Systemic Mastocytosis Screening: Get Standardized
—Investigators from Walter Reed Military Medical Center assessed the impact of a standardized screening protocol for systemic mastocytosis.
In a new study, investigators found that standardization of screening and diagnostic workup for systemic mastocytosis (SM) increased diagnoses and showed that basal serum tryptase level based on genotype had high sensitivity and specificity. Jeremy C. McMurray, MD, of the Walter Reed National Military Medical Center in Bethesda, Maryland, and colleagues, published their report in Blood.1
Early diagnosis of the SM form of mastocytosis is crucial because the symptom burden and disease outcomes vary among SM subtypes.2 Unfortunately, diagnostic delay in SM is common, with a median of 7 years between symptom onset and diagnosis.3
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As McMurray and colleagues described in their study, there are 3 common screening strategies. First, adult-onset monomorphic maculopapular cutaneous mastocytosis (MPCM) should raise suspicion of SM because almost all will have SM.4 Second, scoring systems that incorporate symptoms experienced during anaphylaxis, such as the REMA score, with basal serum tryptase (BST) levels and other factors, have been developed.5 Third, using elevated BST based on the number of tandem copies of the tryptase gene to control for natural variants in gene copy number has been proposed as a more useful alternative to a single threshold BST level.
These strategies can fall short because many patients with SM do not have anaphylaxis, and some have low BST.6,7 In addition, as McMurray and colleagues noted, “there is limited sensitivity or specificity data for screening tests, both individually and in combination, to predict the risk of SM.” Furthermore, “Once screening is completed, there are further challenges in obtaining an accurate diagnosis.”1
In 2021, the Tricare US Military Health System initiated a clinical SM screening registry for its beneficiaries with the goal of standardizing SM evaluations and improving care for patients. The authors of the current study conducted a retrospective analysis to evaluate the impact of the registry on SM diagnosis.
Screening protocol and diagnostic workflows
The authors assessed patient records and claims from Tricare beneficiaries in the Military Health System, which covers military personnel, dependents, retirees, and foreign nationals throughout the US and in 1 market in Europe and 1 market in the Indo-Pacific.
Starting on July 1, 2021, the standardized screening protocol for SM was established to identify adult patients with any one of the following: 1) monomorphic MPCM; 2) anaphylaxis with a REMA score ≥2; or 3) BST ≥11.5 ng per mL. Patients with BST ≥11.5 ng per mL were offered tryptase genotyping to identify those with elevated BST based on genotype.
Patients who met one or more screening criteria or were already diagnosed with SM were referred to a center of excellence for diagnostic workup. All referred patients, including those with a previous diagnosis of SM, were offered PCR genotyping of peripheral blood and bone marrow aspirates for KIT p.D816V. Bone marrow biopsy was offered to all patients except those with a previous SM diagnosis. Patients with monomorphic MPCM, anaphylaxis with a REMA score ≥2, or SM were also offered tryptase genotyping.
The study analyzed patient data from 2 dates. The first, on July 1, 2021, included patients before the standardization. The second date was 2 years after standardization, July 1, 2023. Inclusion criteria for the analysis were 1 of the following: 1) a diagnosis of any subtype of SM; 2) adult-onset monomorphic MPCM; 3) 1 or more BST ≥11.5 ng per mL results and known tryptase genotype; or 4) anaphylaxis with REMA score ≥2 and KIT p.D816V detected in peripheral blood or bone marrow biopsy if KIT p.D816V was negative in peripheral blood.
The investigators compared diagnoses and accuracy of screening tests before and after standardization.
How effective is SM screening standardization?
The investigators identified 249 patients who met inclusion criteria. Of these, 47 had a diagnosis of SM before standardization, and an additional 47 patients received a diagnosis after standardization, for a total of 94. The prevalence of SM increased from 1 in 58,572 before standardization to 1 in 29,286 individuals after standardization. Overall, the most common diagnosis was indolent SM in 79 patients.
The investigators found that 41 out of 47 new diagnoses after standardization had been missed due to errors in bone marrow analysis or bone marrow biopsy not being offered. For some patients diagnosed with mastocytosis by July 1, 2021, the diagnosis was changed after standardization. CM was changed to an SM subtype for 22 patients, and SM was changed to a different subtype for 3 patients. Two other patients were found to have a different myeloid neoplasm.
Among all 94 patients with SM, 63.8% had a history of monomorphic MPCM, 85.1% had BST ≥11.5 ng/mL, 82.5% had a REMA score ≥2, and 84.0% had detectable KIT p.D816V DNA.
Four patients with SM did not have monomorphic MPCM or anaphylaxis with a REMA score ≥2. Two had increased mast cells after bone marrow biopsy for other neoplasms. In 2 additional patients, elevated BST was found during workup for other conditions, 1 for chronic angioedema, and 1 for fractures.
Twelve of 47 (25.5%) patients who received a diagnosis after standardization had BST levels below 11.5 ng per mL.
Reasons for missed diagnoses
Among the 41 patients with missed diagnoses before standardization, common screening errors included not offering bone marrow biopsy due to thinking BST values were too low, not calculating REMA score, and missing the risk in patients with monomorphic MPCM. Common analytical errors were not using high-sensitivity KIT p.D816V tests, not performing mast cell flow cytometry, and making errors in immunohistochemical analyses.
The investigators also claimed support for high-sensitivity testing for KIT p.D816V somatic mutations. The mean variant allele frequency declined from 2.2% among patients who received a diagnosis before standardization to 0.3% among those with a diagnosis after standardization, suggesting better detection of low numbers of diseased cells with more sensitive methods (P = .0124). In fact, the variant allele frequency was below 0.1% in 32 out of 60 (53.3%) patients with SM who had quantitative sequencing tests.
Which screening test is the most accurate?
The investigators examined the accuracy of 6 screening tests: 1) BST ≥11.5 ng per mL; 2) BST ≥20 ng per mL; 3) elevated BST based on genotype; 4) REMA score ≥2; 5) REMA score ≥2 plus elevated BST based on genotype; and 6) adult-onset monomorphic MPCM.
Elevated BST based on genotype had a sensitivity of 84.2% and a specificity of 90.2%. BST of ≥20.0 ng per mL, however, had a lower sensitivity (59.6%) and specificity (71.4%). Although BST ≥11.5 ng per mL had 88.3% sensitivity, the specificity fell short at 23.8%.
REMA score ≥2 had a sensitivity of 34.0% and specificity of 73.8%, and REMA score ≥2 plus elevated BST based on genotype had a sensitivity of 30.3% and specificity of 97.6%.
Adult-onset monomorphic MPCM had a 63.8% sensitivity and a 97.6% specificity.
The value of screening standardization
“Here, we showed that generating a clinical registry and standardizing and centralizing evaluations for SM at [centers for excellence] increased the frequency of timely and correct clinical and molecular diagnoses of SM,” the authors concluded in their paper.
They also wrote, “The present study is the first to validate that an elevated BST based on genotype is an individually sensitive and specific screening test for SM.” Given that some patients did not have elevated BST, the investigators suggested that the World Health Organization and International Consensus Classification criteria for BST >20 ng per mL could be revisited.
In an accompanying editorial, Julien Rossignol, of Necker-Children's Hospital in Paris, France, and Michel Arock, of Pitié Salpêtrière Hospital, also in Paris, added their two cents: “We expect that the implementation of McMurray et al’s standardized approach, specifically intended for [non-advanced systemic mastocytosis] variants, in all centers (including those that are not specialized in SM) will shorten the long diagnostic delay for this category of SM patients.”8
The investigators acknowledged that the limitations of their study included the retrospective design, the inability to generalize to all subtypes of SM because most patients had indolent SM, and missing data from patients who did not complete evaluations.
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