What are the diagnosis and treatment options for a patient with suspected mast cell disorders, such as mastocytosis or mast cell activation syndrome?

Diagnosis and Management of Mast Cell Disorders

Diagnostic Approach

For patients with suspected mast cell activation symptoms, begin with serum tryptase measurement and proceed systematically through bone marrow evaluation if criteria are met, using WHO diagnostic criteria to distinguish between systemic mastocytosis, mast cell activation syndrome, and secondary causes. 1

Initial Clinical Assessment

When evaluating suspected mast cell disorders, look specifically for:

• Episodic symptoms affecting ≥2 organ systems concurrently: skin (flushing, urticaria, pruritus), gastrointestinal (diarrhea, abdominal pain, nausea), cardiovascular (hypotension, syncope, tachycardia), respiratory (wheezing, dyspnea), or neurologic (headache, cognitive dysfunction) 1
• Temporal pattern: spontaneous episodes or triggered by specific factors including physical stimuli (temperature extremes, mechanical irritation), alcohol, certain medications, insect stings, or emotional stress 1
• Adult-onset mastocytosis in the skin (urticaria pigmentosa), which warrants bone marrow evaluation 1

Laboratory Testing Algorithm

Step 1: Baseline Serum Tryptase

• Obtain when patient is completely asymptomatic to establish personal reference value 2
• If baseline tryptase persistently >20 ng/mL, proceed directly to bone marrow biopsy 1, 2

Step 2: Acute Episode Documentation

• Collect serum tryptase 1-4 hours after symptom onset 1, 2
• Diagnostic threshold: increase ≥20% above baseline PLUS absolute increase ≥2 ng/mL confirms mast cell activation 1, 2
• If acute tryptase collection is impractical, obtain 24-hour urine for N-methylhistamine (not plasma/urine histamine), leukotriene E4 (peaks 0-6 hours post-episode), and 11β-prostaglandin F2α (peaks 0-3 hours) 1, 2

Step 3: Clonality Assessment

• Peripheral blood KIT D816V mutation testing using highly sensitive allele-specific oligonucleotide quantitative PCR (ASO-qPCR) 1, 2
• Buccal swab for TPSAB1 α-tryptase copy number variation to identify hereditary α-tryptasemia 1, 2
• If peripheral blood KIT mutation is negative but clinical suspicion remains high, proceed to bone marrow evaluation 1, 2

Step 4: Bone Marrow Biopsy Indications

• Baseline serum tryptase persistently >20 ng/mL 1, 2
• Adult-onset mastocytosis in the skin 1
• Abnormal blood counts or organomegaly 1
• Bone marrow evaluation must include: aspirate, core biopsy, flow cytometry for CD25/CD2 expression, immunohistochemistry, and KIT D816V mutation testing 1, 2

Diagnostic Classification

Systemic Mastocytosis (WHO Criteria)

• Major criterion: multifocal, dense infiltrates of mast cells (≥15 mast cells in aggregates) in bone marrow or extracutaneous organs 1
• Minor criteria (need 1 major + 1 minor, OR ≥3 minor): atypical mast cell morphology, KIT D816V mutation, aberrant CD25±CD2 expression, persistently elevated serum tryptase >20 ng/mL 1

Mast Cell Activation Syndrome (MCAS)

MCAS diagnosis requires ALL three criteria simultaneously 1, 2:

1. Clinical: Recurrent episodic symptoms affecting ≥2 organ systems
2. Laboratory: Documented mediator elevation during episodes (tryptase increase as above, OR elevated urinary metabolites)
3. Therapeutic: Response to mast cell-targeted medications

MCAS Subclassification 1:

• Primary (clonal) MCAS: KIT D816V mutation positive OR aberrant CD25 expression without meeting full SM criteria
• Secondary MCAS: IgE-mediated allergy or other identifiable trigger with normal mast cells
• Idiopathic MCAS: No identifiable trigger or clonal markers
• Hereditary α-tryptasemia: TPSAB1 gene duplications/triplications

Critical Pitfall: Overdiagnosis

Do not diagnose MCAS without documented mediator elevation during symptomatic episodes. 1 Many conditions mimic mast cell activation (functional GI disorders, anxiety, postural orthostatic tachycardia syndrome). The requirement for objective biochemical evidence prevents overdiagnosis. 1, 3

Tests NOT to order 2:

• Plasma or urine histamine (use N-methylhistamine instead)
• Heparin levels (not validated)
• Chromogranin A (neuroendocrine marker, not mast cell-specific)

Treatment Strategy

First-Line Antimediator Therapy

Initiate combination therapy with H1 and H2 antihistamines as foundation, then add targeted agents based on elevated mediator profiles. 1, 4

H1 Antihistamines 1, 4:

• Nonsedating agents (cetirizine, loratadine, fexofenadine) at 2-4 times standard doses
• Example: cetirizine 10 mg up to 40 mg daily

H2 Antihistamines 1, 4:

• Famotidine 20 mg twice daily or ranitidine 150 mg twice daily
• Combine with H1 antihistamines for synergistic effect

Cromolyn Sodium 5, 4:

• FDA-approved for mastocytosis: 200 mg four times daily orally
• Particularly effective for gastrointestinal symptoms (diarrhea, abdominal pain)
• Clinical improvement occurs within 2-6 weeks 5
• Also improves cutaneous manifestations (urticaria, pruritus, flushing) and cognitive function 5

Targeted Therapy Based on Mediator Profiles

Leukotriene Antagonists 1, 4:

• If urinary LTE4 elevated: montelukast 10 mg daily or zileuton 600 mg four times daily
• Zileuton also inhibits mediator synthesis 4

COX Inhibitors 1, 4:

• If prostaglandin metabolites (11β-PGF2α) elevated: aspirin 81-325 mg daily
• Caution: Aspirin can trigger mast cell activation in some patients; start low dose with monitoring 1

Omalizumab 1, 4:

• Consider for refractory cases or when IgE-mediated component present
• Anti-IgE therapy reduces mast cell activatability

Acute Episode Management

Anaphylaxis Protocol 1:

• Assume supine position immediately
• Intramuscular epinephrine 0.3-0.5 mg (1:1000) into anterolateral thigh
• Call emergency services
• Supplemental oxygen and IV fluids
• Secondary management: chlorphenamine and hydrocortisone

All patients with MCAS or mastocytosis must carry epinephrine auto-injectors at all times. 1, 4

Prolonged Episodes 4:

• Corticosteroids (prednisone 40-60 mg daily, taper over 5-7 days)
• Reserve for episodes not responsive to standard antimediator therapy

Advanced Systemic Mastocytosis Treatment

For patients meeting WHO criteria for aggressive SM or mast cell leukemia with C-findings (organ damage):

Midostaurin 1:

• KIT inhibitor, standard dose 100 mg twice daily
• Dose modifications for toxicity: reduce to 50 mg twice daily for grade 3/4 non-hematologic toxicity, resume at 100 mg if tolerated 1
• Administer prophylactic antiemetics (ondansetron or granisetron) 1 hour before dosing; take with food 1
• Monitor for interstitial lung disease/pneumonitis; discontinue if occurs 1

Trigger Avoidance

Specific triggers to eliminate 1:

• Temperature extremes (hot showers, cold exposure)
• Mechanical irritation (vigorous rubbing, friction)
• Alcohol
• NSAIDs (except aspirin if tolerated and indicated)
• Certain antibiotics (vancomycin, fluoroquinolones)
• Radiocontrast media

Opioid Use 2:

• Do not categorically avoid opioids despite theoretical mast cell activation risk
• Use with caution and monitoring when clinically indicated for pain management

Perioperative Management

Coordinate with anesthesia and surgical teams for any procedure 1:

• Pre-anesthetic treatment: anxiolytics, H1/H2 antihistamines, corticosteroids
• Avoid known mast cell degranulators (morphine, succinylcholine, rocuronium)
• Have epinephrine immediately available

Multidisciplinary Care Requirements

Refer to specialized centers with mast cell disease expertise involving 1:

• Hematology/oncology for systemic mastocytosis
• Allergy/immunology for MCAS management
• Gastroenterology for GI symptoms
• Dermatology for cutaneous manifestations
• Pathology for bone marrow interpretation

Monitoring and Follow-Up

For patients on chronic antimediator therapy 2:

• Assess symptom control using Mastocytosis Symptom Assessment Form (MSAF) or Mastocytosis Quality of Life Questionnaire (MQLQ) 1
• Monitor serum tryptase every 6-12 months
• Liver enzymes every 3-6 months if on multiple medications 6
• Bone density monitoring if on chronic corticosteroids

Treatment duration: Continue indefinitely as MCAS is typically chronic; some patients with clonal disease may progress to overt systemic mastocytosis requiring ongoing surveillance. 1, 4