Epidemiology of mastocytosis: a population-based study (Sweden).

BACKGROUND: Mastocytosis is a disease characterized by accumulation of aberrant mast cells and mediator-related symptoms and is divided into systemic mastocytosis (SM) and cutaneous mastocytosis (CM). The epidemiology of mastocytosis remains incompletely understood. OBJECTIVE: To estimate the incidence, prevalence, overall survival (OS) and burden of comorbidities in adult mastocytosis patients identified in Swedish population-based registries. METHODS: Individuals (≥ 20 years of age) with a mastocytosis diagnosis in the National Patient Register (NPR) and/or the Swedish Cancer Register (SCR) between 2001 and 2018, were identified. In a matched cohort design, for each case five randomly selected mastocytosis-free comparators matched on age, sex, and county of residence were chosen from the Population Register. The Kaplan-Meier method was used to compare OS between individuals with mastocytosis and comparators. Information on concomitant disease at baseline was assessed by use of the Charlson Comorbidity Index (CCI). RESULTS: We identified 2,040 adults with a mastocytosis diagnosis yielding an annual incidence of 1.56 per 100,000 (95% CI 1.29-1.87) and a prevalence of 23.9 per 100,000 (95% CI 22.8-25.0). The comorbidity burden was higher, and the OS lower, in patients with mastocytosis compared to comparators. INTERPRETATION: We found a higher incidence and prevalence of mastocytosis compared to assessments in other settings and confirmed that the prognosis generally is favorable. Of special note was evidence of a higher comorbidity burden in mastocytosis patients compared to the background population. LIMITATIONS: Underreporting and inconsistencies in the use of diagnostic codes.

Mastocytosis in the skin in dogs: A multicentric case series.

Canine cutaneous mastocytosis (CM) is rare in contrast to canine mast cell tumours. In humans, CM commonly affects children and is usually indolent with possible spontaneous resolution. Systemic mastocytosis (SM) with bone marrow involvement typically affects adults, can have a poor outcome, and often includes skin lesions. 'Mastocytosis in the skin' (MIS) is the preferred term of skin lesions, if bone marrow evaluations are not available, which is often the cases in dogs. In human SM and CM, KIT mutations are often detected. The veterinary literature suggests clinical resemblances between human and canine MIS, but data is limited, and KIT mutations are rarely assessed. This retrospective study describes clinicopathological findings, treatment and outcome of 11 dogs with suspected MIS. Dogs with multiple mast cell tumours were excluded. Histopathology reports (n = 5) or slides (n = 6) were reviewed. KIT mutation analysis including exons 8, 9, 11, 14 and 17 were analysed in eight dogs. Median age at diagnosis was 4 years (range, 1-12). Typical clinical signs included multifocal to generalised nodules and papules. Histologically, skin lesions were characterised by dermal infiltration of well-differentiated mast cells. KIT mutations were detected in 3/8 dogs (exon 9: n = 2; exon 11: n = 1). One dog had mastocytaemia suggesting possible SM. Glucocorticoids were mostly successful with lesion improvement in all treated dogs (n = 8). This cohort highlights resemblances between human and canine MIS. Further studies are required to confirm these findings and establish diagnostic criteria for CM and MIS associated with SM in dogs.

Granularity in disease classification impacts survival prediction in advanced systemic mastocytosis: A single institution study of 329 informative cases.

The World Health Organization (WHO) classification system categorizes advanced systemic mastocytosis (SM-Adv) into aggressive SM (ASM), mast cell leukemia (MCL), and SM with associated hematological neoplasm (SM-AHN). By contrast, the International Consensus Classification (ICC) requires "immature" MC cytomorphology for the diagnosis of MCL and limits SM-AHN to myeloid neoplasms (SM-AMN). The current study includes 329 patients with SM-Adv (median age 65 years, range 18-88; males 58%): WHO subcategories SM-AHN (N = 212; 64%), ASM (N = 99; 30%), and MCL (N = 18; 6%); ICC subcategories SM-AMN (N = 190; 64%), ASM (N = 99; 33%), and MCL (N = 9; 3%); WHO-defined MCL with "mature" MC cytomorphology and SM-AHN associated with lymphoid neoplasms were operationally labeled as "MCL-mature" (N = 9) and SM-ALN (N = 22), respectively, and distinguished from ICC-defined MCL and SM-AMN. Multivariable analysis that included the Mayo alliance risk factors for survival in SM (age >60 years, anemia, thrombocytopenia, increased alkaline phosphatase) revealed more accurate survival prediction with the ICC versus WHO classification order: (i) survival was significantly worse with MCL-immature versus MCL-mature (hazard ratio [HR] 15; p < .01), (ii) prognostic distinction between MCL and SM-AHN/AMN was confirmed in the context of ICC (HR 9.3; p < .01) but not WHO classification order (p = .99), (iii) survival was similar between MCL-mature and SM-AMN (p = .18), and (iv) SM-AMN (HR 1.7; p < .01) but not SM-ALN (p = .37) was prognostically distinct from ASM. The current study provides evidence for the independent prognostic contribution of both the ICC system for SM-Adv and the Mayo alliance risk factors for survival in SM.

Advanced systemic mastocytosis-Revised classification, new drugs and how we treat.

Mastocytosis constitutes the neoplastic proliferation of mast cells and is broadly classified into systemic mastocytosis (SM), cutaneous mastocytosis and mast cell sarcoma. SM is further partitioned into advanced (AdvSM) and non-advanced (SM-non-Adv) subcategories. AdvSM includes aggressive SM (ASM), SM with an associated haematological neoplasm (SM-AHN) and mast cell leukaemia (MCL). In 2022, two separate expert committees representing the 5th edition of the World Health Organization (WHO5) and the International Consensus (ICC) classification systems submitted revised classification criteria for SM, highlighted by the ICC-proposed incorporation of mast cell cytomorphology in the diagnostic criteria for MCL and myeloid-lineage restriction for the AHN component in SM-AHN. Recent developments in SM also include the introduction of KIT-targeting tyrosine kinase inhibitors (KITi), including midostaurin and avapritinib, both drugs have shown potent activity in reducing mast cell and mutant KIT burden and alleviating mast cell-associated organopathy and mediator symptoms; however, their overall impact on survival or superiority over pre-KITi era treatment options (e.g. cladribine) has not been studied in a controlled setting. In the current review, we provide a summary of recent changes in disease classification and an analysis of recent clinical trials and their impact on our current treatment approach in AdvSM.

Tumor necrosis factor α promotes clonal dominance of KIT D816V+ cells in mastocytosis: role of survivin and impact on prognosis.

ABSTRACT: Systemic mastocytosis (SM) is defined by the expansion and accumulation of neoplastic mast cells (MCs) in the bone marrow (BM) and extracutaneous organs. Most patients harbor a somatic KIT D816V mutation, which leads to growth factor-independent KIT activation and accumulation of MC. Tumor necrosis factor α (TNF) is a proapoptotic and inflammatory cytokine that has been implicated in the clonal selection of neoplastic cells. We found that KIT D816V increases the expression and secretion of TNF. TNF expression in neoplastic MCs is reduced by KIT-targeting drugs. Similarly, knockdown of KIT or targeting the downstream signaling cascade of MAPK and NF-κB signaling reduced TNF expression levels. TNF reduces colony formation in human BM cells, whereas KIT D816V+ cells are less susceptible to the cytokine, potentially contributing to clonal selection. In line, knockout of TNF in neoplastic MC prolonged survival and reduced myelosuppression in a murine xenotransplantation model. Mechanistic studies revealed that the relative resistance of KIT D816V+ cells to TNF is mediated by the apoptosis-regulator BIRC5 (survivin). Expression of BIRC5 in neoplastic MC was confirmed by immunohistochemistry of samples from patients with SM. TNF serum levels are significantly elevated in patients with SM and high TNF levels were identified as a biomarker associated with inferior survival. We here characterized TNF as a KIT D816V-dependent cytokine that promotes clonal dominance. We propose TNF and apoptosis-associated proteins as potential therapeutic targets in SM.

No indication of aberrant neutrophil extracellular trap release in indolent or advanced systemic mastocytosis.

In disease states with chronic inflammation, there is a crosstalk between mast cells and neutrophil granulocytes in the inflamed microenvironment, which may be potentiated by tryptase. In systemic mastocytosis (SM), mast cells are constitutively active and tryptase is elevated in blood. Mast cell activation in SM leads to symptoms from various organs depending on where the active mast cells reside, for example, palpitations, flush, allergic symptoms including anaphylactic reactions, and osteoporosis. Whether neutrophil function is altered in SM is not well understood. In the current study, we assessed nucleosomal citrullinated histone H3 (H3Cit-DNA) as a proxy for neutrophil extracellular trap release in plasma from 55 patients with indolent and advanced SM. We observed a strong trend towards a correlation between leukocyte count, eosinophil count and neutrophil count and H3Cit-DNA levels in patients with advanced SM but not in indolent SM; however, no differences in H3Cit-DNA levels in SM patients compared with healthy controls. H3Cit-DNA levels did not correlate with SM disease burden, tryptase levels, history of anaphylaxis or presence of cutaneous mastocytosis; thus, there is no evidence of a general neutrophil extracellular trap release in SM. Interestingly, H3Cit-DNA levels and leukocyte counts were elevated in a subgroup of SM patients with aberrant mast cell CD2 expression, which warrants further investigation. In conclusion, we found no evidence of global increase in neutrophil extracellular trap release in SM.

Mastocytosis demystified.

Mastocytosis is a rare, clinically heterogenous clonal hematological neoplasm. Over 95% of patients harbor the driver KIT D816V mutation resulting in mast cell (MC) accumulation and proliferation in various organs, leading to variable symptom manifestations that result from MC mediator release in patients with systemic mastocytosis (SM) and end-organ damage in those with advanced SM. The accurate diagnostic and clinical classification of patients with SM is vital to underpin appropriate treatment options and personalize therapy. This review evaluates the current diagnostic criteria, clinical classification, risk stratification, and therapeutic options available for adult patients with nonadvanced and advanced SM.

An Unusual Transition from Cutaneous to Systemic Mastocytosis in a Pediatric Patient.

Background: Cutaneous mastocytosis (CM) occurs when abnormal mast cells accumulate in the skin, whereas in systemic mastocytosis (SM), accumulation also occurs in other tissues. A transition from CM to SM is an atypical occurrence in pediatric patients. Case Presentation: An 8-month-old female presented with a 3-month history of whole body hyperpigmented macules with a normal serum tryptase level, consistent with a diagnosis of CM. At age 2.5 years, cutaneous lesions increased and repeat serum tryptase levels were elevated. Subsequent positive peripheral blood KIT D816V mutation testing furthered concern for a monoclonal mast cell disorder; therefore, prompting a bone marrow biopsy which was consistent with a diagnosis of SM. Conclusion: Our case depicts the possible transition from CM to SM in a pediatric patient. Despite an initial presentation consistent with a diagnosis of CM, watchful monitoring for signs and symptoms indicative of systemic involvement may be warranted in some pediatric patients.

When Mast Cells Run Amok: A Comprehensive Review and Case Study on Severe Neonatal Diffuse Cutaneous Mastocytosis.

Neonatal diffuse cutaneous mastocytosis (NDCM) is defined as the infiltration of the epidermis by a clonal proliferation of mast cells, observed at birth, without initial signs of systemic involvement. The typical driver mutation is in the KIT gene. We report a rare case of a boy, born at term, already presenting at birth with generalized subcutaneous nodules on the face, scalp, trunk, back, hands, and feet. The spleen, liver, and inflammatory markers were normal at birth. Tryptase was significantly elevated. A bone marrow biopsy showed no mast cell involvement at age 2 months. A punch biopsy at age 2 months revealed CD117-positive cells diffusely infiltrating the skin, with subsequent DNA NGS sequencing for the formalin-fixed paraffin embedded tissue (FFPE) identifying the pathogenic NM_000222.3:c.1504_1509dup; p.(Ala502_Tyr503dup) variant in the KIT gene previously associated with cutaneous mastocytosis. At 2 years follow-up, he had splenomegaly and multiple cervical and inguinal adenopathy, while the skin nodules persisted, especially on the scalp with accompanying pruritus. He received oral and local sodium cromoglycate, oral antihistamines, antibiotic cream for skin infection, and iron supplementation; however, compliance to treatment was relatively low. The prognosis is difficult to predict, as he developed systemic involvement, failure to thrive, and mild psychomotor delay. A case aggregation of NDCM reported in the literature was performed to provide a comprehensive overview of this rare pathology, to better understand the prognosis. NDCM is a life-threatening disease with severe complications. Almost half had severe complications, such as mast hepatosplenomegaly, adenopathy, bacterial infections, mast cell leukaemia, and systemic involvement.

Salivary Cystatin D Interactome in Patients with Systemic Mastocytosis: An Exploratory Study.

Mastocytosis, a rare blood disorder characterized by the proliferation of clonal abnormal mast cells, has a variegated clinical spectrum and diagnosis is often difficult and delayed. Recently we proposed the cathepsin inhibitor cystatin D-R26 as a salivary candidate biomarker of systemic mastocytosis (SM). Its C26 variant is able to form multiprotein complexes (mPCs) and since protein-protein interactions (PPIs) are crucial for studying disease pathogenesis, potential markers, and therapeutic targets, we aimed to define the protein composition of the salivary cystatin D-C26 interactome associated with SM. An exploratory affinity purification-mass spectrometry method was applied on pooled salivary samples from SM patients, SM patient subgroups with and without cutaneous symptoms (SM+C and SM-C), and healthy controls (Ctrls). Interactors specifically detected in Ctrls were found to be implicated in networks associated with cell and tissue homeostasis, innate system, endopeptidase regulation, and antimicrobial protection. Interactors distinctive of SM-C patients participate to PPI networks related to glucose metabolism, protein S-nitrosylation, antibacterial humoral response, and neutrophil degranulation, while interactors specific to SM+C were mainly associated with epithelial and keratinocyte differentiation, cytoskeleton rearrangement, and immune response pathways. Proteins sensitive to redox changes, as well as proteins with immunomodulatory properties and activating mast cells, were identified in patients; many of them were involved directly in cytoskeleton rearrangement, a process crucial for mast cell activation. Although preliminary, these results demonstrate that PPI alterations of the cystatin D-C26 interactome are associated with SM and provide a basis for future investigations based on quantitative proteomic analysis and immune validation.

A Review of the Clinical Features and Management of Systemic Congenital Mastocytosis through the Presentation of An Unusual Prenatal-Onset Case.

Mastocytosis is a heterogeneous group of rare hematological disorders that can occur in infancy. We report a 16-year-old girl who presented with an aggressive form of systemic congenital mastocytosis, associated with a significant global developmental delay, deafness, and multiple anomalies. At 4 years of age, she developed a germinoma presenting as an invasive spinal mass. Extensive cytogenetic, metabolic, and molecular genetic studies that included whole-exome sequencing studies revealed a KIT alteration (NM_000222.3(KIT):c2447A > 7 pAsp816Val) and likely pathogenic variant in the DNA from peripheral blood and skin lesions. C-kit was also found to be overexpressed in the spinal tumor cells. We compared the features of this child to those of six previously reported pediatric patients with cutaneous mastocytosis, microcephaly, microtia, and/or hearing loss reported in OMIM as mastocytosis, conductive hearing loss, and microtia (MIM 248910), for which the etiology has not yet been determined. This report extends the currently recognized spectrum of KIT-related disorders and provides clues as to the potential etiology of a syndromic form of congenital mastocytosis. International efforts to understand the benefits of long-term targeted therapy with tyrosine kinase inhibitors for this KIT-altered rare disease should continue to be evaluated in clinical trials.

KIT Mutations and Other Genetic Defects in Mastocytosis: Implications for Disease Pathology and Targeted Therapies.

A KIT activating mutation (usually KIT D816V) is detected in neoplastic cells in greater than 90% of indolent patients with systemic mastocytosis (SM). In more advanced variants of SM, additional genetic defects can be found in several myeloid malignancy-related genes, which can be detected by applying next-generation sequencing. Currently, the techniques recommended to detect the KIT D816V mutation and quantify the mutational burden in peripheral blood, bone marrow, or other organs/tissues are allele specific-quantitative PCR or droplet digital PCR. These techniques are useful for diagnosis, prognostication, follow-up and monitoring of therapeutic efficacy of cytoreductive agents in patients with SM.

Measuring Symptom Severity and Quality of Life in Mastocytosis.

Mastocytosis is a heterogeneous disease with a wide spectrum of signs, symptoms, and concomitant disorders, such as skin lesions, anaphylaxis, osteoporosis, gastrointestinal involvement, and organomegaly. Disease specificity for frequently reported symptoms, such as fatigue, headache, anxiety, and brain fog, is poorly defined and need to be addressed in further studies. Patients with CM and non-AdvSM are mostly affected by mast cell mediator-related symptoms, whereas in AdvSM symptoms also result from organ damage, which makes their assessment challenging. In this paper we discuss approaches currently used to measure symptom burden and QoL impairment in relation to the clinical phenotype.

Effect of Gender and Special Considerations for Women in Mastocytosis and Anaphylaxis.

This article reviews the effects of gender on anaphylaxis in general and focuses on mastocytosis-specific issues. Incidence of anaphylaxis is increased in female compared with male patients during the pubertal years through the fifth decade of life, in which these disparities decrease. Estrogen is thought to increase the severity of anaphylaxis through increased endothelial nitric oxide synthase release. Despite this, all-cause fatal anaphylaxis does not appear to show a gender predilection. Systemic mastocytosis incidence is higher in women; however, mortality is increased in men owing to increased molecular and cytogenetic abnormalities.

Small bowel obstruction: a rare presentation of systemic mastocytosis.

Mastocytosis (MC) is a heterogeneous group of disorders characterised by abnormal growth, neoplastic proliferation and accumulation of mast cells. Approximately, 80% of patients with MC have evidence of skin involvement, while the rest may involve the gastrointestinal tract, liver, spleen or bone. Isolated gastrointestinal presentation of aggressive MC without bone marrow involvement and cutaneous symptoms is rare. Isolated MC with tumour cells infiltrating the ileum presenting with mechanical obstruction has not been reported in the literature to date. Here, we present a case of a patient in his late 50s who presented with malignant MC of the small bowel with obstruction in the emergency surgical outpatient department. The patient underwent surgical resection of the affected bowel. Histopathological examination along with immunohistochemistry revealed malignant MC. The further evaluation consisted of bone marrow biopsies, PET CT and other mutation analyses. However, the patient succumbed to death during the further course of treatment. The differential of MC must be kept in mind when there is the presence of abnormal hematopoietic cells in gastrointestinal biopsies even in the absence of cutaneous manifestations and bone marrow abnormalities.