Why Physicians Struggle to Recognize MCAS
The reluctance to diagnose MCAS stems primarily from the stringent diagnostic criteria requiring objective laboratory documentation during acute episodes, the high risk of misdiagnosis when using nonspecific symptoms, and the lack of widespread physician education about distinguishing true MCAS from other conditions with overlapping presentations.
The Core Diagnostic Challenge
The fundamental issue is that MCAS requires three simultaneous criteria that are difficult to capture in real-world practice: episodic symptoms affecting ≥2 organ systems concurrently, documented mediator elevation during acute episodes (not baseline), and response to mast cell-targeted therapy 1. The critical laboratory requirement—obtaining serum tryptase 1-4 hours after symptom onset and demonstrating an increase ≥20% above baseline PLUS ≥2 ng/mL absolute increase—is logistically challenging when patients present to emergency departments or primary care offices during acute episodes 2.
The Overdiagnosis Problem
Many patients are incorrectly told they have MCAS based on nonspecific symptoms that lack diagnostic precision 1, 3. The 2019 AAAAI guidelines explicitly warn against using symptoms like fatigue, fibromyalgia-like pain, dermographism, chronic pain, headache, mood disturbances, anxiety, weight changes, thyroid dysfunction, and various psychiatric/neurologic disorders as diagnostic criteria for MCAS 1. These symptoms are common in the general population and lead to false-positive diagnoses when proper laboratory confirmation is absent 3, 4.
The literature emphasizes that symptoms must be episodic, not chronic or continuous—a key distinguishing feature that is frequently misunderstood 2. Chronic, persistent symptoms affecting a single organ system do not meet MCAS criteria 1.
Knowledge Gaps and Mechanistic Uncertainty
The underlying mechanisms and pathways leading to mast cell activation in MCAS patients remain poorly understood 5. Whether MCAS exists as a primary syndrome or represents a constellation of symptoms in the context of other inflammatory, allergic, or clonal disorders is not well established 5. This mechanistic uncertainty makes physicians appropriately cautious about making the diagnosis without meeting strict criteria.
The Differential Diagnosis Burden
Physicians must exclude numerous conditions before diagnosing MCAS 2, 3:
- Secondary causes of mast cell activation: IgE-mediated allergies, drug reactions, infections, and other inflammatory conditions must be ruled out first 2
- Systemic mastocytosis: Requires bone marrow biopsy when baseline tryptase is persistently >20 ng/mL 6, 2
- Hereditary alpha-tryptasemia: Can cause elevated baseline tryptase without MCAS 1, 7
- Other conditions with overlapping symptoms: Autoimmune diseases, neoplastic conditions, and infectious processes 8, 3
The algorithm requires evaluating for systemic mastocytosis first using bone marrow biopsy with immunophenotyping, KIT D816V mutation testing, and flow cytometry before considering MCAS 7. This extensive workup is resource-intensive and requires subspecialty expertise.
Lack of Specialized Training
MCAS evaluation requires referral to allergists/immunologists as the primary specialty because they possess expertise in distinguishing MCAS from IgE-mediated allergic reactions, performing diagnostic testing, and applying the three required criteria 6. Most general practitioners and even many specialists lack this training. The National Comprehensive Cancer Network explicitly recommends that comprehensive care requires a multidisciplinary team involving dermatologists, hematologists, pathologists, gastroenterologists, allergists, and immunologists, preferably in specialized centers 6.
The Misdiagnosis Epidemic
The escalating occurrence of patients receiving misdiagnosis of MCAS based on nonspecific criteria has created appropriate skepticism among physicians 4. Many patients are informed they may have MCAS without completing a thorough medical evaluation, and symptoms are misinterpreted while other clinically relevant conditions are not pursued 8. This has led to unnecessary referrals and unjustified fears in patients 3.
Common Pitfalls Leading to Physician Reluctance
- Using chronic symptoms instead of episodic ones: MCAS requires recurrent episodic symptoms, not continuous manifestations 2
- Failing to obtain acute tryptase during episodes: Baseline tryptase alone is insufficient; comparison between baseline and acute levels is essential 2
- Attributing nonspecific symptoms to MCAS: Fatigue, chronic pain, and mood disturbances are not diagnostic 1
- Not excluding secondary causes first: Allergies and other conditions must be ruled out before diagnosing primary MCAS 2, 8
The Reality of True MCAS Prevalence
Overt MCAS is actually an unusual condition, not a prevalent one 8. The perception of high prevalence comes from overdiagnosis using inappropriate criteria 3, 4. Most patients referred for suspected MCAS are ultimately diagnosed with other diseases (autoimmune, neoplastic, infectious) unrelated to mast cell activation, or they have MCA-related allergic disorders without fulfilling criteria for overt MCAS 8.