Review

Authors: Scott Veitch, Deepti H Radia

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.

Topics: Adult; Humans; Mastocytosis; Mastocytosis, Systemic; Mast Cells; Proto-Oncogene Proteins c-kit; Mutation

PubMed: 38066855
DOI: 10.1182/hematology.2023000505

Review

Authors: Lawrence B Afrin, Mary B Ackerley, Linda S Bluestein...

The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of "mast cell activation syndrome" (MCAS) grown significantly. Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a "consensus" (re-termed here as "consensus-1"). Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as "consensus-2"), resembling "consensus-1" in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment). Overdiagnosis by "consensus-2" criteria has potential to be problematic, but underdiagnosis by "consensus-1" criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement. We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful.

Topics: Consensus; Humans; Mast Cells; Mastocytosis

PubMed: 32324159
DOI: 10.1515/dx-2020-0005

Review

Authors: Peter Valent, Cem Akin, Wolfgang R Sperr...

Mastocytosis is a heterogeneous group of neoplasms defined by a numerical increase and accumulation of clonal mast cells (MCs) in various organ systems. The disease may present as cutaneous mastocytosis or systemic mastocytosis (SM). On the basis of histopathological and molecular features, clinical variables, and organ involvement, SM is divided into indolent SM, smoldering SM, SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia. Each variant is defined by unique diagnostic criteria and a unique spectrum of clinical presentations. A key driver of MC expansion and disease evolution is the oncogenic machinery triggered by mutant forms of . The genetic background, additional somatic mutations, and comorbidities also contribute to the course and prognosis. Patients with SM may also suffer from mediator-related symptoms or even an MC activation syndrome. This article provides an update of concepts on the genetics, etiology, and pathology of mastocytosis, with emphasis on diagnostic criteria and new treatment concepts.

Topics: Humans; Mastocytosis; Mast Cells; Mastocytosis, Systemic; Prognosis; Proto-Oncogene Proteins c-kit

PubMed: 36270293
DOI: 10.1146/annurev-pathmechdis-031521-042618

Review

Authors: Clayton Webster Jackson, Cristina Marie Pratt, Chase Preston Rupprecht...

Mast cells are derived from hematopoietic stem cell precursors and are essential to the genesis and manifestations of the allergic response. Activation of these cells by allergens leads to degranulation and elaboration of inflammatory mediators, responsible for regulating the acute dramatic inflammatory response seen. Mast cells have also been incriminated in such diverse disorders as malignancy, arthritis, coronary artery disease, and osteoporosis. There has been a recent explosion in our understanding of the mast cell and the associated clinical conditions that affect this cell type. Some mast cell disorders are associated with specific genetic mutations (such as the D816V gain-of-function mutation) with resultant clonal disease. Such disorders include cutaneous mastocytosis, systemic mastocytosis (SM), its variants (indolent/ISM, smoldering/SSM, aggressive systemic mastocytosis/ASM) and clonal (or monoclonal) mast cell activation disorders or syndromes (CMCAS/MMAS). Besides clonal mast cell activations disorders/CMCAS (also referred to as monoclonal mast cell activation syndromes/MMAS), mast cell activation can also occur secondary to allergic, inflammatory, or paraneoplastic disease. Some disorders are idiopathic as their molecular pathogenesis and evolution are unclear. A genetic disorder, referred to as hereditary alpha-tryptasemia (HαT) has also been described recently. This condition has been shown to be associated with increased severity of allergic and anaphylactic reactions and may interact variably with primary and secondary mast cell disease, resulting in complex combined disorders. The role of this review is to clarify the classification of mast cell disorders, point to molecular aspects of mast cell signaling, elucidate underlying genetic defects, and provide approaches to targeted therapies that may benefit such patients.

Topics: Animals; Humans; Mast Cell Activation Disorders; Mast Cells; Mastocytosis

PubMed: 34681933
DOI: 10.3390/ijms222011270

Authors: Animesh Pardanani

OVERVIEW

Systemic mastocytosis (SM) results from clonal proliferation of mast cells (MC) in extracutaneous organs.

DIAGNOSIS

The major criterion is presence of multifocal MC clusters in the bone marrow and/or extracutaneous organs. Minor diagnostic criteria include elevated serum tryptase level, MC CD25/CD2/CD30 expression, and presence of activating KIT mutations.

RISK STRATIFICATION

Establishing SM subtype as per the International Consensus Classification/World Health Organization classification systems is an important first step. Patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, including aggressive SM (ASM), SM with associated myeloid neoplasm (SM-AMN), and mast cell leukemia. Identification of poor-risk mutations (i.e., ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Several risk models are available to help assign prognosis in SM patients.

MANAGEMENT

Treatment goals for ISM patients are primarily directed toward anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to reverse disease-related organ dysfunction. Tyrosine kinase inhibitors (TKI) (midostaurin, avapritinib) have changed the treatment landscape in SM. While deep biochemical, histological and molecular responses have been documented with avapritinib treatment, its efficacy as monotherapy against a multimutated AMN disease component in SM-AMN patients remains unclear. Cladribine continues to have a role for MC debulking, whereas interferon-α has a diminishing role in the TKI era. Treatment of SM-AMN primarily targets the AMN component, particularly if an aggressive disease such as acute leukemia is present. Allogeneic stem cell transplant has a role in such patients. Imatinib has a therapeutic role only in the rare patient with an imatinib-sensitive KIT mutation.

Topics: Humans; Adult; Mastocytosis, Systemic; Imatinib Mesylate; Mast Cells; Leukemia, Mast-Cell; Risk Assessment

PubMed: 37309222
DOI: 10.1002/ajh.26962

Review

Authors: Jonathan J Lyons

Hereditary alpha tryptasemia is an autosomal dominant genetic trait caused by increased germline copies of TPSAB1 encoding alpha-tryptase. Individuals with this trait have elevated basal serum tryptase, and may present with associated multisystem complaints. Both basal serum tryptase levels and severity of clinical symptoms display a gene-dose relationship with TPSAB1, whereby higher tryptase levels and greater symptom severity are correlated with increasing numbers of alpha-encoding TPSAB1. As the functional effects of increased basal serum tryptase and/or altered tryptase gene expression are elucidated, greater insights will be gained into the symptoms associated with hereditary alpha tryptasemia and their potential therapy.

Topics: Connective Tissue; Disease Progression; Gene Dosage; Gene Duplication; Gene Expression Regulation; Genes, Dominant; Genotype; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Mast Cells; Mastocytosis; Quantitative Trait Loci; Skin; Tryptases

PubMed: 30007465
DOI: 10.1016/j.iac.2018.04.003

Review

Authors: L Blackwood, S Murphy, P Buracco...

In preparing this document the Authors aimed to pool current information on canine and feline mast cell disease. The information was gathered from international studies and a emphasis was placed on material and opinion with a strong evidence base. We intend it to form the basis of our understanding in this disease at the current time and we anticipate that it will be particularly useful for the general practitioner. It should be emphasized that the authors are presenting this work from a European perspective.

Topics: Animals; Cat Diseases; Cats; Dog Diseases; Dogs; Mast Cells; Mastocytosis; Paraneoplastic Syndromes

PubMed: 22882486
DOI: 10.1111/j.1476-5829.2012.00341.x

Review

Authors: A Matito, M M Escribese, N Longo...

The diagnosis of mast cell activation syndrome (MCAS) is defined by 3 criteria: (1) typical clinical signs and symptoms of acute, recurrent (episodic), and systemic mast cell activation (MCA); (2) increase in tryptase level to >20% + 2 ng/mL within 1-4 hours after onset of the acute crisis; and (3) response of MCA symptoms to antimediator therapy. Classification of MCAS requires highly sensitive and specific methodological approaches for the assessment of clonal bone marrow mast cells at low frequencies. The Spanish Network on Mastocytosis score has been used successfully as a predictive model for selecting MCAS candidates for bone marrow studies based on a high probability of an underlying clonal mast cell disorder. In this article, we propose a diagnostic algorithm and focus on the practical evaluation and management of patients with suspected MCAS.

Topics: Anaphylaxis; Humans; Mast Cell Activation Syndrome; Mast Cells; Mastocytosis; Neoplasm Recurrence, Local; Tryptases

PubMed: 33541851
DOI: 10.18176/jiaci.0675

Review

Authors: Peter Valent, Cem Akin, Patrizia Bonadonna...

Mast cell activation (MCA) accompanies diverse physiologic and pathologic processes and is one of the more frequently encountered conditions in medicine. MCA-related symptoms are usually mild and often transient. In such cases, histamine receptor blockers and other mediator-targeting drugs can usually control MCA. In severe cases, an MCA syndrome (MCAS) may be diagnosed. However, overt MCAS is an unusual condition, and many patients referred because of suspected MCAS are diagnosed with other diseases (autoimmune, neoplastic, or infectious) unrelated to MCA or suffer from MCA-related (eg, allergic) disorders and/or comorbidities without fulfilling criteria of an overt MCAS. These considerations are important as more and more patients are informed that they may have MCA or even MCAS without completing a thorough medical evaluation. In fact, in several instances, symptoms are misinterpreted as MCA/MCAS, and other clinically relevant conditions are not thoroughly pursued. The number of such referrals is increasing. To avoid such unnecessary referrals and to prevent misdiagnoses, we here propose a diagnostic algorithm through which a clinically relevant (systemic) MCA can be suspected and MCAS can subsequently be documented or excluded. In addition, the algorithm proposed should help guide the investigating care providers to consider the 2 principal diagnoses that may underlie MCAS, namely, severe allergy and systemic mastocytosis accompanied by severe MCA. Although validation is required, we anticipate that this algorithm will facilitate the management of patients with suspected MCAS.

Topics: Algorithms; Diagnosis, Differential; Humans; Hypersensitivity, Immediate; Mastocytosis; Mastocytosis, Systemic; Proto-Oncogene Proteins c-kit; Tryptases

PubMed: 30737190
DOI: 10.1016/j.jaip.2019.01.006

Review

Authors: Peter Valent, Karin Hartmann, Patrizia Bonadonna...

Mast cell activation syndromes (MCASs) are defined by systemic severe and recurrent mast cell activation, usually in form of anaphylaxis, a substantial, event-related increase of the serum tryptase level beyond the individual's baseline and a response of the symptomatology to drugs directed against mast cells, mast cell-derived mediators, or mediator effects. A number of predisposing genetic conditions, underlying allergic and other hypersensitivity states, and related comorbidities can contribute to the clinical manifestation of MCASs. These conditions include hereditary alpha tryptasemia, mastocytosis with an expansion of clonal KIT-mutated mast cells, atopic diathesis, and overt IgE-dependent and IgE-independent allergies. Several of these conditions have overlapping definitions and diagnostic criteria and may also develop concomitantly in the same patient. However, although criteria and clinical features overlap, each of these conditions is characterized by a unique constellation of variables and diagnostic criteria. Since two, three, or more conditions can coexist in the same patient, with obvious clinical implications, it is of crucial importance to diagnose the variant of MCAS precisely and to take all accompanying, underlying and potentially complicating conditions, and comorbidities into account when establishing the management plan. Indeed, most of these patients require multidisciplinary investigations and only a personalized treatment approach can lead to an optimal management plan providing an optimal quality of life and low risk of anaphylaxis.

Topics: Anaphylaxis; Humans; Immunoglobulin E; Mast Cell Activation Syndrome; Mast Cells; Mastocytosis; Quality of Life; Tryptases

PubMed: 35605594
DOI: 10.1159/000524532