What is the diagnosis and treatment approach for a patient with suspected or confirmed mastocytosis?

Mastocytosis: Diagnosis and Treatment

Diagnostic Approach

The diagnosis of mastocytosis requires a systematic evaluation beginning with assessment for skin involvement, followed by serum tryptase measurement and KIT D816V mutation testing, with bone marrow biopsy reserved for specific clinical scenarios based on these initial findings. 1

Initial Evaluation in Adults

For adults with suspected mastocytosis, first assess for mastocytosis in the skin (MIS):

• If MIS is present: Proceed directly to bone marrow examination regardless of tryptase level 1
• If no MIS: Measure serum tryptase and perform KIT D816V allele-specific quantitative PCR (ASO-qPCR) on peripheral blood 1

Tryptase-Guided Algorithm for Adults Without Skin Lesions

When skin lesions are absent, the serum tryptase level determines next steps:

• Tryptase >15 ng/mL and/or KIT D816V detected in peripheral blood: Bone marrow examination is mandatory 1
• Tryptase <15 ng/mL and KIT D816V negative: Follow clinically; perform bone marrow biopsy only if tryptase increases or new symptoms/signs develop 1
• Tryptase >25-30 ng/mL: Strongly indicates systemic disease requiring bone marrow evaluation even without other findings 2, 3

Comprehensive Diagnostic Studies

When systemic mastocytosis is suspected, obtain the following:

• Complete blood count with differential and peripheral blood smear examination for monocytosis, eosinophilia, or dysplasia 1
• Comprehensive metabolic panel including uric acid, LDH, and liver function tests 1
• CT/MRI or ultrasound of abdomen/pelvis to assess for organomegaly 1
• DEXA scan for osteopenia/osteoporosis evaluation 1
• Metastatic skeletal survey for osteolytic lesions 1

Bone Marrow Evaluation Requirements

When bone marrow biopsy is indicated, the following studies are mandatory:

• Flow cytometry: CD34, CD117, CD25, CD2; CD30 optional 1
• Immunohistochemistry: CD117, CD25, tryptase; CD30 optional 1
• Cytogenetics and FISH as needed for associated hematologic neoplasm-related abnormalities 1
• KIT D816V mutation testing by allele-specific PCR or alternative high-sensitivity method on bone marrow 1
• Myeloid mutation panel (including SRSF2, ASXL1, RUNX1) 1
• Reticulin and collagen staining to assess bone marrow fibrosis grade 1

Critical pitfall: Bone marrow tryptase levels >50 μg/L identify systemic mastocytosis with 93% sensitivity and 90% specificity, providing valuable diagnostic confirmation 4

KIT Mutation Testing Strategy

The KIT D816V mutation is found in >80% of adult systemic mastocytosis cases:

• In adults, KIT D816V is present in at least 80% of patients; in children, only approximately 30% 1
• Extracellular domain mutations are found in approximately 40% of pediatric cases 1
• If KIT D816V is negative on bone marrow: Perform full KIT gene sequencing to identify alternative mutations 1
• Peripheral blood ASO-qPCR can detect KIT D816V with high sensitivity when combined with tryptase measurement 1

Important caveat: Next-generation sequencing myeloid panels have only ~5% sensitivity for KIT D816V detection and should not be used for this purpose 1

Pediatric Diagnostic Approach

In children with suspected cutaneous mastocytosis, the diagnostic strategy differs significantly:

• Skin biopsy (3 mm punch) with histology and mutational studies if possible 1
• If single lesion (mastocytoma): No further studies required 1
• If multiple lesions: Obtain CBC with differential, routine biochemistries, and baseline serum tryptase 1
• Bone marrow biopsy is indicated only if: 1, 5
  • Severe recurrent systemic mast cell mediator-related symptoms
  • Organomegaly or significant lymphadenopathy
  • Persistence of skin lesions after puberty
  • Tryptase significantly elevated (>20 μg/L indicates increased burden requiring close observation) 5

Critical distinction: In pediatric mastocytosis, bone marrow investigation is usually not required even with elevated tryptase, as the disease is generally benign with high spontaneous regression rates (75% of mastocytomas, 56% of urticaria pigmentosa cases resolve completely) 1, 5

Treatment Approach

Indolent and Smoldering Systemic Mastocytosis

All patients with systemic mastocytosis require anti-mediator drug therapy as the foundation of treatment, regardless of dietary modifications:

First-Line Pharmacotherapy

• H1 antihistamines are first-line therapy for controlling mast cell mediator-related symptoms 6, 5
• H2 antihistamines should be added when H1 antihistamines alone are insufficient 6, 5
• Cromolyn sodium oral solution is FDA-approved for mastocytosis management, with clinical improvement in diarrhea, flushing, headaches, vomiting, urticaria, abdominal pain, nausea, and itching occurring within 2-6 weeks at 200 mg four times daily 7

Important note: In pediatric patients, high doses of H1 antihistamines can cause cardiotoxicity 5

Monitoring and Follow-up

• History and physical examination, laboratory studies every 6-12 months or sooner for new clinical issues 1
• DEXA scan every 1-3 years for patients with osteopenia/osteoporosis 1
• Assess symptom burden and quality of life using validated tools (MSAF and MQLQ) 1

Cytoreductive Therapy Considerations

Cladribine and pegylated interferon-alfa are generally reserved for advanced SM, but may be considered in selected patients with indolent or smoldering SM who have:

• Severe, refractory mediator symptoms not responsive to anti-mediator therapy 1
• Bone disease not responsive to bisphosphonates 1

Advanced Systemic Mastocytosis

Patients with C-findings (organ damage) require immediate referral to specialized mastocytosis centers for cytoreductive therapy:

C-findings indicating advanced disease include: 8

• Hepatomegaly with impaired liver function
• Palpable splenomegaly with hypersplenism
• Malabsorption with hypoalbuminemia
• Cytopenias
• Weight loss >10% over 6 months
• Large osteolytic lesions with or without pathologic fractures

Critical red flag: The combination of organomegaly and elevated tryptase (especially >200 ng/mL) indicates high mast cell burden requiring urgent hematology referral and possible hospitalization 8

Pediatric Treatment Strategy

In children, treatment is symptomatic with emphasis on trigger avoidance and family education:

• Cytoreductive therapy is strongly discouraged except in rare aggressive variants with life-threatening risk, due to benign natural history and high spontaneous regression rates 5
• H1 antihistamines (with H2 antihistamines when necessary) for symptom control 5
• Avoidance of triggering factors including temperature extremes, stress, and anxiety 5

Essential Patient Management

Emergency Preparedness

All patients must carry two epinephrine auto-injectors at all times, as anaphylactic reactions are significantly more frequent in patients with indolent systemic mastocytosis 6

During acute mast cell activation attacks with hypotension, wheezing, or laryngeal edema: Administer adrenaline intramuscularly in supine position 5

Trigger Avoidance

Patients must identify and avoid their specific triggers through careful observation:

• Temperature extremes (heat and cold) are well-documented triggers requiring avoidance 6
• Foods can trigger anaphylaxis in adults, though less commonly than Hymenoptera stings 6
• Stress and anxiety should be controlled as they provoke mast cell activation 6, 5

Patient and Family Education

Comprehensive education is fundamental and must include:

• Individualized information about specific identified triggers 6, 5
• Signs and symptoms of mast cell activation 6
• Specific protocols for infections with fever, vaccinations, dental procedures, imaging, and surgery 5
• Clarification that cutaneous mastocytosis is not contagious 5

Perioperative consideration: Baseline prothrombin time and partial thromboplastin time should be measured prior to invasive procedures, and baseline serum tryptase levels should be obtained before surgery to allow comparison if adverse events occur 1

Multidisciplinary Coordination

Coordinate with subspecialists including hematology/oncology, gastroenterology, allergy/immunology, and anesthesia for procedures, with high-risk obstetrics consultation for pregnancy 1, 8