What is the workup and treatment for mast cell (mastocytosis) issues?

Workup for Mast Cell Disease (Mastocytosis)

The workup for suspected mastocytosis requires serum tryptase measurement, comprehensive bone marrow evaluation with KIT D816V mutation testing, and systematic assessment for organ involvement using imaging and laboratory studies, following the NCCN diagnostic algorithm. 1

Initial Diagnostic Studies

History and Physical Examination

• Document prior mast cell activation symptoms (flushing, pruritus, diarrhea, abdominal pain, anaphylaxis) and identify specific triggers (temperature extremes, NSAIDs, alcohol, insect stings, physical stimulation) 1, 2
• Examine for maculopapular cutaneous lesions (urticaria pigmentosa), assess spleen and liver size by palpation, and document weight loss 1
• Record all medications, transfusion history, and prior anaphylactic episodes 1

Essential Laboratory Testing

• Serum tryptase level - the single most important screening test; levels >20 ng/mL suggest systemic mastocytosis, while levels >200 ng/mL indicate high mast cell burden requiring urgent hematology referral 1, 3
• Complete blood count with differential to identify monocytosis, eosinophilia, dysplasia, or cytopenias (C-findings) 1
• Comprehensive metabolic panel including uric acid, LDH, liver function tests, and albumin (to assess for malabsorption) 1, 3
• Blood smear examination for morphologic abnormalities 1

Bone Marrow Evaluation

Bone marrow aspirate and biopsy is mandatory when tryptase is elevated and clinical suspicion exists, as this establishes the diagnosis and classification of systemic mastocytosis. 1, 3

Required Bone Marrow Studies

• Flow cytometry: CD34, CD117, CD25, CD2; CD30 is optional but helpful when CD25 is negative 1
• Immunohistochemistry: CD117, CD25, tryptase (CD30 optional) to quantify mast cell burden and identify aberrant expression patterns 1
• Cytogenetics to detect chromosomal abnormalities, especially in suspected associated hematologic neoplasm (AHN) 1
• FISH as needed for AHN-related abnormalities 1
• KIT D816V mutation testing by allele-specific PCR or alternative high-sensitivity method (>80% sensitivity in bone marrow); can initially screen peripheral blood but must test bone marrow if peripheral blood is negative 1
• Myeloid mutation panel (SRSF2, ASXL1, RUNX1) to identify adverse prognostic markers; note that standard NGS has only ~5% sensitivity for KIT D816V and should not be used for this mutation 1
• Reticulin and collagen staining to assess bone marrow fibrosis grade (MF-0 to MF-3), particularly important in advanced disease 1

Bone Marrow Interpretation

• Aspirate analysis should document percentage of neoplastic mast cells, their morphology (spindle-shaped, well-differentiated, or immature promastocytes), and features of any AHN 1
• Core biopsy must comment on whether mast cells form multifocal dense infiltrates (major diagnostic criterion) versus primarily interstitial pattern 1
• If interstitial pattern with peripheral eosinophilia and negative KIT D816V, test for FIP1L1-PDGFRA fusion gene 1

Assessment of Organ Involvement (B- and C-Findings)

Imaging Studies

• CT/MRI or ultrasound of abdomen/pelvis to evaluate hepatomegaly, splenomegaly, lymphadenopathy, and ascites 1, 3
• DEXA scan to evaluate for osteopenia/osteoporosis (B-finding) 1
• Metastatic skeletal survey to evaluate for osteolytic lesions (C-finding if large with or without pathologic fractures) 1, 3

Organ-Directed Evaluation

• Organ-directed biopsy (endoscopy, liver biopsy) as clinically indicated with immunohistochemistry (CD117, CD25, tryptase, CD3 as control) 1
• Document specific C-findings: hepatomegaly with impaired liver function, palpable splenomegaly with hypersplenism, malabsorption with hypoalbuminemia and weight loss >10%, cytopenias, or large osteolytic lesions 3

Classification and Risk Stratification

• Indolent SM (ISM): No B- or C-findings; managed primarily with anti-mediator therapy 1
• Smoldering SM (SSM): ≥2 B-findings (high mast cell burden, organomegaly without dysfunction, serum tryptase >200 ng/mL); requires closer monitoring 1, 3
• Advanced SM: Presence of any C-finding (organ dysfunction) or associated hematologic neoplasm; requires cytoreductive therapy and referral to specialized mastocytosis center 1, 3

Treatment Approach

For Indolent and Smoldering SM

• Anti-mediator drug therapy is first-line for all symptomatic patients 1, 4
  • H1 antihistamines as first-line 4, 5
  • Add H2 antihistamines when H1 alone is insufficient 4, 5
  • Cromolyn sodium 200 mg QID for gastrointestinal symptoms (diarrhea, abdominal pain) and cutaneous manifestations; clinical improvement occurs within 2-6 weeks 6
  • Leukotriene receptor antagonists, aspirin (if tolerated), or zileuton for additional symptom control 5
• All patients must carry two epinephrine auto-injectors due to increased anaphylaxis risk 4
• Monitor with H&P and labs every 6-12 months; DEXA scan every 1-3 years for osteopenia/osteoporosis 1
• Use validated symptom assessment tools (MSAF and MQLQ) to track disease burden 1, 2

For Advanced SM

• Immediate referral to specialized mastocytosis center for cytoreductive therapy 1, 3
• Consider clinical trial enrollment 1
• Evaluate for allogeneic hematopoietic cell transplantation in appropriate candidates with adequate response to cytoreductive therapy 1
• Avapritinib (selective KIT D816V inhibitor) shows promise for reducing mast cell burden and symptoms in refractory cases 7

Critical Pitfalls to Avoid

• Do not assume normal tryptase excludes mastocytosis - tryptase may be <20 ng/mL in some SM patients with limited disease burden; conversely, hereditary alpha-tryptasemia causes baseline elevation without disease 3
• Do not delay bone marrow biopsy when organomegaly and elevated tryptase coexist, even if tryptase is only modestly elevated 3
• Do not use standard NGS panels to detect KIT D816V - sensitivity is only ~5% compared to >80% with allele-specific PCR 1
• Do not withhold analgesics - pain itself triggers mast cell activation, though exercise caution with certain opioids like codeine or morphine 1
• Do not perform procedures without multidisciplinary coordination - involve anesthesia, surgery, and perioperative teams with premedication using benzodiazepines, H1/H2 blockers, and corticosteroids 1

Patient Counseling

• Educate on individualized trigger avoidance: temperature extremes (hot water, heat, cold), mechanical stimulation (pressure, friction), NSAIDs, alcohol, exercise, emotional stress, and specific foods 4, 2
• Counsel on signs/symptoms of mast cell activation and when to use epinephrine 1, 4
• Coordinate with subspecialists (allergy/immunology, gastroenterology, anesthesia for procedures, high-risk obstetrics for pregnancy) 1
• For cutaneous mastocytosis, refer to centers with specific expertise as management differs from systemic disease 1