Laboratory Assessment of Patients with Systemic Mastocytosis

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Abstract

In pediatric patients, cutaneous mastocytosis accounts for approximately 90% of all cases. Subtypes include maculopapular cutaneous mastocytosis, formerly termed urticaria pigmentosa, diffuse cutaneous mastocytosis (DCM), and mastocytoma. Patients with DCM and higher MC burdens have more severe manifestations of mediator release. Patients with skin disease similar to a DCM pattern with the onset in childhood may be subsequently diagnosed with having well-differentiated SM. In FY22, we performed studies on pediatric mastocytosis patients who were diagnosed with having DCM, each with severe mast cell mediator symptoms and acute elevations of total serum tryptase (ST) that exceeded both the 1.2 baseline tryptase + 2 ng/mL formula and the optimized threshold ratio of 1.685 to help determine whether the increase in serum tryptase supports the diagnosis of systemic anaphylaxis. The first patient was a 25-month white girl admitted to the NIH Clinical Center to rule out systemic disease. This patient had an elevated bST (24.9 ng/mL), thickened reddish skin with severe blistering and flushing with associated gastrointestinal symptoms which began at 4 months. Before the bone marrow (BM) procedure, the patient was maintained on antihistamines and cromolyn sodium. Anesthetics during the procedure included sevoflurane, propofol, and local lidocaine 1%. The patient developed a 10-cm flare at the lidocaine injection site followed by full-body flushing with stable vital signs. She was given intravenous Benadryl 12.5 mg with resolution of flushing. The ST 1 hour postoperatively was 46.4 ng/mL, and mature tryptase was <1 ng/mL. ST subsequently returned to baseline. Bone marrow histopathological analysis, mast cell flow cytometric analysis and KIT gene molecular analysis did not reveal findings that meet World Health Organization criteria for diagnosis of systemic disease. The second patient was an 18-month Hispanic boy with a history of an elevated total bST (33 ng/mL), blistering skin lesions, flushing, and diarrhea. Before the BM procedure, the patient was maintained on antihistamines. On the day before the procedure, the patient had a total bST of 23.4 ng/mL. During his preanesthesia appointment, he became diffusely flushed with stable vital signs. A ST level within 1 hour of this episode was 67.4 ng/mL, with mature tryptase less than 1 ng/mL. This ST level ultimately returned to baseline. A bone marrow biopsy results did not meet World Health Organization criteria for systemic disease. Patient was tested for TPSAB1gene duplication and was negative. This is the first report in patients with DCM of a considerable increase in acute total ST without a rise in mature tryptase or hemodynamic compromise. These are important clinical observations because children with DCM may have flushing episodes associated with reflex tachycardia and diarrhea without hemodynamic compromise observed with anaphylaxis. Importantly, patients with DCM have been reported to be more susceptible to severe mast symptoms to include anaphylaxis. However, these patients with a marked increase in ST were often hemodynamically stable and thus did not meet the criteria for the clinical diagnosis of anaphylaxis. Parents and teachers are often unsure about how aggressive the response should be in managing these children. Our observations highlight a more conservative approach when hemodynamic monitoring is available, and which should be helpful in management and allay some anxiety for caregivers. Systemic mastocytosis (SM) is a heterogeneous group of disorders characterized by clonal mast cell expansion within the hematopoietic compartment and other tissues. Indolent SM is the most common form and is associated with a <3% risk of progression to more aggressive forms of the disease. Prior reports indicate a favorable outcome and normal life expectancy, but little literature exists regarding the potential for disease resolution. In FY22, we investigated the spontaneous remission of ISM in an individual first evaluated at the NIH Clinical Center in 1984 and followed at the NIH since then. The patient first presented at the age of 19 (1977) with skin changes and received diagnosis of urticaria pigmentosa. Approximately 5 years later (1982), patient began to experience fatigue, severe headache, episodic flushing, abdominal cramping, and intermittent diarrhea. Because of suspicion for systemic disease, patient was referred to the NIH. Laboratory assessment and imaging was unrevealing for cytopenia, organomegaly, or evidence of organ dysfunction. Bone marrow biopsy performed in 1987 revealed large aggregates of spindle-shaped mast cells, consistent with the diagnosis of indolent systemic mastocytosis. Despite modest symptomatic improvement with antihistamines, patient experienced progression and developed diffuse musculoskeletal pain. Radiologic assessment was unrevealing. Bone marrow biopsy in 1992 remained consistent with mastocytosis, showing dense infiltrates of spindle-shaped mast cell aggregates involving about 15% of the marrow. Over subsequent years, symptoms of flushing, musculoskeletal pain, abdominal cramping, and diarrhea gradually improved. A follow-up bone marrow biopsy at age 53 (2011) demonstrated decreased mast cell burden with mast cell aggregates involving only about 3% of the marrow. Flow cytometry reported absent CD2 and CD25 expression on mast cells; however, a few small clusters of CD25 positive mast cells were present in the core biopsy by immunohistochemical analysis. KIT D816V mutation was undetectable by RT- PCR/RFLP analysis. However, the presence of mast cell aggregates along with an elevated serum tryptase substantiated the persistent diagnosis of ISM. A subsequent bone marrow biopsy performed in 2019 no longer demonstrated mast cell aggregates. Although there were some aberrantly shaped CD25+ mast cells, it no longer fulfilled the World Health Organization diagnostic criteria for SM. At this time, the patient reported few symptoms and skin lesions had undergone near complete regression. Serum tryptase was within normal range. Patient never received any cytoreductive therapy, or any other therapy including steroids or cromolyn sodium that might affect the mast cell compartment. Retrospective analysis of available blood (2011, 2017, 2018, 2019) and bone marrow (2011, 2019) samples tested negative for KIT p.D816V mutation. Whole exome sequencing (WES) performed in 2019 to evaluate for variants in reported modifier genes that may influence SM disease severity was negative. Somatic mutations in genes associated with myeloid neoplasms were evaluated by a targeted NGS panel encompassing 275 human cancer genes, including KIT, using genomic DNA obtained from the 2011 and 2019 bone marrow aspirates. No relevant mutations were identified. TPSAB1 gene duplication observed in hereditary alpha tryptasemia was not detected. Despite a low risk of disease progression in patients with ISM, and relatively good overall survival compared with age-matched controls, there are no documented cases of disease remission. This is the first documented case where the absence of mast cell aggregates within the marrow, normalization of serum tryptase, and improvement in symptoms indicated disease remission.