Serum Tryptase Levels Research Articles

Abstract 11227: A Rare Case of Echo Contrast Anaphylaxis Complicated by Acute Coronary Syndrome

Introduction: Contrast agents in echocardiography are used frequently to enhance endocardial border visualization and assessment of structural heart disease. Sulfur hexafluoride lipid type A injectable suspension is a generally well-tolerated class of contrast. Anaphylaxis to these agents is exceedingly rare. We now report the first case of acute coronary syndrome in the setting of echo contrast anaphylactic shock. Case: A 49-year-old woman was hospitalized for an ST-elevation myocardial infarction (STEMI) for which a drug-eluting stent had been placed in the left anterior descending artery (LAD). An echocardiogram was performed to evaluate for structural heart disease. Shortly after administration of echo contrast the patient developed sudden-onset tachypnea and suffered a pulseless electrical activity cardiac arrest. She was treated for anaphylactic shock with epinephrine and high-dose steroids and achieved return of spontaneous circulation. Following the arrest an electrocardiogram revealed an anterolateral STEMI. The patient immediately underwent repeat angiography which revealed a 100% in-stent thrombosis of the LAD. The occlusion was successfully revascularized with a drug eluting stent with an Impella CP (Abiomed, Danvers MA) support. Subsequent laboratory exam demonstrated an elevated blood tryptase level consistent with an anaphylactic event. Discussion: We present a unique case of anaphylactic shock with acute coronary syndrome following administration of sulfur hexafluoride echo contrast. The incidence of anaphylaxis to echo contrast is less than one per million, and therefore it may not be immediately recognized as a mechanism of shock. Any prior reactions to polyethylene glycol should be noted before using these agents as this ingredient is thought to be the cause of anaphylaxis. In our case, diagnosis of anaphylaxis was confirmed by measuring the serum tryptase level. Tryptase is released from mast cells during allergic events, so this laboratory test with high specificity for anaphylaxis can be a useful tool in challenging cases such as this. Additionally, mast cell and platelet activation secondary to anaphylaxis may be an important mechanism of acute coronary syndrome with in-stent thrombosis.

HEREDITARY ALPHA TRYPTASEMIA MASKED AS ASTHMA EXACERBATION

<h3>Introduction</h3> Clinical phenotypes of hereditary alpha tryptasemia (HAT) are variable and can range from asymptomatic to anaphylaxis. Due to this broad range of presentations, diagnosis can be challenging, particularly if only one organ system is involved. <h3>Case Description</h3> An 8-year-old male presented to the emergency department with hypoxemia and stridor. His exam was notable for inspiratory and expiratory stridor with increased work of breathing. He received nebulized racemic epinephrine without improvement, and then had resolution of symptoms with intramuscular epinephrine and oral corticosteroids. Spirometry was suggestive but not diagnostic of asthma. Due to symptoms localized only to the respiratory tract, asthma was initially suspected. However, mast cell disorders were also considered since he required epinephrine before symptom improvement. Serum tryptase was elevated on initial and repeat testing. Genetic testing demonstrated increased copies of <i>TPSAB1</i>, consistent with HAT. <h3>Discussion</h3> Hereditary alpha tryptasemia is an autosomal dominant disorder resulting from increased copies of <i>TPSAB1</i> which encodes alpha tryptase. Disease severity varies from asymptomatic to anaphylaxis. Higher tryptase levels and increased symptom severity parallels increased number of <i>TPSAB1</i> copies. Serum tryptase level is the initial screening test. If elevated, genetic testing for <i>TPSAB1</i> should be performed. Though presentations with single organ involvement are not normally concerning for systemic disease, severe presentations of atopic diseases, including asthma, should prompt consideration of HAT. Treatment is symptom directed and may include antihistamines, mast cell stabilizers, leukotriene inhibitors, and epinephrine.

ELEVATED BASELINE SERUM TRYPTASE AND HEREDITARY ALPHA TRYPTASEMIA (HAT)

<h3>Introduction</h3> Hereditary alpha tryptasemia (HaT) is an autosomal dominant genetic trait characterized by elevated basal serum tryptase levels due to extra allelic copies of the tryptase alpha/beta 1 (TPSAB1) gene. HaT has been associated with multisystem complaints and as a modifier of mast cell-associated disorders and anaphylaxis. <h3>Case Description</h3> A 38-year-old male presented for evaluation of food and environmental allergies. He had severe oropharyngeal symptoms and a throat-closing sensation immediately after ingesting raw fruits and tree nuts. He also had symptoms of perennial allergic rhinoconjunctivitis with seasonal variation. Allergy skin testing showed IgE sensitivities to tree, grass and weed pollens, dust mites, mold spores, cat, dog, and cockroach. He had no IgE sensitivities to any of the fruits tested. He had IgE sensitivities to walnut, hazelnut, and almond. Given the severity of his oropharyngeal symptoms a baseline serum tryptase was checked, which was elevated at 20.3 mcg/L. Repeat determinations again showed baseline serum tryptase above 20 mcg/L. CBC with differential and CMP were within normal limits. 24-hour urinary histamine and N-methylhistamine were both within normal. Kit D16 mutation analysis was negative. TPSAB1 copy number analysis showed extra allelic alpha-tryptase copies, consistent with hereditary alpha tryptasemia (HaT). The patient received counseling and standard treatment for environmental/food allergies and tolerates allergen-specific immunotherapy. <h3>Discussion</h3> HaT is an inherited condition considered a biochemical trait and can be present in around 5% of the general population. Patients with elevated baseline serum tryptase may benefit from testing for extra allelic copies of TPSAB1.

KOUNIS SYNDROME, THE ALLERGIC HEART ATTACK

<h3>Introduction</h3> Seldom do allergic reactions progress to involve the heart. Kounis Syndrome is the occurrence of acute coronary syndrome associated with conditions of mast cell activation such as allergy hypersensitivities (1). Here, we describe a case in which an allergic reaction to injected Lidocaine and Kenalog leads to myocardial infarction. <h3>Case Description</h3> A 67-year-old female with cardiac risk factors and osteoarthritis underwent injection of her right ankle with Lidocaine and Kenalog. She developed diffuse erythematous rash with symptoms of lightheadedness, altered mentation, and chest discomfort. Upon admission, she received epinephrine. Electrocardiogram (EKG) demonstrated ST-segment elevation in inferior leads II, III, and aVF. Labs revealed serum tryptase level of 74.8 ug/L. The patient received intravenous (IV) Norepinephrine, IV diphenhydramine, IV Famotidine, IV methylprednisolone, Aspirin, and continuous IV heparin for emergent coronary angiography. The distal right coronary artery revealed occlusive thrombus burden, causing 95% stenosis. Percutaneous coronary intervention was performed with drug-eluting stent placement. Her symptoms resolved, and she was referred to an outpatient allergist. <h3>Discussion</h3> This case illustrates the type II variant of Kounis Syndrome in which inflammatory mediators from an allergic reaction induce atherosclerotic plaque destabilization and rupture in underlying coronary artery disease (CAD). Cardiovascular manifestations associated with allergic conditions are more common than initially perceived, suggesting a causal relationship between allergies and heart disease. This remains underdiagnosed by clinicians in practice (1,2). Biomarkers in allergies, such as serum tryptase, may provide a potential marker of CAD. Novel medications that stabilize mast cells and reduce inflammation known to control allergies may ultimately reduce cardiovascular events (4).

ANSWERS LIE IN THE COMPLETE BLOOD COUNT: A CASE OF EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS PRESENTING WITH ACUTE ST-WAVE ELEVATION MYOCARDIAL INFARCTION

ANSWERS LIE IN THE COMPLETE BLOOD COUNT: A CASE OF EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS PRESENTING WITH ACUTE ST-WAVE ELEVATION MYOCARDIAL INFARCTION

Aggressive Systemic Mastocytosis with a Relatively Non-aggressive Course

Background: Mastocytosis is a heterogeneous group of disorders that is characterized by excessive proliferation and pathologic accumulation of mast cells in various body tissues. The mast cells also have abnormal morphology and aberrant expression of surface receptors. Clinical Description: A 4-year-old boy was brought with a history of generalized skin lesions since birth and abdominal distension for 3 years. The diagnosis had not been established to date. General physical examination revealed severe acute malnutrition, pallor, dental staining, facial hypertrichosis, polymorphous skin lesions (cicatricial alopecia, diffuse erythema, multiple plaques of variable diameter, skin-colored nodules, and hypertrophic irregular scars), and positive Darier's sign. He also had hepatosplenomegaly. The differentials considered were congenital erythropoietic porphyria, systemic mastocytosis (SM), multifocal Langerhans cell histiocytosis, and linear immunoglobulin A bullous dermatosis. The presence of mast cells on skin biopsy and elevated serum tryptase levels led us to suspect SM and perform bone marrow studies. The diagnosis of “aggressive” SM was initially made on the application of the diagnostic criteria but revised to “smoldering” SM with the emergence of Vitamin B12 deficiency as the probable cause of pancytopenia. Management: Management was planned by a multidisciplinary team: pediatrician, dermatologist, and hematopathologist. The parents were counseled about the nature, natural history, treatment options, and prognosis of the disorder. The child was provided with nutritional rehabilitation and medication for the cutaneous symptoms (selective histamine H1 receptor inverse agonist, H2-receptor antagonist, and application of topical tacrolimus and calamine lotion). Conclusion: The prognosis varies according to subtype. Careful correlation of clinical and laboratory investigations is required when applying the diagnostic criteria for staging.

Hypersensitivity to Intravenous Iron Preparations.

Intravenous iron is widely used for the treatment of iron deficiency anemia when adherence to oral iron replacement is poor. Acute hypersensitivity reactions during iron infusions are very rare but can be life threatening. Major risk factors for hypersensitivity reactions include a previous reaction to an iron infusion, a fast iron infusion rate, multiple drug allergies, atopic diseases, high serum tryptase levels, asthma, and urticaria. The management of iron infusions requires meticulous observation, and, in the event of an adverse reaction, prompt recognition and severity-related interventions by well-trained medical and nursing staff. Avoidance of IV iron products in patients with iron hypersensitivity reactions may not be considered as a standard practice.

Hereditary alpha-tryptasemia: Brief overview of current knowledge and proposal of indications

Human tryptases are serine proteases, which are synthesized nearly exclusively by mast cells (MCs). Immature pro-tryptases, under the form of α- and β-monomers are constantly released by MCs, can be measured in the serum of normal individuals and constitute the basal serum tryptase (bST) level, usually below 6μg/L. By contrast, tetramers of tryptases, which are the mature forms of the enzyme, are normally retained in the secretory granules of MCs. These mature (α- and β-tetramers of tryptase) are only released when MC are activated by different stimuli, leading to a transient increase in serum tryptase level. Such event occurs for instance after IgE-mediated MC degranulation (immediate hypersensitivity reaction). The mature tryptases, through their various biological activities, account for the pathophysiology of immediate hypersensitivity. Of note, recent studies have reported that around 5% of the general population present with increased bST levels related to a genetic trait called hereditary α-tryptasemia (HαT). While there is still a debate on the fact that HαT+ patients may present more frequently various clinical phenotypes, it is now clearly established that the clinical phenotype of patients with primary (clonal) MC disorders, including mastocytosis, is modified by the presence of the HαT trait. In addition, HαT penetrance seems clearly increased in such patients (up to 18% of the cases), leading to the conclusion that HαT is a disease penetrance and phenotype modifier. In the present manuscript, we will describe briefly the genetic patterns of HαT and the clinical phenotypes encountered in HαT+ patients harboring or not a clonal MC disorder. Finally, we will describe the situations when the search for HαT in human can be considered and the preferred method to be used for such investigation.

Clinical utility of serum tryptase levels in pediatric anaphylaxis.

Introduction: This study aimed to evaluate the preliminary diagnosis, demographic characteristics, and outcomes of patients whose serum total tryptase levels were measured while in a tertiary pediatric hospital and to ascertain the role of serum tryptase levels in the etiology, diagnosis, severity, and course of systemic anaphylaxis. Methods: Patients ages between 1 month and 17 years who were followed up in the pediatric emergency department or as inpatients and with a diagnosis of immediate-type reactions between September 1, 2019, and August 31, 2021, were included in the study. Patient data were obtained retrospectively by examination of medical records and patient observation forms. Results: It was determined that serum tryptase levels were measured in a total of 310 patients during the study period. One hundred and fifty-five patients who met the defined diagnostic criteria were named as the anaphylaxis group and their data were detailed. The serum tryptase elevation was detected in 15.5% of the patients among the samples that met the anaphylaxis diagnostic criteria. No relationship was found between the serum total tryptase levels, the triggering factor, and the severity of anaphylaxis. Discussion: Anaphylaxis is a complex syndrome that involves different phenotypes that develop with various triggers in which different immunologic pathways, cell types, and mediators play a role. Serial measurements, including the basal value measured at least 24 hours after the symptoms disappear, are useful to confirm the diagnosis and guide the diagnostic tests during the follow-up, especially allergy evaluation.

Anaphylaxis: Mediators, Biomarkers, and Microenvironments.

The life-threatening nature of anaphylactic reactions has increased interest in discovering new biomarkers that could improve diagnosis and prevention. However, the diverse nature of the clinical features and the etiology and pathogenesis of anaphylaxis hinder the identification of valuable molecular indicators of disease. Most studies on anaphylaxis focus on the immune system. Anaphylactic reactions are characterized primarily by IgE-mediated activation of mast cells and basophils and release of mediators. Determination of serum tryptase levels is the main in vitro test used to confirm the reaction, although there are no biomarkers that can predict it. Nevertheless, recent research has postulated that alternative pathways, cell types, and systems are involved. Consequently, various molecular products have been explored and considered potential biomarkers, although none of them are yet used in clinical practice. The products that are altered in patients with anaphylaxis include vasoactive agents, proteases, proteoglycans, lipids, interleukins, cytokines, products of the complement-contact and coagulation systems, circulating proteins, extracellular vesicles, microRNAs, and metabolites. The recognition of biological processes and molecular pathways affecting the microenvironments involved in anaphylaxis will considerably improve clinical practice and the identification of better molecular markers. We offer a broad review of the various mediators described in anaphylaxis, consider their usefulness as potential biomarkers of this pathological event, and examine their role in the molecular basis of the reaction.

Functional imaging with dual-energy computed tomography for supplementary non-invasive assessment of mast cell burden in systemic mastocytosis

Systemic mastocytosis (SM) is characterized by multifocal accumulation of neoplastic mast cells (MCs), predominately affecting the bone marrow (BM). Imaging with computed tomography (CT) is used for assessment of bone mineral density and structure. However, the value of functional imaging with dual-energy CT (DECT) and the assessment of virtual-non-calcium attenuation values (VNCa-AV) for visualization of BM disease burden in SM has not yet been assessed. DECT of the axial skeleton was performed in 18 patients with SM (indolent SM [ISM], n = 6; smoldering SM [SSM]/advanced SM [AdvSM], n = 12) and 18 control subjects. VNCa-AV were obtained in 5 representative vertebraes per patient and correlated with laboratory, morphologic and molecular parameters. VNCa-AV strongly correlated with quantitative BM MC infiltration (r = 0.7, R2 = 0.49, P = 0.001) and serum tryptase levels (r = 0.7, R2 = 0.54, P < 0.001). Mean VNCa-AV were significantly higher in SSM/AdvSM as compared to ISM (− 9HU vs. − 54HU, P < 0.005) and controls (− 38HU, P < 0.005). Nine of 10 (90%) patients with a VNCa-AV > − 30HU and 7/7 (100%) patients with a VNCa-AV > − 10HU had SSM or AdVSM. BM VNCa-AV provide information about the MC burden of SM patients and correlate with SM subtypes. DECT may therefore serve as a supplementary tool for SM diagnosis, subclassification and monitoring in a one-stop-shop session.

Mast cells and tryptase are linked to itch and disease severity in mycosis fungoides: Results of a pilot study.

IntroductionIn mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, itch is a frequent clinical symptom. Whether mast cells (MCs), eosinophils (Eos) or their mediators play a role in MF-associated itch or disease severity is controversially discussed. Here, we explored the role of MC and Eo numbers in the skin as well as blood levels of their mediators in disease severity and itch.MethodsIn 10 patients with MF and 10 matched control subjects we assessed disease severity, itch, and quality of life impairment using dedicated tools such as the mSWAT, ItchyQoL and DLQI. We analyzed skin biopsies and measured serum levels of tryptase, a mast cell mediator, as well as of the eosinophil products eosinophil cationic protein (ECP) and major basic protein (MBP).ResultsThe presence of chronic itch, in four of 10 patients, was associated with significantly higher disease severity (mSwat), larger body surface area affected, and stronger QoL impairment (Itchy-Qol, DLQI). Serum levels of tryptase, but not ECP and MBP, were linked with patient-reported disease severity, body surface area affected, and the presence of itch. Three of the four patients with chronic itch, but none of the six patients without, had tryptase levels above >6µg/l. Numbers of MCs in the papillary dermis were higher in MF skin lesions then in non-lesional skin of MF patients and skin of healthy controls.DiscussionThe MC-mediator tryptase, in MF, is linked to disease activity and impact, most prominently to itch. Our findings call for larger studies that explore the role of MCs, tryptase and other MC mediators as drivers of itch and their role in MF pathogenesis.

Patients with elevated basal tryptase serum levels should be tested for hereditary alpha-tryptasemia.

Patients with elevated basal tryptase serum levels should be tested for hereditary alpha-tryptasemia.

Temporal variation of tryptase and interlaboratory variability

The diagnosis of anaphylaxis and mast cell activation syndrome (MCAS) relies largely on history with laboratories assisting in diagnosis as an objective demonstration of mast cell activation.1-3 Serum tryptase is the most readily available and typically used marker in this regard.4 Consensus expert opinion recommends using an objective rise in mast cell mediators as a requirement for the diagnosis of MCAS, and 1 equation that is typically used is an increase in serum tryptase level above the individual's baseline of 20% plus 2 ng/mL.

Presence of neoplastic mast cells in ascites in advanced systemic mastocytosis

Systemic mastocytosis (SM) is characterized by clonal expansion of mast cells (MCs) in different organs, usually in bone marrow (BM) and variably also in other tissues like skin and gastrointestinal tract.1-3 Clinical manifestations are heterogeneous and can include MC mediator symptoms and a dysfunction of various organ systems, such as cytopenia, hepatosplenomegaly, ascites, and weight loss. Most patients with SM carry the activating mutation KIT D816V. Typically, patients with SM are also characterized by elevated serum levels of tryptase, an enzyme produced by MCs, and aberrant expression of CD25 and/or CD2 on MCs in BM and possibly other tissues.

Systemic Mastocytosis and Other Entities Involving Mast Cells: A Practical Review and Update.

Simple SummaryIn this article, we outline recent updates in systemic mastocytosis (SM) classification, including the bone marrow mastocytosis subtype; and discuss the mast cell leukemia subtype (acute or chronic), the rare variant of SM known as well-differentiated SM (morphologic variant), and other diseases involving mast cells (i.e., myelomastocytic leukemia and mast cell activation syndrome) that may be diagnostically challenging. We also provide a concise clinical update of new adjusted risk stratification models and overview new treatments that were approved for advanced SM (midostaurin, avapritinib).Evidence in the recent literature suggests that the presentation spectrum of mast cell neoplasms is broad. In this article, we elaborate on recent data pertaining to minor diagnostic criteria of systemic mastocytosis (SM), including sensitive testing methods for detection of activating mutations in the KIT gene or its variants, and adjusted serum tryptase levels in cases with hereditary α-tryptasemia. We also summarize entities that require differential diagnosis, such as the recently reclassified SM subtype named bone marrow mastocytosis, mast cell leukemia (an SM subtype that can be acute or chronic); the rare morphological variant of all SM subtypes known as well-differentiated systemic mastocytosis; the extremely rare myelomastocytic leukemia and its differentiating features from mast cell leukemia; and mast cell activation syndrome. In addition, we provide a concise clinical update of the latest adjusted risk stratification model incorporating genomic data to define prognosis in SM and new treatments that were approved for advanced SM (midostaurin, avapritinib).

Efficacy of avapritinib versus best available therapy in the treatment of advanced systemic mastocytosis

Advanced systemic mastocytosis (AdvSM) is a rare myeloid neoplasm associated with poor overall survival (OS). This study (NCT04695431) compared clinical outcomes between patients with AdvSM treated with avapritinib in the Phase 1 EXPLORER (NCT0256198) and Phase 2 PATHFINDER (NCT03580655) trials (N = 176) and patients treated with best available therapy (BAT; N = 141). A multi-center, observational, retrospective chart review study was conducted at six study sites (four European, two American) to collect data from patients with AdvSM who received BAT; these data were pooled with data from EXPLORER and PATHFINDER. Comparisons between outcomes of OS, duration of treatment (DOT), and maximum reduction in serum tryptase were conducted between the treatment cohorts, with adjustment for key covariates. The results indicated that the avapritinib cohort had significantly better survival (adjusted hazard ratio (HR) (95% confidence interval (CI)): 0.48 (0.29, 0.79); p = 0.004) and significantly longer DOT (HR: 0.36 (0.26, 0.51); p < 0.001) compared to the BAT cohort. Additionally, the mean difference in percentage maximum reduction in serum tryptase levels was 60.3% greater in the avapritinib cohort (95% CI: −72.8, −47.9; p < 0.001). With no randomized controlled trials comparing avapritinib to BAT, these data offer crucial insights into the improved efficacy of avapritinib for the treatment of AdvSM.

Comparison of serum tryptase as a diagnostic oncological marker in canine versus human mast cell neoplasms

Canine mast cell tumors (MCTs) are a promising translational model for human mast cell neoplasms with striking similarities such as the Darier's sign and mutations in the KIT gene. Whereas mast cell neoplasms are rare in humans, MCTs are the most frequent malignant neoplasms of the skin in dogs. In human systemic mastocytosis, serum tryptase is an important diagnostic criterion. Surprisingly, serum tryptase levels were not yet investigated in dogs with MCTs. Therefore, the aim of this study was to investigate whether serum tryptase levels in dogs with cutaneous MCTs were elevated compared to those of a non-MCT control group. As a secondary aim, it was investigated whether surgical manipulation caused an increase in serum tryptase in canine MCT patients. A total of 48 serum samples were collected from dogs with different grades of cutaneous MCTs (n = 24) and non-MCT controls (n = 24). In dogs with cutaneous MCTs, blood was collected prior to and within 1 h after surgery. Serum tryptase levels were measured using a commercially available canine-specific ELISA kit. No significant difference in serum tryptase levels was found between cutaneous MCT patients and non-MCT controls, nor in these levels before versus after surgery. Our findings in canine cutaneous MCTs are in accordance with human cutaneous mastocytosis, where serum tryptase levels tend to remain within the normal range. However, despite various similarities between aggressive mast cell tumors in dogs and humans, serum tryptase cannot be considered a diagnostic biomarker in dogs with cutaneous MCTs as part of a comparative oncologic strategy.

Intracutaneous Skin Tests and Serum IgE Levels Cannot Predict the Grade of Anaphylaxis in Patients with Insect Venom Allergies.

BackgroundAllergies against Hymenoptera venoms are a major cause of severe anaphylaxis. Risk assessment for subjects with suspected allergy is difficult because there are currently no biomarkers that predict the likelihood of high-grade anaphylaxis other than several associated comorbidities.ObjectiveWe investigated the relationship between the severity of anaphylaxis and the results of intracutaneous skin tests (ICTs) together with serum levels of tryptase, total IgE, and venom-specific IgE, IgG, and IgG4.MethodsWe performed a retrospective evaluation of 194 patients who presented to a single medical center with allergies to bee venoms (Apis mellifera, Bombus spp.; n=24, 12.4%), vespid venoms (Vespula spp., Vespa spp., Polistes spp.; n=169, 87.1%), or both (n=1, 0.5%).ResultsIndex bee stings occurred earlier in the year than vespid stings, although the latter were reported more frequently overall. On average, subjects who previously experienced grade IV anaphylaxis required higher dosages of venom to yield positive ICTs than those who exhibited lower grade responses. Patients diagnosed with grade IV anaphylaxis exhibited significantly lower levels of venom-specific IgE and IgG and trended toward elevated levels of tryptase. No significant differences in average levels of venom-specific IgG4 and total IgE were observed.ConclusionOur findings reveal that intracutaneous skin testing and levels of venom-specific IgE do not predict the degree of anaphylaxis that develops in patients with venom allergy. Furthermore, the month of the index sting is not a reliable means to differentiate bee from vespid stings in patients presenting with an uncertain history.

Mast cell sarcoma: clinicopathologic and molecular analysis of 10 new cases and review of literature

AbstractMast cell sarcoma (MCS) is an exceedingly rare form of mastocytosis characterized by invasive malignant mast cell growth and metastatic potential. Diagnosis of MCS is very challenging due to its marked morphologic variations and significant immunophenotypic overlap with other neoplasms. In this study, we undertook an extensive study of 10 cases of MCS from our series, with review of additional 24 cases from the literature, to better clarify the clinicopathologic and molecular features of MCS. From the analyses of our 10 cases, MCS equally involved males and females with a median age of 54.5 years (range 1-63). The bone was the most common site of involvement, as noted in 9/10 of cases. Two patients had prior germ cell tumors (mediastinal germ cell tumor and ovarian dysgerminoma), and concurrent systemic mastocytosis was noted in one of nine patients. Serum tryptase levels were elevated in 6/7 of patients, and 3/9 of patients had mast cell activation symptoms. Morphologically, the tumor cells were typically large and pleomorphic with frequent reactive eosinophils. By immunohistochemical staining, MCS consistently expressed CD43 (8/8), CD117 (10/10), and mast cell tryptase (10/10), as well as CD13 (3/3) and CD33 (10/10), with variable positivity of CD2 (1/9), CD25 (4/9), CD30 (5/8), and CD68 (5/9). Notably, KIT D816V was not detected in nine cases in our study, although two cases had other mutations of KIT gene. Seven out of eight patients received chemotherapy with or without radiotherapy. However, the response was poor, and four out of eight patients died within a median follow-up interval of five months. Taken together, there are no standardized therapeutic regimens available for MCS at this time, and the prognosis is dismal. Therefore, it is critical to further investigate and characterize this rare entity, with the hope of improving diagnostic accuracy and providing more effective, targeted therapies.