Mastocytosis

Clonal mast cell proliferation (often driven by a KIT D816V mutation) causing mast cell accumulation in tissues; may be confined to skin (cutaneous mastocytosis) or involve multiple organs (systemic mastocytosis).

• Mast cells release histamine and other mediators causing allergy-like symptoms; in mastocytosis this process is chronic and can be severe. Recognizing mastocytosis explains recurrent anaphylaxis, atypical rashes, and can prevent misdiagnosis as simple allergies. Also, systemic mastocytosis is a myeloid neoplasm with potentially life-threatening complications and targeted treatments.

• Cutaneous mastocytosis (children): skin-limited mast cell proliferations like urticaria pigmentosa (brown macules/papules that urticate with rubbing); often presents in infancy and can blister or itch, but typically resolves by puberty.
• Systemic mastocytosis (adults): clonal mast cell infiltration of bone marrow and other organs (±skin lesions). Causes episodic mediator release (flushing, pruritus, abdominal pain, anaphylaxis) and may lead to hepatosplenomegaly, lymphadenopathy, or bone pain/osteoporosis in advanced cases.
• Systemic subtypes (WHO 2022): indolent SM (most common, low mast cell burden, often skin lesions, no organ damage), smoldering SM (high mast cell burden, borderline findings), aggressive SM (mast cell infiltrates cause organ dysfunction/failure), SM-AHN (SM with an associated hematologic neoplasm, e.g. SM + CMML or AML), and mast cell leukemia (rare, circulating mast cells with fulminant course).

1. Suspect mastocytosis in patients with recurrent unexplained anaphylaxis, flushing, or persistent urticarial skin lesions. Measure baseline serum tryptase; a level >20 ng/mL is a strong clue for systemic mastocytosis.
2. Confirm diagnosis with tissue biopsy: a skin biopsy (if only cutaneous signs) or bone marrow biopsy (for systemic signs) showing dense mast cell aggregates (CD117⁺, tryptase⁺ cells with metachromatic granules on toluidine blue stain). Genetic testing for the KIT D816V mutation (peripheral blood or marrow) confirms clonality in ~90% of cases.
3. Assess for organ involvement: perform lab tests (CBC for cytopenias, liver enzymes, alkaline phosphatase, bone profile) and imaging if needed (e.g., bone density scan for osteoporosis) to evaluate disease extent. Findings like cytopenias, hepatosplenomegaly, or malabsorption suggest progression to advanced systemic mastocytosis.
4. Distinguish mastocytosis from look-alikes: e.g., chronic idiopathic urticaria (allergic in nature, normal baseline tryptase), carcinoid syndrome (flushing and diarrhea from neuroendocrine tumor, elevated 5-HIAA not tryptase), or pheochromocytoma (episodic flushing with hypertension from catecholamines).

1. Avoid mast cell triggers: e.g., alcohol, extreme temperatures, NSAIDs, opioids, insect stings. All patients should carry an epinephrine auto-injector for anaphylaxis and be premedicated before surgeries (antihistamines, glucocorticoids, leukotriene blockers).
2. Symptom control (anti-mediator therapy): H1 blockers (antihistamines) for pruritus and flushing; H2 blockers or proton pump inhibitors for gastric hypersecretion; cromolyn sodium for GI symptoms; topical steroids or PUVA phototherapy for cutaneous lesions.
3. Advanced systemic disease (organ involvement or high burden): cytoreductive therapy with tyrosine kinase inhibitors targeting KIT (e.g., midostaurin, avapritinib for KIT D816V-mutated disease) or interferon-α/cladribine in select cases. Refractory aggressive disease may warrant hematopoietic stem cell transplant in eligible patients.

• Classic Darier's sign: stroking a mastocytosis skin lesion causes it to urticate (redden and swell) due to mast cell degranulation – a key bedside clue for cutaneous mastocytosis.
• Remember tryptase: Mast cell tryptase is almost exclusively from mast cells – a persistently elevated serum tryptase is a hallmark of systemic mastocytosis (and a minor diagnostic criterion).

• Any anaphylactic shock (hypotension, airway compromise) in a mastocytosis patient → emergency management with IM epinephrine; these patients have high fatality risk from anaphylaxis (e.g., after bee stings or contrast). Ensure they have epinephrine and proper education.
• New organ failure signs in previously indolent mastocytosis (e.g., cytopenias, liver dysfunction, pathologic fractures) → suspect progression to advanced SM (aggressive or SM-AHN); requires urgent hematology evaluation and therapy escalation.

1. Recurrent flushing, unexplained syncope, or urticarial rash + high tryptase → suspect mastocytosis.
2. Check baseline serum tryptase: >20 ng/mL warrants further workup (mast cell activation).
3. Biopsy involved tissue: skin (if lesions present) or bone marrow (if systemic symptoms) to identify mast cell infiltrates; send molecular testing for KIT D816V mutation.
4. Diagnose systemic mastocytosis per WHO criteria (major: ≥15 mast cells clustered in marrow/organ; minor: KIT D816V, atypical mast cell morphology, CD25⁺ mast cells, or tryptase >20). Need 1 major + 1 minor or 3 minor criteria.
5. Classify systemic disease as indolent vs advanced (assess "C findings" of organ damage). Indolent SM → manage with trigger avoidance and mediator blockade; Advanced SM → add cytoreductive therapy (e.g., midostaurin) and consider transplant.

• Infant with dozens of brown patchy lesions that urticate when rubbed (Darier's sign positive) but is otherwise well → cutaneous mastocytosis (urticaria pigmentosa, likely to improve by adolescence).
• Middle-aged adult with episodes of flushing, syncope, and abdominal cramping; exam shows diffuse red-brown maculopapular rash and labs reveal elevated tryptase → systemic mastocytosis (indolent form with mediator release symptoms).
• Patient with known indolent mastocytosis who develops weight loss, ascites, anemia, and bone lesions → progression to aggressive systemic mastocytosis (organ damage from mast cell infiltration).