What is mastocytosis and how is it diagnosed?

What is Mastocytosis?

Mastocytosis is a rare clonal neoplastic disease characterized by pathologic accumulation of mast cells in one or multiple organs, most commonly the skin and bone marrow, caused primarily by activating KIT mutations (especially D816V in >80% of adult cases). 1

Disease Classification and Age-Related Patterns

Mastocytosis presents in two distinct age-related patterns with fundamentally different prognoses:

Pediatric-Onset Mastocytosis

• Typically diagnosed before age 2 years, predominantly affects only the skin (cutaneous mastocytosis), and has a marked tendency for spontaneous regression by puberty. 1
• 60-80% of patients develop lesions during the first year of life, with lesions sometimes present at birth. 1
• Only 43% of pediatric patients have detectable c-kit mutations in skin biopsies, with only one-third presenting the KIT D816V mutation found in most adults. 1
• Internal organ involvement is infrequent in children. 1

Adult-Onset Mastocytosis

• Almost invariably systemic and chronic, affecting the bone marrow in most cases, with progressive course that increases in extent and severity over time. 1
• The KIT D816V mutation is found in >80% of adult systemic mastocytosis cases. 1
• Median survival varies dramatically by subtype: indolent systemic mastocytosis (ISM) has median survival of 301 months, while aggressive systemic mastocytosis (ASM) has only 41 months. 2

WHO Classification Categories

The World Health Organization distinguishes 7 categories: 1

1. Cutaneous mastocytosis (CM) - MC infiltration confined to skin
2. Indolent systemic mastocytosis (ISM) - most common adult form, 85% have skin involvement 2
3. SM with associated clonal hematologic non-MC disease (SM-AHNMD) - occurs in 5-20% of SM patients 1
4. Aggressive systemic mastocytosis (ASM) - defined by presence of C-findings (organ damage) 2
5. Mast cell leukemia (MCL) - extremely rare, progressive and fatal 3
6. Mast cell sarcoma (MCS) - malignant extracutaneous variant 3
7. Extracutaneous mastocytoma - benign localized tumor 3

Clinical Manifestations

Cutaneous Forms (70-90% of pediatric cases)

• Urticaria pigmentosa (UP): Red to brown to yellow macules, plaques or nodules measuring few mm to 1-2 cm, predominantly on trunk and extremities. 1
• Darier's sign: Wheal and flare formation after stroking lesions, typically present and pathognomonic. 1
• Solitary mastocytoma: Single lesion that can blister and form bullae, particularly at friction sites. 4
• Erythema, swelling, and blister formation can occur after rubbing, associated with pruritus and dermatographism. 1

Systemic Symptoms

Symptoms result from mast cell mediator release and/or organ infiltration: 1

• Flushing (up to 36% of UP patients) 1
• Gastrointestinal: abdominal cramping, diarrhea (up to 40% in cutaneous, 80% in systemic), nausea, vomiting, malabsorption 2
• Cardiovascular symptoms including hypotension and anaphylaxis 2
• Respiratory symptoms 2
• Neuropsychiatric symptoms 2
• In ASM/MCL: organomegaly and organ damage from MC infiltration 1

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How to Test for Mastocytosis

Diagnostic Algorithm

Step 1: Clinical Assessment and Initial Testing

For suspected cutaneous mastocytosis (especially pediatric):

• Examine entire body for characteristic skin lesions (UP, mastocytomas, diffuse involvement). 1, 4
• Test for Darier's sign by gently rubbing suspicious lesions and observing for wheal and erythema formation. 1, 4
• Skin biopsy of lesional skin reveals MC infiltration, sometimes with atypical MCs forming aggregates. 1
• Measure baseline serum tryptase level. 1

For suspected systemic mastocytosis (especially adults):

• Bone marrow biopsy with immunohistochemistry is the cornerstone diagnostic test. 1, 2
• Measure baseline serum tryptase (persistently >20 ng/mL is a minor diagnostic criterion). 1, 2
• KIT D816V mutation testing in bone marrow, peripheral blood, or extracutaneous organs. 1, 2
• Flow cytometry to detect aberrant CD25 and/or CD2 expression on mast cells. 1, 2

Step 2: WHO Diagnostic Criteria for Systemic Mastocytosis

Diagnosis requires: 1 major + 1 minor criterion, OR ≥3 minor criteria 1, 2

Major Criterion:

• Multifocal, dense infiltrates of ≥15 aggregated mast cells in bone marrow and/or other extracutaneous organs (identified through tryptase immunohistochemistry). 1, 2

Minor Criteria:

1. 25% of mast cells are atypical/spindle-shaped in bone marrow or extracutaneous organs 1, 2

2. Activating KIT mutation at codon 816 (or other activating mutation) detected in bone marrow, peripheral blood, or extracutaneous organ 1, 2
3. Aberrant expression of CD25 ± CD2 on mast cells by flow cytometry 1, 2
4. Persistently elevated baseline serum tryptase >20 ng/mL (unless associated clonal myeloid disorder is present) 1, 2

Step 3: KIT Mutation Testing Methodology

Using highly-sensitive allele-specific PCR assays, KIT D816V can be detected in peripheral blood leukocytes in most patients with systemic mastocytosis, which is a major step forward in screening and SM detection. 1

• Conventional PCR with sequencing has relatively low sensitivity and may result in false-negatives, especially in indolent SM where MC burden is low. 1
• Highly-sensitive assays are required for detection and quantification of mutant allele burden. 1
• KIT D816V allele burden can be followed quantitatively during natural course or therapy. 1

Step 4: Distinguishing from Mast Cell Activation Syndrome (MCAS)

If WHO criteria for systemic mastocytosis are NOT met: 2

• Measure acute tryptase during symptomatic episodes (within 1-4 hours of symptom onset). 2
• MCAS requires: episodic systemic anaphylaxis affecting ≥2 organ systems, acute tryptase elevation during symptoms, absence of WHO SM criteria, and symptom improvement with mast cell-directed therapy. 2
• Exclude secondary causes: IgE-mediated allergies, drugs, infections, other inflammatory conditions. 2
• Consider hereditary alpha-tryptasemia (TPSAB1 gene testing) if baseline tryptase elevated without meeting SM criteria. 2

Step 5: Additional Investigations Based on Subtype

For aggressive SM or suspected organ involvement:

• Assess for C-findings: cytopenias, hepatic dysfunction (elevated liver enzymes, ascites, portal hypertension), skeletal involvement (pathologic fractures, severe osteoporosis), splenic dysfunction (hypersplenism), gastrointestinal malabsorption with weight loss. 2
• Hepatosplenomegaly assessment in pediatric patients as marker of systemic disease. 5

Common Pitfalls and How to Avoid Them

• Never extrapolate adult diagnostic and treatment approaches to pediatric mastocytosis—the diseases differ fundamentally in presentation, prognosis, and genetic pathophysiology. 1, 6
• Do not rely on conventional PCR alone for KIT mutation detection; use highly-sensitive allele-specific assays to avoid false-negatives in low MC burden cases. 1
• Do not diagnose MCAS without measuring both baseline tryptase AND acute tryptase during symptomatic episodes within 1-4 hours of symptom onset. 2
• Avoid unnecessary bone marrow biopsies in children with isolated cutaneous findings and normal baseline tryptase, as systemic involvement is rare. 1, 5
• Refer complex or borderline cases to specialized centers with expertise in mastocytosis for definitive diagnosis. 2