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Systemic mastocytosis (SM) is a clonal mast cell disorder that can lead to potentially severe anaphylactic reactions. Hymenoptera sting is one of the most frequent triggers of anaphylaxis in these patients, and diagnosis of indolent SM (ISM) without skin involvement (ISMs) is not rare. In this subgroup of patients, venom immunotherapy (VIT) is an effective treatment decreasing subsequent systemic reactions, and lifelong administration is recommended. An individualized diagnosis is necessary to offer the most adequate VIT, and molecular diagnosis (MD) may be useful to discriminate between primary sensitization and cross-reactivity. Nevertheless, other techniques such as ImmunoCAP inhibition assays may be necessary to identify the genuine sensitization to offer the most suitable VIT. We present a male patient with an anaphylactic reaction following several wasp stings. The patient was diagnosed with ISM, and allergy to both Polistes dominula and Vespula sp venom was confirmed. In this scenario, MD did not discriminate between a genuine double sensitization and venom cross-reactivity between both vespids. Thus, CAP-inhibition assay was performed. This case indicated the importance of an accurate diagnosis of hymenoptera venom allergy (HVA). It also highlights the usefulness of CAP-inhibition assays when MD fails to distinguish between genuine double Polistes-Vespula sensitization and cross-reactivity.

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BACKGROUND: The rate of diagnosis of mast cell activation syndrome (MCAS) has increased since the disorder's original description as a mastocytosis-like phenotype. While a set of consortium MCAS criteria is well described and widely accepted, this increase occurs in the setting of a broader set of proposed alternative MCAS criteria. OBJECTIVE: Effective diagnostic criteria must minimize the range of unrelated diagnoses that can be erroneously classified as the condition of interest. We sought to determine if the symptoms associated with alternative MCAS criteria result in less concise or consistent diagnostic alternatives, reducing diagnostic specificity. METHODS: We used multiple large language models, including ChatGPT, Claude, and Gemini, to bootstrap the probabilities of diagnoses that are compatible with consortium or alternative MCAS criteria. We utilized diversity and network analysis to quantify diagnostic precision and specificity compared to control diagnostic criteria including systemic lupus erythematosus (SLE), Kawasaki disease, and migraines. RESULTS: Compared to consortium MCAS criteria, alternative MCAS criteria are associated with more variable (Shannon diversity 5.8 vs. 4.6, respectively; p-value=0.004) and less precise (mean Bray-Curtis similarity 0.07 vs 0.19, respectively; p-value=0.004) diagnoses. The diagnosis networks derived from consortium and alternative MCAS criteria had lower between-network similarity compared to the similarity between diagnosis networks derived from two distinct SLE criteria (cosine similarity 0.55 vs. 0.86, respectively; p-value=0.0022). CONCLUSION: Alternative MCAS criteria are associated with a distinct set of diagnoses compared to consortium MCAS criteria and have lower diagnostic consistency. This lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.

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Advanced systemic mastocytosis (AdvSM) is a rare hematologic malignancy with organ damage and compromised life expectancy arising from organ accumulation of neoplastic mast cells. Identification of the gain-of-function KITD816V in the majority of cases has accelerated pharmaceutical development culminating with the development of selective KIT inhibitors such as avapritinib. While the advent of these therapies has improved the quality and quantity of life in patients with AdvSM, current challenges remain in the management of this disease. In this review, we summarize the present and future therapeutics landscape of AdvSM, highlighting the development of novel KIT inhibitors including elenestinib and bezuclastinib. We also explore the continued role of additional treatment modalities including allogeneic stem cell transplantation before discussing unresolved clinical challenges in the management of AdvSM.

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Background: Systemic mastocytosis (SM), a rare condition affecting about 32,000 individuals in the United States, is often misdiagnosed or underdiagnosed owing to its nonspecific symptoms and the need for invasive biopsies. Objective: Our aim was to identify, classify, and characterize the natural history of patients with SM. Methods: In a retrospective cohort study, administrative data from a large managed care organization was used to identify patients with confirmed SM, based on World Health Organization criteria. Demographic data, delay to diagnosis, disease progression, and health care resource utilization were examined. Results: Of 116 patients with confirmed SM, 77% had indolent SM, 2% had smoldering SM, 12% had SM with associated hematologic neoplasm, 9% had aggressive SM, and none had mast cell leukemia. In all, 5 patients were misclassified as having a less advanced SM subtype initially and 3 were completely undiagnosed (missed diagnosis). The average delay to diagnosis of SM was 58.3 plus or minus 73.1 months. In all, 18% of patients progressed from a nonadvanced form of SM (indolent or smoldering SM) to an advanced form of SM (aggressive SM, SM with associated hematologic neoplasm, or mast cell leukemia) over an average of 88.3 plus or minus 82.7 months. Patients with SM had increased health care utilization, including increases in their numbers of hospital admissions, emergency room visits, urgent care visits, and specialty provider visits, after diagnosis versus before. Conclusions: Rare diseases such as SM would benefit from increased understanding and awareness to improve diagnostic accuracy. Prospective studies are needed to better characterize this patient population and determine the type of follow-up needed to recognize advanced forms of SM so that appropriate treatment can be implemented.

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BACKGROUND: Bidirectional interactions between eosinophils and mast cells (MCs) have been reported in various allergic diseases. Bone marrow (BM) eosinophilia, and to a lesser extent blood eosinophilia, is common in systemic mastocytosis (SM), but its significance remains unknown. OBJECTIVE: We described blood and BM eosinophil characteristics in SM. METHODS: A large collection of BM biopsy samples was analyzed using immunohistochemical staining and whole-slide imaging. Eosinophil and extracellular granules were detected by eosinophil peroxidase (EPX) staining and MCs by KIT staining. Complementary analyses were conducted using flow cytometry and immunofluorescence. RESULTS: Eosinophil infiltrates and large areas of eosinophil degranulation were observed within or around BM MC infiltrates in SM. EPX staining surface, highlighting intact eosinophils and eosinophil degranulation, was higher in nonadvanced SM (n = 37 BM biopsy samples) compared with both controls (n = 8, P = .0003) and advanced SM (n = 24, P = .014). In nonadvanced SM, positive correlations were observed between serum tryptase levels and percentages of eosinophil counts in BM aspirations (Spearman r coefficient r = 0.38, P = .038), eosinophils count in BM biopsy samples (r = 0.45, P = .007), EPX staining (r = 0.37, P = .035), and eosinophil degranulation (r = 0.39, P = .023). Eosinophil counts in BM biopsy samples also correlated with MC counts (r = 0.47, P = .006) and KIT staining surface (r = 0.49, P = .003). BM MCs expressed IL-5 receptor and other usual eosinophil cytokine/chemokine receptors, and blood eosinophils displayed several increased surface markers compared with controls, suggesting an activated state. CONCLUSION: Our data suggest possible cross talk between MCs and eosinophils, supporting MC tryptase release and MC activation-related symptoms. This suggests a rationale for targeting eosinophils in nonadvanced SM not fully controlled by other therapies.

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Patients with Hymenoptera venom allergy (HVA), especially those with severe anaphylaxis, frequently have concomitant clonal mast cell disease (MCD) in the form of systemic mastocytosis or monoclonal mast cell activation syndrome. Detection of clonal MCD is important since it will have significant consequences for management of HVA. Therefore, we recommend patients with HVA be systematically screened for clonal MCD. The pre-test probability of clonal MCD can be assessed in a stepwise fashion starting with examination of the skin for typical monomorphic maculopapular cutaneous mastocytosis (MPCM) lesions; measurement of the baseline serum tryptase (BST) and tryptase genotyping for patients with BST>11 ng/mL; followed by the REMA score which is calculated by utilizing anaphylaxis clinical features, BST, and patient sex. A bone marrow biopsy should be performed in patients with monomorphic MPCM, a REMA score ≥2, or an elevated BST based upon tryptase genotype. Patients with HVA and a clonal MCD should be treated with immunotherapy directed against the Hymenoptera venom for which they are sensitized. For this high-risk subgroup of HVA patients, it is recommended to continue immunotherapy for more than 5 years or indefinitely and to carry at least three epinephrine autoinjectors. Future studies should determine whether KIT D816V-selective tyrosine kinase inhibitors are effective at preventing or reducing severity of Hymenoptera-venom triggered anaphylaxis in patients with clonal MCD.

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PURPOSE OF REVIEW: Since identification of Systemic mastocytosis (SM) as a distinct disease entity by the World Health Organisation (WHO), there has been a wealth of new research in therapeutic targeting of the pathogenic C-KIT D816V mutation. RECENT FINDINGS: Avapritinib, the first licensed drug in SM capable of disease modification alongside the increasingly potent, oral and highly selective KIT tyrosine kinase inhibitors (TKIs) Bezuclastinib and now Elenestinib have enabled the prospect of long-term remissions. Studies have shown improved survival and symptomatic control in patients with SM. Of great triumph, this has been achieved in an outpatient setting with apparent tolerable and minimal toxicity. The importance of molecular profiling is being demonstrated in administering combination therapies for SM with an associated haematological neoplasm (AHN), allowing more personalised and streamlined treatment regimes. This review focuses on current management strategies of SM, focusing on state-of-the-art directed therapies, the evidence behind their use with presentation of two clinical cases to highlight key messages.

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Systemic mastocytosis (SM) is a heterogeneous myeloid neoplasm, characterized by clonal proliferation of mast cells (MCs) in ≥ 1 extracutaneous organs, including the bone marrow (BM) and gastrointestinal tract. Aberrant MC proliferation is driven by mutation KIT D816V in ≈90-95% of SM patients. Indolent SM (ISM) is the most common SM subtype with various symptoms that can be severe. Advanced SM (AdvSM) has markedly poor prognosis. The advent of KIT inhibitors, targeting mutant KIT and neoplastic MCs, led to a paradigm shift in SM management and markedly improved outcomes. Midostaurin inaugurated the era of KIT inhibitors and was approved for AdvSM in 2017. Avapritinib is the first highly potent and selective inhibitor of KIT D816V that was approved to treat AdvSM and symptomatic ISM (platelets ≥ 50 × 109/L), in the US, in 2021 and 2023, respectively. Pooled analysis of the EXPLORER and PATHFINDER studies, assessing avapritinib in AdvSM, demonstrated rapid and profound reductions (≥ 50%) in markers of MC burden, high response rates (71-75%), and prolonged survival. In the PIONEER study, avapritinib significantly and rapidly improved symptoms/quality of life, and reduced markers of MC burden in ISM patients. The investigational agents bezuclastinib and elenestinib are highly potent and selective inhibitors of KIT D816V with minimal blood-brain barrier penetration. Bezuclastinib reduced markers of MC burden by ≥ 50% in ≈50% of AdvSM patients and ≈90-100% of nonAdvSM patients and reduced symptoms (≥ 50%) in the APEX and SUMMIT studies, respectively. Elenestinib demonstrated dose-dependent efficacy in reducing MC burden markers and improved symptoms in ISM patients in the HARBOR study.

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Aggressive systemic mastocytosis (ASM) is an advanced subtype of systemic mastocytosis characterized by organ involvement. In this article, we report a case with ASM in a 54-year-old woman with characteristic findings on computed tomography (CT) and fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/CT. Contrast-enhanced CT on admission revealed hepatosplenomegaly, generalized osteosclerosis, colonic edema, edematous thickening of the wall in the ascending colon and edema in the surrounding regions of these organs and mesentery, ileus, subcutaneous edema, periportal collar sign, and multiple mesenteric lymphadenopathies. There was no 18F-FDG uptake in the lesions other than mild 18F-FDG uptake in the vertebrae, making the possibility of differential diagnoses such as metastasis, lymphoma, and extramedullary leukemia lower. Based on bone marrow biopsy results and clinical findings, the diagnosis of ASM was established. ASM can be a potentially fatal disease with a poor prognosis, and understanding its distinctive clinical course and imaging findings is crucial for early therapeutic intervention.

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Systemic mastocytosis (SM) poses a diagnostic challenge. This hematologic disorder involves abnormal mast cell proliferation and concurrent tissue infiltration. SM clinical presentation is not uniform, with patients displaying a wide array of symptoms related to different organ infiltration and mast cell mediators. Splenomegaly, while not typical or specific to SM, might be present from an early stage to advanced stage, especially in the presence of thrombocytopenia. Early detection is crucial for optimal patient outcomes. We present an atypical case of SM with spleen involvement in a 63-year-old male patient with a history of persistent thrombocytopenia for five years. Upon splenectomy, histological findings were compatible with infiltration with mast cells. Remarkably, the patient showed improvement and did not require additional cytoreductive therapy. This case underlines the importance of recognizing this rare presentation and highlights the potential therapeutic role of splenectomy in aggressive SM.

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BACKGROUND: KIT p.D816 mutation is strongly associated with systemic mastocytosis (SM). Next-generation sequencing (NGS) is now routinely performed in almost all bone marrow sample and KIT mutations are detected from patients who are not known or suspected to have SM. Therefore, we wanted to assess if KIT mutations in this patient population are associated with unsuspected SM. METHODS: We searched NGS result in our institution with positive result for KIT mutation from patients with known/suspected myeloid neoplasms. Patients with previously documented history of systemic mastocytosis were excluded. Bone marrow biopsies from patients with KIT mutation were assessed with immunohistochemical stains for CD117 and mast cell tryptase (MST). RESULTS: Bone marrow biopsies were assessed with immunohistochemical stains for CD117 and mast cell tryptase (n = 49). Most patients had acute myeloid leukemia (AML, n = 38) or chronic myelomonocytic leukemia (CMML, n = 6). Immunohistochemical stains for CD117 and tryptase were performed in all 49 patients. A total of 4 patients (8.2%) showed mast cell nodules where spindled shaped mast cells were present, meeting the WHO criteria for SM. All four patients had KIT p.D816V mutation and had high mutant allelic frequency (∼ 50%) except one patient (1%). CONCLUSION: We discovered approximately 8% of patients who had myeloid neoplasms with unexpected KIT mutations fulfilled the diagnostic criteria for systemic mastocytosis after additional immunohistochemical studies. Our data support that application of additional immunohistochemical studies is recommended to identify underrecognized SM when KIT mutations are found by molecular assays.

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Background: Symptoms in patients with systemic mastocytosis (SM) are associated with an increase in mast cell burden and release of mast cell-derived mediators. The most frequent presentation of SM is indolent SM (ISM), with moderate symptoms and prognosis. Basophil numbers in these patients are generally normal. However, when examining basophil activation in patients with ISM, we noted an abnormal response to N-formylmethione-leucyl-phenylalanine (fMLP). Objective: Our aim was to compare basophil responsiveness to fMLP and anti-IgE in healthy volunteers and patients with ISM and relate the findings to fMLP receptor (FPR) expression. Methods: Basophils isolated from peripheral blood of 15 patients with ISM and 14 healthy volunteers were stimulated with fMLP or anti-IgE. CD63 expression to assess basophil activation and expression of FPRs were assessed by flow cytometry. Results: Baseline expression of CD63 on basophils was similar between the healthy volunteers and patients with ISM. fMLP induced higher expression of CD63 on basophils from patients with ISM, whereas responses to anti-IgE were similar between groups. Basophils from patients with ISM also had higher fMLP1 receptor (FPR1) expression, wheresas FPR2 and FPR3 were not detected. fMLP blocked the binding of anti-FPR1 antibody to FPR1, consistent with the conclusion that fMLP signals through FPR1. Conclusions: Level of fMLP-induced basophil activation is higher in patients with ISM, which is associated with an increase in FPR1 expression. Further investigation is needed to determine why FPR1 expression is elevated, whether such expression might serve as an additional surrogate marker in the diagnosis of ISM, and whether enhanced responses of basophils to fMPL might have some relationship to unexplained episodes of mediator release.

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Mastocytosis or an elevated basal serum tryptase (bST) level are known risk factors for patients with insect venom allergy. We report on 3 patients with a history of severe anaphylactic insect sting reactions who underwent a detailed workup for insect venom allergy before starting venom immunotherapy. In addition to insect venom sensitization, an elevated concentration of bST (15.5, 20.8, and 23.2 µg/L) was found in all cases. There was no evidence of mastocytosis in the skin (MIS). Further testing revealed hereditary α-hypertryptasemia (HαT) in 2 patients and a D816V mutation by liquid biopsy in 1 patient, which is a minor diagnostic criterion for indolent systemic mastocytosis. Even without iliac crest puncture, causes of elevated bST can be narrowed down with minimally invasive diagnostic measures. As this has practical implications, patients with elevated bST should always undergo further work-up to determine the cause of this abnormal finding.

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Mastocytosis is a clonal myeloid disorder defined by an increase and accumulation of mast cells (MC) in one or multiple organ systems. The complex pathology of mastocytosis results in variable clinical presentations, courses, and outcomes. The World Health Organization (WHO) divides the disease into cutaneous mastocytosis (CM), several forms of systemic mastocytosis (SM), and MC sarcoma. In most SM patients, a somatic KIT mutation, usually D816V, is identified. Patients diagnosed with CM or non-advanced SM, including indolent SM, have a near-normal life-expectancy, whereas those with advanced SM, including aggressive SM and MC leukemia, have limited life-expectancy. Since 2001, a multidisciplinary consensus group consisting of experts from the European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM), has supported the field by developing diagnostic criteria for mastocytosis. These criteria served as the basis for the WHO classification of mastocytosis over two decades. More recently, an international consensus group (ICC) proposed slightly modified diagnostic criteria and a slightly revised classification. In this article, these changes are discussed. Furthermore, we propose harmonization among the proposals of the AIM/ECNM consensus group, WHO, and ICC. Such harmonization will facilitate comparisons of retrospective study results and the conduct of prospective trials.

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Introduction: We previously showed enteric nerve activation after application of colonic mucosal biopsy supernatants from patients with irritable bowel syndrome (IBS). The question remains whether this is a region-specific or a generalized sensitization. We tested the nerve-activating properties of supernatants from large and small intestinal regions of IBS patients with diarrhea (IBS-D) in comparison to those from mastocytosis patients with diarrhea (MC-D) or non-IBS/non-MC patients with GI-complaints. MC-D patients were included to test samples from patients with an established, severe mast cell disorder, because mast cells are suggested to play a role in IBS. Methods: Voltage-sensitive dye imaging was used to record the effects of mucosal biopsy supernatants from IBS-D, MC-D, and non-IBS/non-MC on guinea pig submucous neurons. Mast cell density and histamine concentrations were measured in all samples. Results: The median neuroindex (spike frequency × % responding neurons in Hz × %) was significantly (all p < 0.001) increased for IBS-D (duodenum and colon, proximal and distal each, 49.3; 50.5; 63.7; 71.9, respectively) compared to non-IBS/non-MC (duodenum and colon, proximal and distal each, 8.7; 4.9; 6.9; 5.4, respectively) or MC-D supernatants (duodenum and colon, proximal and distal each, 9.4; 11.9; 0.0; 7.9, respectively). Nerve activation by MC-D and non-IBS/non-MC supernatants was comparable (p>0.05). Mast cell density or histamine concentrations were not different between IBS-D, MC-D, and non-IBS/non-MC samples. Discussion: Nerve activation by biopsy supernatants is an IBS hallmark that occurs throughout the gut, unrelated to mast cell density or histamine concentration. At least as important is our finding that GI complaints per se were not associated with biopsy supernatant-induced nerve activation, which further stresses the relevance of altered nerve behavior in IBS.

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BACKGROUND: Mast cell leukemia (MCL), a subtype of systemic mastocytosis (SM), is an extremely rare clinical entity characterized by a very poor prognosis. Chemotherapy, tyrosine kinase inhibitors, and allogeneic hematopoietic cell transplantation are the only treatment options, but they cannot provide the desired outcomes in most cases of MCL. However, other types of SM can be successfully treated. The disease has no specific manifestation, but gastroenterological symptoms are present in most cases. CASE SUMMARY: The authors, hereby, report a case of a 46-year-old female patient diagnosed with MCL-the rarest subtype of SM. The patient presented to the gastroenterology clinic with multiple, various, and unspecific gastroenterological symptoms. Concomitance of skin lesions significantly contributed to a relatively prompt diagnosis. The serum tryptase level was extremely high and bone the marrow aspirate showed an infiltration of atypical mast cells. The disease was rapidly progressive and primary refractory to chemotherapy and the patient succumbed to the illness about a month after the initiation of treatment. CONCLUSION: Despite its "hematological nature", MCL, in most cases presents dominantly with unspecific gastroenterological symptoms. Thus, a high disease awareness among physicians other than hematologists is necessary to improve treatment outcomes. Serum tryptase level, due to its non-invasive nature and easy access, may serve as an initial step to estimate the probability of mastocytosis.

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Systemic mastocytosis (SM) is a rare type of myeloproliferative neoplasm characterized by abnormal proliferation and infiltration of different tissue by clonal mast cells. The uncontrolled proliferation and activation of mast cells trigger the release of vasoactive and inflammatory mediators, resulting in a cascade of systemic symptoms. Around 95% of SM arise from a gain-of-function mutation at the KIT gene, specifically at codon 816, which highlights its essential role in SM and makes it an attractive target for therapy. Although KIT-negative SM is exceptionally rare, the increased number of cases documented in the literature makes it an intriguing dimension of this disorder. The reported clinical manifestations of KIT-negative SM are widely variable, but many are similar to KIT-positive SM. KIT-targeted therapeutic options have been a game-changer in KIT-positive SM, however their role in KIT-negative SM remains controversial. This report aimed to further understand KIT-negative SM by presenting two cases of KIT-negative SM, one of which was responsive to KIT-targeted therapy, and analyzing reported cases in the existing literature.

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Ehlers-Danlos syndrome (EDS) is a collection of genetic disorders caused by abnormalities in collagen and typified by hyperflexible joints, hyperextensible skin, and a tendency for easy bruising and tissue injuries. Hypermobile Ehlers-Danlos syndrome (hEDS), the most common subtype, presents a diagnostic challenge due to the lack of specific genetic markers. This case report describes a 13-year-old girl with hEDS, presenting with hypermobility, thoracolumbar scoliosis, constipation, glucosuria, microscopic hematuria, urticaria, and intermittent episodes of bilateral hand and feet swelling. Genetic testing revealed a variant of uncertain significance in the COL9A2 gene. An echocardiogram showed a mildly dilated aortic root. The complexity of her presentation underscores the challenges in diagnosing and managing hEDS with multisystem involvement.