What is systemic mastocytosis?

What is Systemic Mastocytosis

Systemic mastocytosis (SM) is a clonal myeloproliferative disorder characterized by abnormal proliferation and accumulation of neoplastic mast cells in one or more extracutaneous organs (bone marrow, liver, spleen, gastrointestinal tract), with or without skin involvement. 1

Pathophysiology and Molecular Basis

• The disease is driven by activating mutations in the KIT gene in >90% of adult cases, with KIT D816V being the most common mutation. 1, 2
• The clonal mast cells accumulate in tissues and release inflammatory mediators (histamine, tryptase, prostaglandins, leukotrienes) causing both local organ damage and systemic symptoms. 1, 3
• SM represents a distinct disease entity separate from other myeloproliferative neoplasms in the WHO classification. 1

Clinical Manifestations

Patients present with two major categories of symptoms:

Mediator-Related Symptoms

• Flushing, pruritus, urticaria, and skin lesions (urticaria pigmentosa in 85% of indolent cases). 1
• Gastrointestinal symptoms including diarrhea, nausea, abdominal pain, and malabsorption. 1
• Cardiovascular symptoms including hypotension and syncope. 1
• Anaphylaxis is a life-threatening manifestation requiring immediate epinephrine administration. 1
• Neuropsychiatric symptoms including headache, cognitive impairment, and mood disturbances. 1

Organ Infiltration Symptoms

• Bone involvement causing osteoporosis, osteolytic lesions, and pathologic fractures. 1, 2
• Hepatosplenomegaly with or without organ dysfunction. 1
• Cytopenias from bone marrow infiltration in advanced disease. 1
• Lymphadenopathy. 1

Diagnostic Criteria

The WHO diagnostic criteria require either:

• 1 major criterion + ≥1 minor criterion, OR
• ≥3 minor criteria 1, 4

Major Criterion

• Multifocal, dense infiltrates of ≥15 mast cells in aggregates detected in bone marrow or extracutaneous organ biopsies. 1, 4

Minor Criteria

1. 25% of mast cells with atypical/spindle-shaped morphology in lesional tissues. 1, 4

2. Detection of KIT D816V or other activating KIT mutation. 1, 4
3. Aberrant expression of CD25 with or without CD2 on neoplastic mast cells by flow cytometry or immunohistochemistry. 1, 4
4. Persistently elevated baseline serum tryptase >20 ng/mL (unless there is an associated myeloid neoplasm). 1, 4

Disease Classification

SM is classified into subtypes based on mast cell burden and organ dysfunction:

Indolent Systemic Mastocytosis (ISM)

• Low mast cell burden with no C-findings (organ damage) or associated hematologic neoplasm. 1
• Life expectancy similar to age-matched general population with median survival of 301 months. 1
• Younger age at presentation, higher prevalence of skin lesions (85%), and lower constitutional symptoms (15%). 1

Smoldering Systemic Mastocytosis (SSM)

• Presence of ≥2 B-findings (high mast cell burden indicators) without C-findings or associated hematologic neoplasm. 1
• Higher mast cell burden, older age, more constitutional symptoms (45%). 1
• Inferior median survival (120 months) and higher risk of transformation to acute myeloid leukemia or aggressive SM (18%). 1

Aggressive Systemic Mastocytosis (ASM)

• Presence of ≥1 C-finding indicating organ damage from mast cell infiltration. 1
• Examples include cytopenias (ANC <1×10⁹/L, hemoglobin <10 g/dL, platelets <100×10⁹/L), hepatomegaly with liver dysfunction, large osteolytic lesions, splenomegaly with hypersplenism, or malabsorption with weight loss. 1

SM with Associated Hematologic Neoplasm (SM-AHN)

• SM criteria met along with a separate myeloid or lymphoid neoplasm. 1, 5

Mast Cell Leukemia (MCL)

• Rare, aggressive variant with circulating mast cells and diffuse bone marrow infiltration. 5

B-Findings vs C-Findings

B-findings indicate high mast cell burden but no organ damage: 1

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

• Hepatomegaly, splenomegaly, or lymphadenopathy without organ dysfunction
• Dysplasia in non-mast cell lineages without meeting criteria for another hematologic neoplasm

C-findings indicate organ damage requiring cytoreductive therapy: 1

• Cytopenias from bone marrow dysfunction
• Hepatomegaly with impaired liver function, ascites, or portal hypertension
• Large osteolytic lesions with or without pathologic fractures
• Splenomegaly with hypersplenism
• Malabsorption with hypoalbuminemia and weight loss

Key Diagnostic Pitfalls

• Elevated tryptase alone does not diagnose SM—consider hereditary alpha-tryptasemia (TPSAB1 gene duplications) in patients with elevated baseline tryptase without meeting SM criteria. 1, 4
• Exclude secondary causes of mast cell activation (allergies, drugs, infections, inflammatory conditions) before diagnosing primary mast cell disorders. 1, 4
• Bone marrow biopsy with immunophenotyping is essential for diagnosis—peripheral blood findings are insufficient except in mast cell leukemia. 4, 3
• Referral to specialized centers with mastocytosis expertise is strongly recommended for accurate diagnosis and management. 1, 4

Prognosis

• ISM patients have excellent prognosis with survival similar to the general population. 1
• Advanced SM subtypes (ASM, SM-AHN, MCL) have significantly worse outcomes with 15-fold higher mortality risk compared to ISM. 6
• Age is an independent predictor of survival across all subtypes. 1