CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurses: 1.00 Nursing contact hour
Physicians: maximum of 1.00 AMA PRA Category 1 Credit™
ABIM MOC: maximum of 1.00 Medical Knowledge MOC point
Released: December 16, 2024
Expiration: December 15, 2025
Leslie, 58 Yr-Old Woman
Let’s take a look at a patient case.
Epidemiology and Pathway to Diagnosis
Mastocytosis is a rare disorder. In the United States, it is classified as an orphan disease, meaning that fewer than 200,000 people are affected.1 Mastocytosis can be classified as shown on the right. The majority of patients have ISM. The more advanced variants are rare and less common when examining people with mastocytosis as a general population. Another important point to note is that mastocytosis is difficult to diagnose because of its heterogeneous symptoms; a tissue biopsy is needed. Therefore, many patients experience symptoms for a long time, even up to 12 years, before an accurate diagnosis is made.2
Differential Diagnosis
Other mast cell disorders should be considered in the differential, particularly anaphylaxis. One should determine whether this is an isolated episode in response to foods or drugs or part of a larger umbrella of mast cell disorders. Other aspects that are important to consider include chronic spontaneous urticaria, a dermatologic condition, and a host of other symptoms that can mimic mast cell activation, such as gastrointestinal (GI), endocrinologic, neurologic, and psychologic conditions. Anxiety and panic attacks, including sensations of impending doom, tachycardia, and flushing, can also mimic anaphylaxis and should be considered.3-5
Clinical Presentation and Triggers
Clinical presentation and triggers make mast cell disorders difficult to diagnose. Mast cells are generally not tissue restricted, meaning they are present throughout the body, including the skin, lungs, liver, GI tract, and endothelium. Because of this, mast cell activation can cause symptoms in many different organs. The main purpose of this slide is to show that mastocytosis can affect multiple organs, as can any mast cell disorder.
Common triggers are shown on the right.6 Hymenoptera venom is probably the largest single trigger of anaphylaxis in patients with mastocytosis.7
Adult-Onset vs Pediatric-Onset Mastocytosis
There are very important differences between adult-onset and pediatric-onset mastocytosis. In general, in adults, cutaneous lesions are monomorphic. These lesions are approximately 2-3 mm in diameter with the same size, shape, and morphology. Upon scraping, Darier sign is apparent. This sign is typically synonymous with lifelong disease, meaning it is in the bone marrow and will be present for the life of the organism. On the other hand, pediatric mastocytosis often resolves spontaneously. The key differentiating factor is the type of lesion. In children, these lesions are polymorphic; some are large, and some are small. Some are oddly shaped, with some being circular and others being oval.
Another important point addressed on this slide is the different mutational profiles. In adults, the vast majorities (>85%-90%) show evidence of KIT D816V, whereas children harbor a variety of mutations. Exon 17 mutations may be present but tend to be less common than in adults, where they are basically universal.8
Adult-Onset Mastocytosis
Adult-onset mastocytosis is considered to occur after age 16 years. Any new spots that develop in a patient past age 16 are often monomorphic, and this generally means lifelong disease. Most adult patients with cutaneous lesions are diagnosed with ISM. Occasionally patients harbor more advanced variants. Workup for a patient with adult-onset cutaneous lesions typically involves measuring serum tryptase levels and high-sensitivity testing for KIT D816V. If there is any clinical question, a skin biopsy can be considered, as can a bone marrow biopsy, as ranked here: serum tryptase level, KIT D816V, skin biopsy, and bone marrow biopsy.9
Skin Lesions of Mastocytosis
This slide shows a visual representation of monomorphic and polymorphic lesions. Shown on the left is a patient with many small, monomorphic-appearing spots. Although there are some differences within monomorphic lesions, in general the spots are similar in size. The image on the right shows a patient with polymorphic lesions of different shapes and sizes.8
KIT Mutations in Mast Cell Disease: Implications for TK Inhibitors
Shown here is a schematic of the KIT receptor. KIT is a receptor tyrosine kinase (TK) located on the extracellular portion of the surface with a transmembrane portion. Its signaling component, located intracellularly, is a TK. Stem cell factor (SCF) binds to KIT. Two KIT receptors come together and dimerize, causing a signal to move through the bottom of the cell. In the example here with D816V, the dependence on SCF is lost. A KIT D816V mutation results in constitutive activity regardless of whether SCF is present.10
2022 Diagnostic Criteria for SM
When diagnosing SM, a tissue-based biopsy (bone marrow biopsy or GI biopsy) is required.
To receive a diagnosis of SM, there needs to be 1 major criterion and 1 minor criterion or at least 3 minor criteria. It is necessary to understand, at a minimum, the major and minor criteria.11,12
2022 Classification of Mastocytosis
The classification of mastocytosis was updated in 2022. As shown here, several researchers have tried to harmonize its diagnosis, because the WHO and International Consensus Classification have different diagnostic criteria. What should be highlighted is the mast cell location. The 3 major classifications are cutaneous mastocytosis, SM, and mast cell sarcoma, and within cutaneous mastocytosis and SM, there are several variants.
Within SM, there are bone marrow mastocytosis, ISM, smoldering SM, aggressive SM, and mast cell leukemia, among others. The purpose of a bone marrow biopsy is to accurately identify the mastocytosis subtype because the subtype has both prognostic and treatment-specific implications.11,12
Minor Criterion 1: Atypical Mast Cell Morphology
Minor criterion 1 is atypical mast cell morphology. The image on the top right shows mast cells with a spindle-shaped morphology—the hallmark morphologic feature of atypical mast cells. This mast cell is elongated in general, but the nucleus in particular is flattened and slightly more oval, whereas a normal mast cell has a spherical nucleus. This is a good example of a spindle-shaped mast cell.13
Minor Criterion 2: KIT Activating Point Mutation at Codon 816 or in Other Regions of the KIT Gene
Minor criterion 2 is the detection of a KIT activating mutation at codon 816 or in other regions of the KIT gene. In mastocytosis, mast cells leave the bone marrow, circulate through peripheral blood, and mature in peripheral tissue. One of the challenges associated with mastocytosis is that few mast cells are actually circulating in peripheral blood at any given time. Because of the low frequency of circulating mast cells, the target sample should be enriched via polymerase chain reaction (PCR) amplification of the D816V mutation. PCR testing has a much higher level of sensitivity than the previously used NGS.
NGS misses events occurring at a frequency of <1%. Some laboratories do not report anything <1% as positive. However, assays such as ddPCR, an ultrasensitive assay, can detect events occurring at frequencies down to 0.01%.14
Minor Criterion 3: CD2, CD25, and/or CD30 Expression on Mast Cells
Minor criterion 3 is aberrant expression of CD2, CD25, and/or CD30 on mast cells. The image in the top left shows mast cells that have been stained with hematoxylin and eosin. The images on the top right and bottom left show the expression of CD117 and CD25, extracellular markers. In mastocytosis, CD117 expression is high, staining brown with a ringlike appearance on the cell surface. The same is true for CD25. The bottom right image shows staining for tryptase. Unlike the CD117 and CD25 markers, tryptase is intracellular and is found in the granules of mast cells. Here, the intracellular portion of mast cells is positive for tryptase.15
Minor Criterion 4: Elevated Basal Serum Tryptase >20 ng/mL
Minor criterion 4 is elevated basal serum tryptase. At present, a concentration of ≥20 ng/mL is a minor criterion for mastocytosis. Approximately 6% of the general population has an elevated baseline serum tryptase level. Healthcare professionals should screen, where available, for α-tryptasemia. If present, it should be factored into the patient’s baseline serum tryptase concentration. Consensus criteria suggest adjusting for α-tryptasemia.11,16,17
Mastocytosis Classification
Once the SM diagnosis is made, the healthcare professional should determine the variant of SM. For a diagnosis of smoldering SM, 2 or more burden of disease (B) findings are necessary. Shown in this slide on the bottom left is a list of B findings. Smoldering SM is similar to ISM, with a large burden of mast cells (as measured by the number of mast cells in the bone marrow, baseline serum tryptase level, or KIT D816V allele fraction), and indicates a more dangerous or high-risk variant.
These patients have signs of organ impairment but not organ failure—for example, hepatomegaly with normal synthetic function.18,19
Advanced SM
Advanced SM is associated with fulminant organ failure. The advanced variants of SM have a higher risk of mortality and should be treated with cytoreductive therapy. Mast cell leukemia is defined exclusively by the presence of mast cells on a peripheral blood smear. Advanced SM is diagnosed based on a cytoreduction requirement (C) finding. A C finding generally represents organ failure (eg, hepatomegaly with impaired function, meaning the liver is not making clotting factors, the presence of ascites, and portal hypertension). There are also C findings for other organs (eg, cytopenias in the bone marrow, skeletal involvement with pathologic fractures in the musculoskeletal system, and palpable splenomegaly and the splitting of spleen manifestations).11,19
Mastocytosis Pathology Testing Standard of Care
Noninvasive laboratory measures are shown in the top left and include serum tryptase level, a complete blood cell count, and a chemistry panel. Morphologic factors (eg, the appearance and number of mast cells), shown at the top right, can be examined via a blood smear, bone marrow aspirate, and bone marrow biopsy. The mast cell phenotype can be determined mainly via surface markers: the presence of CD117, CD25, CD30, or CD2. CD2 can also be assessed via immunohistochemistry. Genetic tests are shown on the bottom left. These tests are used to examine for the presence of the D816V mutation, other myeloid mutations, those observed in α-tryptasemia, and so on.
This could be viewed as an escalating workup proceeding clockwise from the top left.15
Following up with Leslie, 58-Yr-Old
Let’s return to our patient case.
Hereditary α-Tryptasemia
Hereditary α-tryptasemia (HαT) was first reported in 2016.20 It is reported that 5% to 7% of Western populations (ie, the United Kingdom, parts of Western Europe, and the United States) are affected. Most of these patients are asymptomatic, but many do have mast cell activation syndrome (MCAS), with anaphylaxis being the most consistent association.21 By contrast, approximately 12% to 20% of people with SM have HαT. Although this finding is very interesting, it is currently unexplained.20,22
Elevated Basal Serum Tryptase Levels in HαT
HαT can mimic mastocytosis. As shown in this slide, nearly 10% of patients with HαT have a normal baseline serum tryptase level, whereas approximately 5% have levels of >30 ng/mL. However, most patients with HαT have levels between 10 and 30 ng/mL.23
A genetic study of a third-generation family of Belgian ancestry found 5 tryptase genes on each chromosome. Two of the family members had a tryptase level of approximately 120 ng/mL at baseline. Therefore, it is important to keep in mind that tryptase levels can be quite high with this genetic trait.
HαT and Increased Risk for Severe Anaphylaxis
HαT increases the risk for severe anaphylaxis. In one study, investigators examined patients with the risk of venom anaphylaxis and found that people who have HαT have disproportionately more severe variants of anaphylaxis (ie, classically Mueller grade 3 and grade 4), which means decreased blood pressure, decreased oxygenation, and, in extreme cases (grade 4), complete loss of consciousness and passing out with low blood pressure.20
Mast Cell Activation Symptoms and Associated Mediators
Mediator release can be thought of as occurring in 3 “waves.” The first wave involves preformed mediators which are released via degranulation within minutes. Then lipid mediators are released after approximately 20-30 minutes, and cytokines and chemokines are released last. Shown at the right are mediators that are associated with particular symptoms, such as flushing and urticaria, which are driven by histamine.24
Mast Cell Mediator Metabolites During Episodes in Mast Cell Activation Syndromes
It is important to understand the mediators released by mast cells because this is how diagnostic criteria are reached and how mast cell activation is perceived. Shown here (from left to right) are prostaglandin, followed by leukotriene, methyl histamine, and tryptase. In this study, investigators examined tryptase and urine mediators at baseline and again when experiencing anaphylaxis or acute symptoms. As shown here, these laboratory measures in combination are very discriminative for mast cell activation events. The key finding from this study was that if only 1 or 2 mediators are measured, events are often missed. Therefore, it is good practice to check all 4 mediators when looking for mast cell activation.25
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