What is mastocytosis?

What is Mastocytosis

Mastocytosis is a rare, heterogeneous disease characterized by the pathological accumulation of clonal mast cells in one or more organs, most commonly affecting the skin in children and the bone marrow in adults. 1

Disease Classification and Epidemiology

The World Health Organization recognizes seven distinct categories of mastocytosis, which fundamentally divide into cutaneous and systemic forms 1:

• Cutaneous mastocytosis (CM) - limited to skin involvement only, most commonly diagnosed in children 1
• Indolent systemic mastocytosis (ISM) - the most common adult form with low mast cell burden 1
• Smoldering systemic mastocytosis (SSM) - characterized by ≥2 B-findings without C-findings 1
• Systemic mastocytosis with associated hematologic neoplasm (SM-AHNMD) - occurs in 5-20% of systemic cases 1
• Aggressive systemic mastocytosis (ASM) - presence of C-findings indicating organ damage 1
• Mast cell leukemia (MCL) - rare aggressive variant 1
• Mast cell sarcoma (MCS) and extracutaneous mastocytoma - extremely rare forms 1

The estimated prevalence is approximately 1 in 10,000 people, with an incidence of 1 per 100,000 people per year 2.

Pathophysiology and Molecular Basis

The disease is predominantly driven by activating KIT mutations, with the D816V mutation found in >80% of adult systemic cases. 1 This mutation occurs in the phosphotransferase domain of the KIT receptor, a type III tyrosine kinase that is essential for mast cell development and survival 1.

In pediatric cutaneous mastocytosis, KIT mutations are found in approximately 75% of cases, but only one-third harbor the D816V variant 1. Other mutations, particularly deletions at position 419 in the extracellular domain, are more common in children 1.

Clinical Presentation

Pediatric Disease

In children, mastocytosis predominantly affects the skin with a tendency toward spontaneous regression 1. The disease rarely progresses to systemic involvement in this population 2.

Adult Disease

In adults, the disease is typically systemic and chronic, almost invariably affecting the bone marrow, with approximately 85% also having skin involvement. 1 Symptoms arise from two mechanisms 1:

1. Mediator-related symptoms - flushing, pruritus, anaphylaxis, gastrointestinal symptoms from histamine and tryptase release 1, 3
2. Organ infiltration - in aggressive forms, causing organomegaly, cytopenias, and organ dysfunction 1

Diagnostic Approach

Systemic mastocytosis requires either 1 major criterion plus 1 minor criterion, or ≥3 minor criteria according to WHO diagnostic standards. 1, 4

Major Criterion

Multifocal dense infiltrates of ≥15 aggregated mast cells in bone marrow or extracutaneous organs identified by tryptase immunohistochemistry 1, 4

Minor Criteria

• 25% atypical or spindle-shaped mast cells in bone marrow or other organs 1, 4

• Detection of KIT D816V or other activating KIT mutation 1, 4
• Aberrant expression of CD25 and/or CD2 on mast cells 1, 4
• Persistently elevated baseline serum tryptase >20 ng/mL 1, 4

Essential Diagnostic Workup

The NCCN recommends the following evaluation for suspected systemic mastocytosis 1, 4:

• Bone marrow biopsy with immunophenotyping
• KIT D816V mutation testing (highly sensitive assays can detect this in peripheral blood in most SM patients) 1
• Mast cell immunophenotyping by flow cytometry and/or immunohistochemistry for CD117, CD25, and CD2 1
• Serum tryptase level measurement 1

Disease Burden Assessment

B-findings and C-findings are critical for determining disease subtype and prognosis. 1

B-Findings (High Mast Cell Burden)

• 30% mast cell infiltration on bone marrow biopsy and serum tryptase >200 ng/mL 1

• Hepatomegaly, splenomegaly, or lymphadenopathy without organ dysfunction 1
• Dysplasia in non-mast cell lineages without definitive associated hematologic neoplasm 1

C-Findings (Organ Damage)

• Cytopenias from bone marrow dysfunction 1
• Hepatomegaly with impaired liver function, ascites, or portal hypertension 1
• Skeletal involvement with large osteolytic lesions ± pathologic fractures 1
• Splenomegaly with hypersplenism 1
• Malabsorption with weight loss from gastrointestinal infiltration 1

Prognosis

Prognosis varies dramatically by subtype. Patients with indolent systemic mastocytosis have a median survival of 301 months, similar to age-matched controls 1. In contrast, smoldering systemic mastocytosis has a median survival of 120 months with an 18% risk of transformation to acute myeloid leukemia or aggressive disease 1. Aggressive systemic mastocytosis carries a median survival of only 41 months 1.

Critical Clinical Pitfalls

Mastocytosis should be suspected in patients with recurrent unexplained anaphylaxis, severe insect sting reactions, or unexplained osteoporosis, even without skin lesions. 3 The absence of cutaneous signs does not exclude systemic disease 3.

Referral to specialized centers with expertise in mastocytosis is strongly recommended for diagnosis and management, as the disease requires multidisciplinary care involving dermatologists, hematologists, pathologists, and allergists 1, 4.

When evaluating elevated tryptase, hereditary alpha-tryptasemia must be considered if systemic mastocytosis criteria are not met, and TPSAB1 gene testing may be indicated 4.