Mastocytosis¶
Chapter 366 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology · Chapter 366
Key Clinical Points¶
- Mastocytosis is defined by the accumulation of clonally expanded mast cells in tissues such as skin, bone marrow, liver, spleen, and gut.
- Prevalence is estimated at ~1 in 10,000 people.
- Over 90% of patients carry the KIT D816V mutation (somatic gain-of-function in the stem cell factor receptor gene).
- Cutaneous mastocytosis (CM) is common in children and indicates disease limited to skin without internal organ involvement.
- Systemic mastocytosis (SM) involves extracutaneous sites, most commonly bone marrow.
- Darier's sign: Rubbing or irritation of a mastocytoma lesion → systemic symptoms such as flushing and urticaria.
- Smoldering Systemic Mastocytosis (SSM) requires ≥2 B findings in the absence of any C findings.
- Aggressive Systemic Mastocytosis (ASM) requires ≥1 C finding attributable to high tissue mast cell infiltration.
- Anaphylaxis is commonly triggered by Hymenoptera stings and nonsteroidal anti-inflammatory drugs (NSAIDs).
- Prognosis: CM and Indolent Systemic Mastocytosis (ISM) have a normal life expectancy; ASM and Mast Cell Leukemia (MCL) have a poor prognosis.
1. DEFINITION & OVERVIEW¶
• Definition: Accumulation of clonally expanded mast cells in tissues such as skin, bone marrow, liver, spleen, and gut. • Pathophysiology: ◦ Most forms are characterized by somatic gain-of-function mutations in the stem cell factor receptor (KIT) gene. ◦ KIT D816V mutation is found in >90% of patients. ◦ Genetics: Familial occurrence is rare; atopy is not increased compared with the general population.
2. EPIDEMIOLOGY¶
• Prevalence: Approximately 1 in 10,000 people. ◦ Primary driver: Somatic gain-of-function mutations in the KIT gene (specifically KIT D816V in >90% of cases).
3. CLASSIFICATION & PATHOPHYSIOLOGY¶
• Cutaneous Mastocytosis (CM): Most common diagnosis in children; indicates disease limited to skin with no internal organ involvement. ◦ Maculopapular cutaneous mastocytosis (MPCM) ◦ Solitary mastocytoma ◦ Diffuse cutaneous mastocytosis (DCM) • Systemic Mastocytosis (SM) Variants: ◦ Indolent systemic mastocytosis (ISM): >70% of adult patients; no organ dysfunction, associated hematologic disorder, or mast cell leukemia. ◦ Smoldering systemic mastocytosis (SSM): High mast cell burden but no associated clonal hematologic non-mast cell lineage disease or aggressive features. ◦ Systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD): Prognosis determined by the nature of the associated disorder. ◦ Aggressive systemic mastocytosis (ASM): Mast cell infiltration in multiple organs (liver, spleen, gut, bone, marrow) but not in gastrointestinal tissue or skin. ◦ Mast cell leukemia (MCL): Rare; involves circulating metachromatically staining, atypical mast cells. ◦ Aleukemic form: No circulating mast cells, but >20% high-grade immature mast cells in bone marrow smears. ◦ Mast cell sarcoma (MCS): Rare solid mast cell tumor with malignant invasive features.
4. CLINICAL FEATURES¶
4.1 Cutaneous Lesions¶
• Maculopapular cutaneous mastocytosis (MPCM): Reddish-brown macules, papules, or plaques. ◦ Polymorphic vs. Monomorphic forms. ◦ Darier's sign: Rubbing/irritation → urtication and erythema. ◦ Solitary Mastocytoma: Yellow, brown, or red; size varies from mm to cm. ◦ Interaction: Rubbing → systemic symptoms (flushing, urticaria). ◦ Diffuse Cutaneous Mastocytosis (DCM): Generalized thickening of skin and "peau d'orange" appearance. ◦ Complications: Associated with bullae formation and severe systemic symptoms (GI irritation, vascular collapse).
4.2 Systemic Symptoms¶
• General: Intermittent urticaria, flushing, tachycardia, and vascular collapse. ◦ Gastrointestinal: Gastric acid hypersecretion, crampy lower abdominal pain, diarrhea (due to increased motility), and malabsorption. ◦ Organ-Specific Effects: ◦ Liver: Periportal fibrosis → potential portal hypertension. ◦ Bone: Pain due to high mast cell burden. ◦ Anaphylaxis: Rapid/life-threatening vascular collapse; triggered by Hymenoptera stings or NSAIDs. ◦ Neuropsychiatric: Impaired recent memory, decreased attention span, and "migraine-like" headaches. ◦ Exacerbation Factors: Alcohol, temperature changes, stress, mast cell–interactive opioids, or NSAIDs.
5. INVESTIGATIONS & DIAGNOSIS¶
• Diagnostic Criteria (B and C Findings): 1. B Findings (2 required for SSM; 0 C findings allowed): ◦ High MC burden: Bone marrow infiltration >30% OR basal serum tryptase >200 ng/mL OR KIT D816V >10% VAF in bone marrow. ◦ Hypercellular bone marrow with signs of dysmyelopoiesis (without cytopenias meeting C criteria or WHO criteria for MDS/MPN). ◦ Organomegaly: Palpable hepatomegaly, splenomegaly, or lymphadenopathy (>2 cm on CT/ultrasound) without impaired liver function or hypersplenism. 2. C Findings (1 required for ASM; must be attributable to high tissue MC infiltration): ◦ Cytopenia(s): ANC <1000/μL OR Hb <10 g/dL OR PLT <100,000/μL. ◦ Hepatomegaly with ascites and impaired liver function. ◦ Palpable splenomegaly with associated hypersplenism and ascites. ◦ Malabsorption with hypoalbuminemia and weight loss. ◦ Skeletal lesions: Large area(s) of osteolysis with pathologic fractures (Note: Osteoporosis alone eq criterion).
- Diagnostic Pathway: ◦ Smoldering Systemic Mastocytosis (SSM): 2 or more B findings AND 0 C findings. ◦ Aggressive Systemic Mastocytosis (ASM): 1 or more C findings attributable to high tissue MC infiltration.
6. MANAGEMENT & TREATMENT¶
- Symptomatic Management: Focus on treating systemic symptoms caused by bioactive substance release and tissue response.
- Trigger Mitigation: ◦ Identify and avoid triggers for anaphylaxis (Hymenoptera stings, NSAIDs). ◦ Discontinue drugs inducing allergic symptoms if alternatives are unavailable or less effective.
- Pharmacological Protocols: ◦ Utilize DD protocols to allow safe reintroduction of first-line therapies.
7. PROGNOSIS & COMPLICATIONS¶
• Cutaneous Mastocytosis (CM): Normal life expectancy; polymorphic MPCM usually resolves spontaneously. ◦ Progression to ISM: ~10% of children, especially with high mast cell burden (DCM) or morphomorphic MPCM (small uniform lesions <2 cm). • Indolent Systemic Mastocytosis (ISM): Normal life expectancy. ◦ Progression to advanced form: Uncommon (~5% lifetime risk); requires monitoring for hematologic disease and ASM end-organ manifestations. • Smoldering Systemic Mastocytosis (SSM): Intermediate prognosis. • Aggressive Systemic Mastocytosis (ASM) & Mast Cell Leukemia (MCL): Poor prognosis. ◦ SM-AHNMD: Prognosis determined by the non-mast cell component.
8. SPECIAL CONSIDERATIONS¶
• Pediatric Population: ◦ Clinical Presentation: MPCM, mastocytoma(s), or bullous lesions; visceral involvement usually lacking. ◦ Resolution: Spontaneous resolution common prior to adolescence. ◦ Progression Risk Factors (to ISM): ◦ High mast cell burden (e.g., DCM). ◦ Hematologic abnormalities. ◦ Morphomorphic MPCM (smaller uniform lesions, diameter <2 cm).
9. KEY PEARLS & CLINICAL TRAPS¶
• Darier's sign: Rubbing/irritation of a mastocytoma → urtication and erythema. ◦ Anaphylaxis Triggers: Hymenoptera stings and NSAIDs. ◦ Neuropsychiatric Symptoms: Impaired memory, decreased attention, migraine-like headaches. ◦ Exacerbation Factors: Alcohol, temperature changes, stress, mast cell–interactive opioids, or NSAIDs.
Reference Tables¶
TABLE 366-1 Classification of Mastocytosis Cutaneous mastocytosis (CM)¶
Harrison's 22e, p.2820
- Cutaneous mastocytosis (CM)
Maculopapular cutaneous mastocytosis (MPCM)
Solitary mastocytoma of skin
Diffuse cutaneous mastocytosis
Systemic mastocytosis
Indolent systemic mastocytosis (ISM)
Smoldering systemic mastocytosis
Systemic mastocytosis with associated clonal hematologic non–mast cell
lineage disease (SM-AHNMD)
Aggressive systemic mastocytosis (ASM)
Mast cell leukemia (MCL)
Mast cell sarcoma (MCS)
TABLE 366-2 B and C Findings for Diagnosis of SSM and ASM B Findings (2 or more in the absence of any C findings are…¶
Harrison's 22e, p.2820
- B Findings (2 or more in the absence of any C findings are required for a
diagnosis of SSM):
1. High MC burden: MC infiltration in bone marrow of >30%, basal serum
tryptase level >200 ng/mL, and/or KIT D816V >10% VAF in bone marrow
2. Hypercellular bone marrow with signs of dysmyelopoiesis but without
cytopenias meeting C criteria or WHO criteria for an MDS or MPN
3. Palpable hepatomegaly, palpable splenomegaly, or lymphadenopathy (on CT
or ultrasound: >2 cm) without impaired liver function or hypersplenism - C Findings (1 or more required for a diagnosis of ASM). C findings should be
reasonably attributable to high tissue MC infiltration:
1. Cytopenia(s): ANC <1000/μL or Hb <10 g/dL or PLT <100,000/μL
2. Hepatomegaly with ascites and impaired liver function
3. Palpable splenomegaly with associated hypersplenism
4. Malabsorption with hypoalbuminemia and weight loss
5. Skeletal lesions: large area(s) of osteolysis with pathologic fractures
(presence of osteoporosis alone without osteolytic lesions does not satisfy
this criterion)