope. Histamine also causes pruritus and stimulates gastric acid hypersecretion from parietal cells. Elevated serum levels of tumor necrosis factor-α and interleukin-6 may contribute to the fatigue and accelerated osteoporosis that are observed in some patients. In rare aggressive forms of mastocytosis, mast cells may extensively infiltrate into tissues such as the gastrointestinal tract, where they may result in malabsorption, and the liver, where they may cause portal fibrosis with associated portal hypertension.

Activation of mast cells and their release of mediators may occur after triggers, such as temperature changes (e.g., hot showers), exercise, ingestion of alcohol or spicy foods, emotional stress, insect stings, and exposure to certain drugs (e.g., opioid analgesics, nonsteroidal anti-inflammatory drugs, or muscle relaxants). Sometimes, however, activation occurs spontaneously without an obvious trigger. The prevalence of atopic disease in patients with mastocytosis is similar to that in the general population, but patients with anaphylactic sensitivity to Hymenoptera venoms appear to have a disproportionately high prevalence of mastocytosis.

Cutaneous Manifestations

Maculopapular skin lesions of urticaria pigmentosa (known as maculopapular cutaneous mastocytosis) are the most common presentation of cutaneous mastocytosis ( Fig. 235-1 ). These lesions are also present in 50 to 90% of patients with systemic mastocytosis. Remarkably different in appearance from urticaria or hives ( Chapter 232 ), lesions of urticaria pigmentosa are fixed, tan- to salmon-colored lesions that vary in size from a few millimeters to a few centimeters. Lesions are most prominently observed on the trunk and extremities and tend to spare the face and sun-exposed areas of the skin, although facial and scalp involvement may be seen in children. Blistering of the lesions may occur in children, mostly in the first 3 years of life. The lesions are generally not initially pruritic but may urticate after exposure to a number of triggers. Many patients note that the skin lesions become more prominent after exposure to heat or after physical irritation such as rubbing. A localized wheal-and-flare reaction limited to the lesional skin within a few minutes after rubbing or scratching it is known as the Darier sign. The lesions may be concentrated in skin areas that are prone to irritation, such as the axillae and groin. Patients with cutaneous mastocytosis may also manifest other symptoms such as abdominal pain, diarrhea, and flushing.

Uncommon presentations of cutaneous mastocytosis include mastocytomas and diffuse cutaneous mastocytosis. Mastocytomas are benign and generally solitary mast cell tumors, but they can sometimes precede urticaria pigmentosa. Mastocytomas occur almost exclusively in children, and physical irritation of the lesion may result in generalized flushing and other symptoms caused by the release of mediators from their mast cells. Diffuse cutaneous mastocytosis is also seen exclusively in children and is characterized by diffuse thickening of the skin and appendages with a peau d’orange appearance without individual urticaria pigmentosa lesions.

Telangiectasia macularis eruptiva perstans is a rare form of cutaneous mastocytosis that is characterized by diffuse telangiectatic macules. Because the lesions of telangiectasia macularis eruptiva perstans are generally seen in the presence of urticaria pigmentosa, it is uncertain whether telangiectasia macularis eruptiva perstans represents a distinct form of cutaneous mastocytosis.

Systemic Manifestations

Degranulation of mast cells can cause brief, recurrent, and self-limited multiorgan manifestations or recurrent complaints with a prolonged time course. A typical mast cell degranulation episode may variably involve flushing, conjunctival hyperemia, nausea, vomiting, abdominal cramping, diarrhea, tachycardia, and lightheadedness. These symptoms of mast cell activation may occur when mast cells are activated as a reaction to stimuli generated by another pathologic process, but a consistent trigger can be identified in only a small number of patients. Angioedema, hives, and wheezing are uncommon in mastocytosis. Flushing usually involves the face and upper chest area. The episodes usually persist for 30 minutes to a few hours. Hypotension may develop, and the episode can progress to full loss of consciousness. Hypotensive episodes can be life-threatening, particularly in the presence of comorbid conditions, such as cardiac or pulmonary disease.