What are the key clinical features that differentiate systemic mastocytosis from cutaneous mastocytosis in a primary care setting?

Key clinical features differentiating systemic mastocytosis (SM) from cutaneous mastocytosis (CM) in primary care include the extent and nature of symptoms, systemic involvement, and laboratory findings.

• Cutaneous mastocytosis primarily presents with skin-limited manifestations such as persistent, often pruritic, brownish macules, papules, or nodules (urticaria pigmentosa), typically without systemic symptoms. Darier’s sign (urtication and erythema upon rubbing lesions) is commonly positive in CM and is a hallmark in primary care examination NICE NG12 Madigan et al. 2025.
• Systemic mastocytosis involves extracutaneous organs, most commonly the bone marrow, liver, spleen, and gastrointestinal tract, leading to systemic symptoms such as unexplained anaphylaxis, flushing, abdominal pain, diarrhoea, hepatosplenomegaly, and bone pain NICE NG12 Gülen et al. 2016.
• In SM, skin lesions may be present but are often less prominent or atypical compared to CM, and systemic symptoms predominate. The presence of constitutional symptoms (weight loss, fatigue) and signs of organomegaly should raise suspicion of SM in primary care NICE NG12 Chiu & Orazi 2012.
• Laboratory findings in SM may include elevated baseline serum tryptase levels (>20 ng/mL), which is uncommon in isolated CM. This biomarker can aid differentiation in primary care when systemic involvement is suspected NICE NG12 Madigan et al. 2025.
• Bone marrow biopsy and genetic testing for KIT mutations are definitive for SM diagnosis but are beyond primary care scope; however, referral should be considered when systemic features or elevated tryptase are present NICE NG12 Gülen et al. 2016.

In summary, primary care differentiation hinges on the presence of systemic symptoms and signs, elevated serum tryptase, and the nature of skin lesions, with CM confined to skin and SM involving multiple organ systems with systemic manifestations.