• Previously considered one of the myeloproliferative neoplasms, SM have been moved to a separate disease category as more is understood about the pathogenesis and treatment of these diseases.
• The clinical manifestations of mastocytosis are diverse and may be divided into those that are systemic or localized.
  • Systemic effects of this disorder result from the release of mast cell mediators into the circulation. Clinical signs and symptoms that comprise systemic mediator release are those reported with anaphylaxis and include flushing, pruritus, hypotension, syncope, palpitations, and tachycardia.
    • GI symptoms are commonly associated with mastocytosis and include nausea, vomiting, abdominal cramping, bloating, and/or diarrhea. Peptic ulcer disease, which appears to reflect at least partially increased gastric acid secretion as a result of hyperhistaminemia, may occur in up to 50% of patients with systemic disease. Malabsorption, although less common, tends to be mild, but when present, reflects advanced disease.
  • Local sequelae of mastocytosis are largely caused by the effects of mast cell collections at specific organ sites and may result in severe end-organ damage caused by infiltration of normal tissue with mast cells and subsequent fibrosis (eg, end-stage liver disease caused by fibrosis and bone marrow failure).
    • The most frequently involved organs in SM are the skin, bone marrow, lymph nodes, spleen, liver, and GI tract. The lungs are usually spared in mastocytosis. Atopy (eg, eczema and allergic rhinitis) and airway hyperreactivity (eg, asthma) are generally not the features of this disease.

Mast Cell Activation

Signs and Symptoms

• Anaphylaxis
• Flushing of the face, neck, and chest
• Pruritus, itching, +/- rash
• Hives, skin rashes
• Angioedema (swelling)
• Nasal itching and congestion
• Wheezing and shortness of breath
• Throat itching and swelling
• Headache and/or brain fog, cognitive dysfunction, anxiety, depression
• Gastric distress, diarrhea, nausea, vomiting, abdominal pain, bloating, gastroesophageal reflux disease (GERD)
• Bone/muscle pain, osteosclerosis, osteopenia, osteoporosis
• Light-headedness, syncope/fainting
• Rapid heart rate, chest pain
• Low blood pressure, high blood pressure at the start of a reaction, blood pressure instability
• Fatigue
• Neuropsychiatric symptoms

Potential Triggers

• Heat, cold, or sudden temperature changes
• Stress: emotional, physical, including pain, or environmental (eg, weather changes, pollution, pollen, pet dander)
• Exercise
• Food or beverages, including alcohol
• Drugs (opioids, NSAIDs, antibiotics, and some local/systemic anesthetics) and contrast dyes
• Natural odors, chemical odors, perfumes, and scents
• Insect stings
• Venoms (eg, bee, wasp, mixed vespids, spiders, fire ants, jelly fish, snakes)
• Infections (viral, bacterial, or fungal)
• Mechanical irritation, friction, or vibration
• Sun/sunlight
• Lack of sleep/sleep deprivation
• Surgery
• Vaccinations
• Procedures (eg, endoscopy, colonoscopy)

ASM, aggressive systemic mastocytosis; ISM, indolent systemic mastocytosis; SM, systemic mastocytosis.

Diagnosis

c. Serum tryptase level may be <20 ng/mL or only transiently elevated. e. Mast cell markers by flow cytometry immunophenotyping include CD117, CD25, and CD2. Immunohistochemistry markers include CD117, CD25, and tryptase. For both techniques, CD30 is optional. f. Specific criteria have been established for primary and secondary MCAS. Primary MCAS has also been referred to as monoclonal mast cell activation syndrome (MMAS). g. Hereditary alpha-tryptasemia is a multi-system disorder characterized by duplications and triplications in the TPSAB1 gene encoding a-tryptase associated with elevation of the basal serum tryptase level and symptoms including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility.

Morphology

• Mast cells express CD33, CD43, CD68, CD117, and tryptase, with tryptase being the most lineage-specific of these markers. Neoplastic mast cells express CD25 and/or CD2, detectable either by immunohistochemistry or flow cytometry.
  • A typical immunohistochemical panel of CD25, CD117, and tryptase is recommended for most cases to confirm cell lineage and aberrant immunophenotype.
• In the bone marrow, immunohistochemistry can be performed on the core biopsy and will show paratrabecular aggregates of mast cells with associated fibrosis in SM.
  • Mast cells can range from aggregates of round cells with fine granular pink abundant cytoplasm to more spindled cells with associated fibrosis.
  • Mast cells are often accompanied by eosinophils and small lymphocytes, even plasma cells, and may be overlooked because of these cellular components.
• On bone marrow aspirate smears, mast cells are most easily identified in the central portion of marrow particles as round or spindled cells with fine basophilic granules that obscure the nucleus. Nuclei may be round to oval in shape, with irregular nuclear contours yielding “dumbbell-shaped” forms.
  • Immature mast cell features tend to correlate with the more aggressive clinical syndromes, but morphology alone is not adequate for classification.

Subtyes

Cutaneous Mastocytosis (CM)

• Skin lesions demonstrating the typical findings of urticaria pigmentosa (UP)/maculopapular cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis or solitary mastocytoma, and typical histological infiltrates of mast cells in a multifocal or diffuse pattern in an adequate skin biopsy (both the dense focal and the diffuse mast cell infiltrates in the biopsy.).
• Absence of features/criteria sufficient to establish the diagnosis of SM.

Systemic Mastocytosis (SM)

CD25 is the more sensitive marker, by both flow cytometry and immunohistochemistry.