Clinical Approach to MCAS Diagnosis and Cutaneous Mastocytosis
Diagnosis and Treatment of MCAS (Part 2 of 3)
After careful symptom assessment, it is important to evaluate for any specific laboratory abnormalities that support the diagnosis of MCAS or suggest the presence of another condition with similar symptoms (Table 3). Serum tryptase, the most common mediator, should be drawn within 4 hours (ideally 30 minutes to 2 hours) of symptom onset or anaphylaxis [10, 13]. Compare acute serum tryptase (sAT) to basal serum tryptase (sBT), drawn when asymptomatic or at least 24 hours after symptom resolution [10, 13]. A significant increase is defined as sBT × 1.2 + 2 ng/mL [2, 14]. For instance, if a patient has a sBT of 10 ng/mL, then a level of ≥14 ng/mL during an acute onset of symptoms would be significant and suggestive of MC. Other authors have proposed utilizing sBT x 1.685 as a relevant increase in tryptase, especially for those with HαT, mastocytosis and myelodysplastic syndromes [15, 16]. Tryptase levels may be elevated in many other conditions, including hypereosinophilic syndromes, hematologic malignancies, myelodysplastic syndrome, atopic disease, helminth infestation, end-stage renal disease, HαT, and on occasion, idiosyncratic variance from the normative distribution or false positivity related to heterophilic antibodies interfering with the laboratory assay [5, 17].
Table 3 Biochemical tests for MCAS (ideally documented ≥ 2 separate episodes, [10]) [1, 2, 8- 11, 13, 18-23]
During an acute event (within 2-4 hours of onset of symptoms) | Notes |
Serum tryptase | Drawn within 4 hours of onset of symptoms (ideally between 30 minutes and 2 hours) |
N-methylhistamine | 24-hour or spot urine > 200% baseline [9] |
9α-11β-prostaglandin F2 (11β PGF2α) | 24-hour or spot urine > 200% baseline [9] |
Leukotriene E4 (LTE4) | 24-hour or spot urine > 200% baseline [9] |
Baseline labs (when asymptomatic) | |
Serum basal tryptase (sBT) | sBT × 1.2 + 2 ng/mL to calculate whether tryptase level when symptomatic is significant [2] *Others have proposed an increase of 1.685 (sAT ≥ 1.685 x sBT) to improve specific amongst individuals with hereditary alpha tryptasemia (HaT) and indolent systemic mastocytosis (ISM) [15, 16] |
Genetic testing | |
D816V mutation analysis | Whole blood or bone marrow in lavender (EDTA) preferred. Also acceptable: Green (sodium heparin) |
HαT | Buccal swab to GeneByGene.com is the only commercial test for HαT |
When to consider bone marrow biopsy | |
Adults | D816V mutation identified in peripheral blood, regardless of tryptase level or HαT [24] |
Children | -CM with hepatosplenomegaly, lymphadenopathy or severe systemic symptoms -Abnormal blood counts (cytopenias, immature forms), organ dysfunction (abnormal liver/kidney function) -Tryptase *no absolute threshold identified, as even those with extremely high sBT typically have normal bone marrow findings [25-27] *some sources recommend biopsy with sBT > 20 [24] or > 100 ng/mL [28] or significant increase sBT continues to be above the upper limit of normal (without HαT) in adolescence [27] -D816V mutation identified -Failure of lesions to regress [27] |
Tests to consider, based on clinical history, ROS, and PE | |
Cortisol | Adrenal disease |
BUN/creatinine | Renal insufficiency |
Thyroid stimulating hormone (TSH) | Thyroid disease |
Calcitonin | Medullary thyroid tumor (globus, hoarseness) |
Gastrin | Zollinger-Ellison Syndrome (GERD/heartburn, diarrhea, tarry stool) |
Vasoactive intestinal protein (VIP) | VIPoma (diarrhea, flushing) |
5-hydroxy indoleacetic acid (urine, serum) | Carcinoid (diarrhea, flushing, tachycardia) |
Metanephrines, catecholamines | Pheochromocytoma (episodic headache, palpitations, tachycardia, sweating) |
Histamine has a short half-life, peaking at 5-10 minutes and returning to baseline within 15-60 minutes [29]. Measuring n-methylhistamine (nMH) in 24-hour or spot urine collection provides a more reliable assessment of histamine elevation [30]. Other urinary mediators include 9α-11β-prostaglandin F2 (11β-PGF2α) and leukotriene E4 (LTE4) [31]. These tests lack standardization, and prostaglandin measurement is unreliable in those on COX inhibitors. Levels >30% above normal or >200% from baseline may be significant [2, 13]. Though MCAS is not typically a histopathological diagnosis, cKIT mutation analysis, including CD25 expression, may be considered for clonal +D816V MCAS.
Based on the clinical history, review of systems, and physical exam, other biochemical and infectious tests may be needed to rule out other non-MC conditions in the differential diagnosis (Tables 4, 5). RareNeoplastic conditions like Zollinger-Ellison Syndrome, VIPoma, carcinoid, pheochromocytoma, and medullary thyroid tumor should be considered, especially if symptoms like flushing, diarrhea, abdominal pain, or throat tightness occur with normal MC activation tests. Cortisol and thyroid stimulating hormone (TSH) can help evaluate for endocrine disorders that may mimic MCAS. Swelling and vomiting can be signs of renal insufficiency, and end stage renal disease can cause elevated serum tryptase levels.
Biopsy
Adults should almost always undergo complete staging, including bone marrow examination, when presenting with CM or SM [1]. In contrast, routine bone marrow biopsy is not indicated in children presenting with signs of CM alone unless there are clear signs or symptoms for advanced SM or another hematologic neoplasm [1, 27].