What are Indolent Systemic Mastocytosis (ISM), Bone Marrow Mastocytosis (BMM), and Aggressive Systemic Mastocytosis (ASM)?

Systemic Mastocytosis Subtypes: ISM, BMM, and ASM

Indolent Systemic Mastocytosis (ISM)

ISM is the most common form of systemic mastocytosis, characterized by low mast cell burden, absence of organ damage (no C-findings), younger age at presentation, and excellent prognosis with median survival of 301 months—similar to the general population. 1

Key Clinical Features of ISM:

• Low mast cell burden with no evidence of C-findings (organ damage) or associated hematologic neoplasm 1
• Skin involvement is common: 85% have skin lesions (typically urticaria pigmentosa) and 78% experience cutaneous symptoms 1
• Constitutional symptoms are uncommon: only 15% of patients experience systemic symptoms 1
• Younger age at presentation compared to other SM subtypes 1
• Excellent prognosis: life expectancy matches age-matched general population with median survival of 301 months 1

Diagnostic Criteria:

• Must meet WHO criteria for systemic mastocytosis (1 major + 1 minor criterion, OR ≥3 minor criteria) 2
• Major criterion: multifocal dense infiltrates of ≥15 mast cells in bone marrow or extracutaneous organs 2
• Minor criteria include: >25% spindle-shaped mast cells, KIT D816V mutation (found in >80% of adult SM cases), aberrant CD25/CD2 expression on mast cells, and serum tryptase >20 ng/mL 1, 2

Bone Marrow Mastocytosis (BMM)

BMM is a specific subvariant of ISM where mast cell infiltration is strictly confined to the bone marrow without skin lesions or multiorgan visceral involvement. 1

Distinguishing Features of BMM:

• Bone marrow-only disease: mast cell infiltration limited to bone marrow with no skin or multiorgan visceral lesions 1
• Higher mediator-release symptoms: 86% of BMM patients experience symptoms from mast cell mediator release, compared to 67% in ISM and 50% in smoldering SM 1
• Superior survival: median survival has not been reached in BMM patients, exceeding the 301 months seen in ISM 1
• Absence of cutaneous manifestations distinguishes it from typical ISM 1

Clinical Pitfall:

Despite lacking skin lesions, BMM patients paradoxically have the highest incidence of mediator-related symptoms (86%), so clinicians must maintain high suspicion even without visible cutaneous disease 1.

Aggressive Systemic Mastocytosis (ASM)

ASM is defined by the presence of one or more C-findings (organ damage from mast cell infiltration) without meeting criteria for mast cell leukemia, and carries a significantly worse prognosis with median survival of only 41 months. 1

Defining C-Findings (Organ Damage):

• Cytopenias: ANC <1 × 10⁹/L, hemoglobin <10 g/dL, or platelets <100 × 10⁹/L due to bone marrow dysfunction from mast cell infiltration 1
• Hepatic dysfunction: palpable hepatomegaly with impaired liver function, ascites, and/or portal hypertension 1
• Skeletal involvement: large osteolytic lesions with or without pathologic fractures 1
• Splenic dysfunction: palpable splenomegaly with hypersplenism 1
• Gastrointestinal malabsorption: hypoalbuminemia with weight loss from GI mast cell infiltrates 1

Key Clinical Features of ASM:

• Requires ≥1 C-finding but does not meet criteria for mast cell leukemia (<20% mast cells in bone marrow) 1
• Skin lesions are less common compared to ISM 1
• Poor prognosis: median survival of 41 months 1
• Organ infiltration drives symptoms rather than mediator release 1

Critical Diagnostic Distinction:

If C-findings are present along with an associated hematologic neoplasm (AHN), the diagnosis is SM-AHN rather than ASM, even if the C-findings appear related to the mast cell component 1. This distinction is crucial because SM-AHN has different prognostic implications and treatment approaches 1.

Algorithmic Approach to Classification

Step 1: Confirm systemic mastocytosis diagnosis using WHO criteria (requires bone marrow biopsy with immunophenotyping, KIT D816V testing, serum tryptase, and flow cytometry for CD25/CD2) 2

Step 2: Assess for C-findings (organ damage):

• If no C-findings present → proceed to Step 3
• If ≥1 C-finding present → ASM (unless AHN coexists, then SM-AHN) 1

Step 3: Evaluate disease distribution:

• If bone marrow only (no skin/visceral lesions) → BMM 1
• If skin and/or other organs involved → ISM 1

Step 4: Assess B-findings (high disease burden without organ damage):

• If ≥2 B-findings present → consider smoldering SM (separate entity, not ISM) 1
• B-findings include: >30% bone marrow mast cell infiltration with tryptase >200 ng/mL, hepatosplenomegaly/lymphadenopathy without dysfunction, or dysplasia in non-mast cell lineages 1

Prognostic Implications

The distinction between these subtypes has profound implications for mortality and quality of life:

• ISM/BMM: Near-normal life expectancy (>300 months), <1% risk of transformation to AML or ASM 1
• ASM: Median survival 41 months, requires cytoreductive therapy consideration 1
• Referral to specialized centers is strongly recommended for complex or borderline cases 2