Systemic Mastocytosis

Systemic mastocytosis is a clonal hematologic neoplasm of mast cells characterized by abnormal proliferation and accumulation in extracutaneous organs (bone marrow, liver, spleen, gastrointestinal tract, lymph nodes), distinct from cutaneous mastocytosis where mast cell infiltration is limited to skin. The driving genetic alteration in 95% of cases is the KIT D816V mutation in exon 17 (a gain-of-function mutation in the KIT receptor tyrosine kinase causing ligand-independent activation), confirmed by allele-specific quantitative PCR (highly sensitive — detects 0.01% allele burden) on bone marrow and/or peripheral blood. Other rare KIT mutations occur (D820G, V560G, F522C, K509I), with some cases having no detectable mutation (KIT-wild-type). The 2017/2022 WHO classification recognizes seven categories: bone marrow mastocytosis (BMM, indolent), indolent systemic mastocytosis (ISM, most common 80-85%), smoldering systemic mastocytosis (SSM), systemic mastocytosis with associated hematologic neoplasm (SM-AHN, ~10-15%), aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL, rare), mast cell sarcoma.

Diagnostic criteria (1 major + 1 minor or 3 minor): Major: multifocal dense aggregates of mast cells (≥15 in aggregate) in bone marrow or other extracutaneous tissue. Minor (any 3): >25% of mast cells in infiltrate are spindle-shaped or atypical morphology; KIT D816V or other activating KIT mutation; mast cells co-express CD117 with aberrant CD2 and/or CD25 (and CD30 in advanced forms); persistent serum total tryptase >20 ng/mL (not applicable if SM-AHN). C-findings (criteria for aggressive disease, organ damage): cytopenias (Hb <10 g/dL, platelets <100,000/uL, ANC <1000/uL), hepatomegaly with impaired liver function (elevated transaminases, ascites, portal hypertension), splenomegaly with hypersplenism, malabsorption with weight loss >10%, large osteolytic bone lesions and/or pathologic fractures.

Clinical presentation includes mediator release symptoms (caused by mast cell degranulation releasing histamine, tryptase, prostaglandins, leukotrienes, cytokines): flushing (most common), pruritus (with or without urticaria pigmentosa), urticaria, anaphylaxis (with idiopathic, hymenoptera sting, or unknown triggers), gastrointestinal (cramping, diarrhea, peptic ulcer disease, malabsorption), cardiovascular (palpitations, hypotension, syncope), neuropsychiatric (headache, fatigue, brain fog, depression, anxiety, irritability), musculoskeletal (bone pain, joint pain), osteoporosis with fragility fractures (very common, can be presenting feature), and in advanced forms: B-symptoms, organ damage features (cytopenias, hepatosplenomegaly, malabsorption, ascites). Diagnosis: bone marrow biopsy and aspirate (essential — multifocal mast cell aggregates with characteristic morphology and immunohistochemistry CD117+ CD25+ CD2+/-), serum tryptase (elevated in 90%), KIT D816V testing, comprehensive metabolic panel, CBC, hematology evaluation, GI workup if symptoms, bone densitometry (DEXA scan), evaluation for SM-AHN with comprehensive cytogenetics and molecular testing. Treatment by category: ISM/BMM — symptomatic mediator-blocking therapy, no need for cytoreduction (normal life expectancy in most). Mediator-blocking: H1 antihistamines (cetirizine, fexofenadine, loratadine — all 4 generations may be needed at high doses), H2 antihistamines (famotidine, ranitidine), proton pump inhibitors, cromolyn sodium for GI symptoms, leukotriene antagonists (montelukast), omalizumab (anti-IgE — for refractory anaphylaxis), aspirin and other NSAIDs for prostaglandin-mediated symptoms (with caution), epinephrine auto-injector and anaphylaxis action plan, avoidance of known triggers, glucocorticoids for severe symptoms (limited course). Osteoporosis: bisphosphonates (zoledronic acid, alendronate), denosumab. Advanced disease (ASM, MCL, SM-AHN): midostaurin (multikinase inhibitor including KIT) — first-line, response rate 60-70% with median duration 24 months; avapritinib (highly selective KIT D816V inhibitor) — superior efficacy with response rate 75% in advanced disease, FDA-approved 2021; cladribine, interferon alpha (older agents); allogeneic stem cell transplantation for fit younger patients. SM-AHN: treat the AHN component appropriately. Disease monitoring: serial tryptase, KIT D816V allele burden, organ function. Prognosis: ISM 25+ years median survival (near normal); ASM 3.5 years median; MCL <1 year median (improving with avapritinib); SM-AHN dependent on AHN.