c-kit D816V Provides a Strong Signal for Myelomastocytic Differentiation and Cluster Formation in Murine Ba/F3 Cells.
Matthias MayerhoferKarl J. AichbergerStefan FlorianMaria‐Theresa KrauthMartin BilbanHarald EsterbauerOswald WagnerReinhard KodymKarl SotlarJack LongleyHans‐Peter HornyChristian SillaberPeter Valent
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Systemic mastocytosis (SM) is a hematopoietic neoplasm characterized by pathologic expansion of tissue mast cells in one or more extracutaneous organs. In most children and most adult patients, skin involvement is found. Childhood patients frequently suffer from cutaneous mastocytosis without systemic involvement, whereas most adult patients are diagnosed as suffering from SM. In a smaller subset of patients, SM without skin lesions develops which is a diagnostic challenge. In the current article, a diagnostic algorithm for patients with suspected SM is proposed. In adult patients with skin lesions and histologically confirmed mastocytosis in the skin (MIS), a bone marrow biopsy is recommended regardless of the serum tryptase level. In adult patients without skin lesions who are suffering from typical mediator-related symptoms, the basal serum tryptase level is an important diagnostic parameter. In those with slightly elevated tryptase (15-30 ng/ml), additional non-invasive investigations, including a KIT mutation analysis of peripheral blood cells and sonographic analysis, is performed. In adult patients in whom i) KIT D816V is detected or/and ii) the basal serum tryptase level is clearly elevated (> 30 ng/ml) or/and iii) other clinical or laboratory features are suggesting the presence of occult mastocytosis, a bone marrow biopsy should be performed. In the absence of KIT D816V and other indications of mastocytosis, no bone marrow investigation is required, but the patient's course and the serum tryptase levels are examined in the follow-up.
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Mastocytosis refers to a heterogeneous group of clinical disorders characterized by an abnormal accumulation of mast cells (MCs) in various tissues. The skin is the organ most frequently involved, but all organs may be affected. The clinical signs and symptoms are produced by the functional effects of mast cell-derived mediators and the anatomical distribution of the mast cells. The 2008 WHO-classification defines 7 categories of mastocytosis. Skin disease, with or without systemic involvement, is by far the most common form of childhood mastocytosis. Measurement of serum tryptase is important in the diagnostic algorithm of pediatric mastocytosis. In children with tryptase <20 ng/mL, the diagnosis of cutaneous mastocytosis (CM) may be decided upon without bone marrow examination (BME), unless other signs of SM are present. If the baseline tryptase level exceeds 100 ng/mL, a BME should be considered regardless of age. If the serum tryptase is 20-100 ng/mL in children without other signs of SM, the provisional diagnosis "mastocytosis in the skin" (MIS) can be established and monitored until puberty. If MIS remains present after puberty, a BME should be performed. In adult-onset mastocytosis a complete staging and application of the systemic mastocytosis criteria should always be performed. Treatment is mainly directed at alleviation of symptoms. As c-kit mutations prove to be very important in the pathogenesis of mastocytosis, targeted therapies using kit inhibitors may evolve as important future therapeutic options.
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This article was originally published online on 8 April 2015 Mastocytosis is a group of heterogeneous diseases characterized by an abnormal expansion and accumulation of mast cells (MCs) in different tissues. While systemic mastocytosis (SM) is defined by the accumulation of MCs in bone marrow (BM) and different tissues, cutaneous mastocytosis (CM) is characterized as an accumulation of MC in the skin with no other organ involvement. How gender differences, tryptase levels and episodes of anaphylaxis affect cutaneous versus systemic mastocytosis is not well understood. We report a case series of 109 patients with SM and 59 with CM from the Mastocytosis Center at Brigham and Women's Hospital in Boston. The diagnosis of SM and CM were done according to the International Classification of Mastocytosis from WHO. We reviewed gender, tryptase levels and episodes of anaphylaxis in both populations. There was a female predominance which was more pronounced in SM (68,8%) than in CM (52,7%). The mean serum tryptase level was 11.5 ng/ml in CM, and 14.9% of CM patients had serum tryptase levels above 20 ng/ml. In SM patients the mean serum tryptase level was 97.2 ng/ml and 84% of the patients presented levels above 20 ng/ml. The symptoms of CM included pruritus, flushing, urticaria, and dermatographism and 10.8% of the patients (number) had episodes of anaphylaxis. The rate of anaphylaxis in SM patients was found to be 29.4% similar to the previously reported. A female predominance was seen in both cutaneous and systemic mastocytosis in contrast to other studies indicating that there is no gender predominance. Elevations of serum tryptase above 20 ng/ml and anaphylaxis were seen in a small proportion of patients with cutaneous mastocytosis, raising the question of the potential progression to systemic mastocytosis and the need to closely monitor this subset of patients.
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Summary Background Mastocytosis is difficult to diagnose, especially when systemic mast cell activation symptoms are not present or involve only one extracutaneous organ. Objective The main objective was to evaluate the accuracy of the bone marrow tryptase level in the diagnosis of systemic mastocytosis in patients with a clinical suspicion of mastocytosis. Methods We included all adult patients evaluated in our centre between December 2009 and 2013 for suspected mastocytosis as part of a standardized procedure and who had a bone marrow and serum tryptase assay on the same day. The diagnosis of systemic mastocytosis was established on the basis of the World Health Organization criteria as the gold standard. The accuracy of the bone marrow tryptase level in the diagnosis of systemic mastocytosis was assessed by a receiver operating characteristics curve analysis. The different sensitivity and specificity values, corresponding to the set of possible bone marrow tryptase level cut‐off values, were estimated with 95% confidence intervals. Results Seventy‐three patients were included. The diagnosis of systemic mastocytosis was established in 43 patients (58.9%). The median bone marrow tryptase level was 423 μg/L [95% CI : 217–868] in the systemic mastocytosis group and 7.5 μg/L [95% CI : 4.6–17.1] in the non‐systemic mastocytosis group ( P < 0.001). A cut‐off value of 50 μg/L for bone marrow tryptase identified systemic mastocytosis with a sensitivity of 93.0% [95% CI : 80.9–98.5%] and a specificity of 90.0% [95% CI : 73.5–97.9%]. Conclusion and Clinical Relevance The bone marrow tryptase level appears to be a valuable diagnostic criterion for confirming systemic mastocytosis. If this diagnosis can reliably be excluded by evaluation of the bone marrow tryptase level, there would be no need to perform a bone marrow biopsy.
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