Mastocytosis, MCAS, and Related Disorders-Diagnosis, Classification, and Therapy.

Mastocytosis is a heterogeneous group of hematologic neoplasms defined by an accumulation of neoplastic mast cells (MC) in the skin, bone marrow, and other visceral organs [...].

Pediatric mastocytosis.

PURPOSE OF REVIEW: The current article highlights recent developments in the field of pediatric cutaneous mastocytosis. Mastocytosis is a spectrum of conditions that range from fleetingly benign to aggressively malignant. Through recognizing the natural progression of disease, the role of biomarkers and mutational analysis, treatment and risk of triggers, physicians can confidently stage, counsel and manage patients with pediatric cutaneous mastocytosis. RECENT FINDINGS: Many lesions of cutaneous mastocytosis are chronic with some resolving around the mid-teenage years. KIT mutations are found in the majority of pediatric cutaneous mastocytosis but are not correlated with prognosis. Serum tryptase levels may be elevated in pediatric cutaneous mastocytosis patients without systemic mastocytosis. Pimecrolimus, omalizumab and tyrosine kinase inhibitors are effective treatment options. The low risk of NSAIDs and vaccinations has been characterized and epinephrine autoinjectors are rarely utilized in the pediatric cutaneous mastocytosis patient. SUMMARY: Pediatric cutaneous mastocytosis is a heterogeneous disease with good outcome overall. Organomegaly, elevated tryptase levels and the presence of KIT mutation in peripheral blood may aid in the decision to pursue bone marrow biopsy. The armamentarium of treatments has expanded and better understanding of the significance of triggers and vaccination safety allows the clinician to thoughtfully counsel and allay anxiety around pediatric cutaneous mastocytosis.

Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts.

Over the past few years, substantial advances have been made in understanding the pathogenesis, evolution, and complexity of mast cell neoplasms. New diagnostic and prognostic parameters and novel therapeutic targets with demonstrable clinical impact have been identified. Several of these new markers, molecular targets, and therapeutic approaches have been validated and translated into clinical practice. At the same time, the classification of mastocytosis and related diagnostic criteria have been refined and updated by the consensus group and the World Health Organization (WHO). As a result, more specific therapies tailored toward prognostic subgroups of patients have been developed. Emerging treatment concepts use drugs directed against KIT and other relevant targets in neoplastic mast cells and will hopefully receive recognition by health authorities in the near future. This article provides an overview of recent developments in the field, with emphasis on the updated WHO classification, refined criteria, additional prognostic parameters, and novel therapeutic approaches. Based on these emerging concepts, the prognosis, quality of life, and survival of patients with advanced mastocytosis are expected to improve in the coming years.

Diagnosis and classification of mastocytosis in non-specialized versus reference centres: a Spanish Network on Mastocytosis (REMA) study on 122 patients.

The diagnosis of 'rare diseases', such as mastocytosis, remains a challenge. Despite this, the precise benefits of referral of mastocytosis patients to highly specialized reference centres are poorly defined and whether patients should be managed at non-specialized versus reference centres remains a matter of debate. To evaluate the quality and efficiency of diagnostic procedures performed at the reference centres for mastocytosis in Spain (REMA) versus other non-reference centres, we retrospectively analysed a series of 122 patients, for the overall degree of agreement obtained for the World Health Organization (WHO) diagnostic and classification criteria betwen the referring and REMA centres. Our results showed that not all WHO diagnostic criteria were frequently investigated at the referring centres. Among the five WHO diagnostic criteria, the highest degree of agreement was obtained for serum tryptase levels [median 90% (95% confidence interval 84-96%)]; in turn, the overall agreement was significantly lower for the major histopathological criterion [80% (72-89%)], and the other three minor criteria: cytomorphology [68% (56-80%)] immunophenotyping of BM mast cells [75% (62-87%)] and detection of the KIT mutation [34% (8-60%)]. Referral of patients with diagnostic suspicion of mastocytosis to a multidisciplinary reference centre improves diagnostic efficiency and quality.

Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease.

Mastocytosis is a complex disorder characterized by the accumulation of abnormal mast cells (MC) in the skin, bone marrow and/or other visceral organs. The clinical manifestations result from MC-derived mediators and, less frequently, from destructive infiltration of MCs. Patients suffer from a variety of symptoms including pruritus, flushing and life-threatening anaphylaxis. Whilst mastocytosis is likely to be suspected in a patient with typical skin lesions [i.e. urticaria pigmentosa (UP)], the absence of cutaneous signs does not rule out the diagnosis of this disease. Mastocytosis should be suspected in cases of recurrent, unexplained or severe insect-induced anaphylaxis or symptoms of MC degranulation without true allergy. In rare cases, unexplained osteoporosis or unexplained haematological abnormalities can be underlying feature of mastocytosis, particularly when these conditions are associated with elevated baseline serum tryptase levels. The diagnosis is based on the World Health Organization criteria, in which the tryptase level, histopathological and immunophenotypic evaluation of MCs and molecular analysis are crucial. A somatic KIT mutation, the most common of which is D816V, is usually detectable in MCs and their progenitors. Once a diagnosis of systemic mastocytosis (SM) is made, it is mandatory to assess the burden of the disease, its activity, subtype and prognosis, and the appropriate therapy. Mastocytosis comprises seven different categories that range from indolent forms, such as cutaneous and indolent SM, to progressive forms, such as aggressive SM and MC leukaemia. Although prognosis is good in patients with indolent forms of the disease, patients with advanced categories have a poor prognosis.

Multidisciplinary Management of Mastocytosis: Nordic Expert Group Consensus.

Mastocytosis is a heterogeneous group of diseases defined by an increased number and accumulation of mast cells, and often also by signs and symptoms of mast cell activation. Disease subtypes range from indolent to rare aggressive forms. Mastocytosis affects people of all ages and has been considered rare; however, it is probably underdiagnosed with potential severe implications. Diagnosis can be challenging and symptoms may be complex and involve multiple organ-systems. In general it is advised that patients should be referred to centres with experience in the disease offering an individualized, multidisciplinary approach. We present here consensus recommendations from a Nordic expert group for the diagnosis and general management of patients with mastocytosis.

Update on Mastocytosis (Part 2): Categories, Prognosis, and Treatment.

Mastocytosis is a term used to describe a heterogeneous group of disorders characterized by clonal proliferation of mast cells in different organs. The organ most often affected is the skin. The World Health Organization classifies cutaneous mastocytosis into mastocytoma, maculopapular cutaneous mastocytosis, and diffuse mastocytosis. The systemic variants in this classification are as follows: indolent systemic mastocytosis (SM), aggressive SM, SM with an associated clonal hematological non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma, and extracutaneous mastocytoma. The two latest systemic variants are rare. Although the course of disease is unpredictable in children, lesions generally resolve by early adulthood. In adults, however, the disease tends to persist. The goal of treatment should be to control clinical manifestations caused by the release of mast cell mediators and, in more aggressive forms of the disease, to reduce mast cell burden.

Mast cell activation syndromes: definition and classification.

Mast cell activation (MCA) occurs in a number of different clinical conditions, including IgE-dependent allergies, other inflammatory reactions, and mastocytosis. MCA-related symptoms may be mild, moderate, severe, or even life-threatening. The severity of MCA depends on a number of different factors, including genetic predisposition, the number and releasability of mast cells involved in the reaction, the type of allergen, presence of specific IgE, and presence of certain comorbidities. In severe reactions, MCA can be documented by a substantial increase in the serum tryptase level above baseline. When symptoms are recurrent, are accompanied by an increase in mast cell-derived mediators in biological fluids, and are responsive to treatment with mast cell-stabilizing or mediator-targeting drugs, the diagnosis of mast cell activation syndrome (MCAS) is appropriate. Based on the underlying condition, these patients can further be classified into i) primary MCAS where KIT-mutated, clonal mast cells are detected, ii) secondary MCAS where an underlying inflammatory disease, often in the form of an IgE-dependent allergy, but no KIT-mutated mast cells, is found, and iii) idiopathic MCAS, where neither an allergy or other underlying disease, nor KIT-mutated mast cells are detectable. It is important to note that in many patients with MCAS, several different factors act together to lead to severe or even life-threatening anaphylaxis. Detailed knowledge about the pathogenesis and complexity of MCAS, and thus establishing the exact final diagnosis, may greatly help in the management and therapy of these patients.

Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal.

Activation of tissue mast cells (MCs) and their abnormal growth and accumulation in various organs are typically found in primary MC disorders also referred to as mastocytosis. However, increasing numbers of patients are now being informed that their clinical findings are due to MC activation (MCA) that is neither associated with mastocytosis nor with a defined allergic or inflammatory reaction. In other patients with MCA, MCs appear to be clonal cells, but criteria for diagnosing mastocytosis are not met. A working conference was organized in 2010 with the aim to define criteria for diagnosing MCA and related disorders, and to propose a global unifying classification of all MC disorders and pathologic MC reactions. This classification includes three types of 'MCA syndromes' (MCASs), namely primary MCAS, secondary MCAS and idiopathic MCAS. MCA is now defined by robust and generally applicable criteria, including (1) typical clinical symptoms, (2) a substantial transient increase in serum total tryptase level or an increase in other MC-derived mediators, such as histamine or prostaglandin D(2), or their urinary metabolites, and (3) a response of clinical symptoms to agents that attenuate the production or activities of MC mediators. These criteria should assist in the identification and diagnosis of patients with MCAS, and in avoiding misdiagnoses or overinterpretation of clinical symptoms in daily practice. Moreover, the MCAS concept should stimulate research in order to identify and exploit new molecular mechanisms and therapeutic targets.

[Mastocytosis and eosinophilic leukemia: diagnostics and classification]. / Mastozytosen und myeloische Neoplasien mit Eosinophilie: Diagnostik und Klassifikation.

Mastocytosis and myeloid eosinophilic neoplasms are rare diseases of the bone marrow and are often a diagnostic challenge for hematopathologists. In mastocytosis, compact mast cell infiltrates represent the main diagnostic criterion and for myeloid eosinophilic neoplasms, eosinophilic granulocytes dominate the histological picture. Both disease groups include phenotypically and prognostically very different entities which are each defined by WHO criteria. For systemic mastocytosis (SM), a differentiation between indolent and aggressive or even leukemic forms is of prognostic importance. In indolent variants of SM, a local and/or systemic, usually reactive increase in eosinophilic granulocytes (SM-eo) is often observed. In contrast, an increase in neoplastic eosinophils is often observed in advanced SM, predominantly in diseases designated SM with associated non-mastocytic hematological neoplasms (SM-AHNMD), e.g. in SM with chronic eosinophilic leukemia (SM-CEL). Apart from mastocytoses, immunophenotypically aberrant tissue mast cells are only observed in certain rare forms of myeloid neoplasms with eosinophilia, in particular in myeloproliferative neoplasms (MPN-eo) with cytogenic anomalies in the platelet-derived growth factor receptor (PDGFR). The World Health Organization (WHO) classification of eosinophilic leukemias, however, fulfils the morphological and clinical requirements in a limited way only and needs an update.

Evaluation of the WHO criteria for the classification of patients with mastocytosis.

Diagnosis and classification of mastocytosis is currently based on the World Health Organization (WHO) criteria. Here, we evaluate the utility of the WHO criteria for the diagnosis and classification of a large series of mastocytosis patients (n=133), and propose a new algorithm that could be routinely applied for refined diagnosis and classification of the disease. Our results confirm the utility of the WHO criteria and provide evidence for the need of additional information for (1) a more precise diagnosis of mastocytosis, (2) specific identification of new forms of the disease, (3) the differential diagnosis between cutaneous mastocytosis vs systemic mastocytosis, and (4) improved distinction between indolent systemic mastocytosis and aggressive systemic mastocytosis. Based on our results, a new algorithm is proposed for a better diagnostic definition and prognostic classification of mastocytosis, as confirmed prospectively in an independent validation series of 117 mastocytosis patients.

[Cutaneous Manifestations in Mastocytosis: Update]. / Manifestações Cutâneas nas Mastocitoses: Atualização.

INTRODUCTION: Mastocytosis is characterized by the clonal expansion of morphological and immunophenotypically abnormal mast cells in different organs. The skin is the most frequently affected tissue. Virtually all children and more than 80% of adult patients with mastocytosis show cutaneous lesions. MATERIAL AND METHODS: The present article describes the symptoms and signs in cutaneous mastocytosis, based on the review of recently published international consensus guidelines. DISCUSSION: According to the 2016 World Health Organization classification, mastocytosis can be divided in cutaneous mastocytosis, systemic mastocytosis and mast cell sarcoma. Cutaneous mastocytosis is subclassified in three subtypes: maculopapular cutaneous mastocytosis, diffuse cutaneous mastocytosis and cutaneous astocytoma. Telangiectasia macularis eruptiva perstans is no longer considered a distinct entity. CONCLUSION: Based on the age of onset, cutaneous manifestations of mastocytosis can be variable. The classification of cutaneous mastocytosis has recently been updated. Typically, in patients with childhood-onset mastocytosis, the disease occurs as cutaneous mastocytosis and shows spontaneous resolution around puberty. In contrast, adult patients, despite having also cutaneous lesions, often show systemic involvement and the course of the disease is usually chronic.

Introdução: As mastocitoses caraterizam-se pela expansão clonal de mastócitos, com acumulação de mastócitos morfológica e imunofenotipicamente anormais em diferentes órgãos. A pele é o órgão mais frequentemente envolvido. Virtualmente, todas as crianças e mais de 80% dos adultos com mastocitose apresentam lesões cutâneas.Material e Métodos: O presente artigo descreve os sinais e sintomas associados à mastocitose na pele, tendo por base a revisão das normas de orientação de consenso internacionais, recentemente publicadas.Discussão: De acordo com a classificação proposta pela Organização Mundial de Saúde em 2016, a mastocitose divide-se em mastocitose cutânea, mastocitose sistémica e sarcoma de mastócitos. A mastocitose cutânea pode subdividir-se em três subtipos: a mastocitose cutânea maculopapular (também denominada urticária pigmentosa), mastocitose cutânea difusa e mastocitoma cutâneo. A telangiectasia macular eruptiva perstans já não é considerada uma entidade independente.Conclusão: As manifestações cutâneas da mastocitose são variáveis, dependendo da idade de início da doença. Recentemente a classificação da mastocitose cutânea foi atualizada. Nas crianças, a mastocitose ocorre como mastocitose cutânea que tende à regressão espontânea durante a adolescência. Quando tem início na idade adulta, a mastocitose é geralmente sistémica, sendo a forma mais frequente a mastocitose sistémica indolente, que normalmente também cursa com manifestações cutâneas e tem um curso crónico.

Mast cells and mastocytosis.

Mast cells (MCs) typically reside at barrier sites of the body, including the intestinal mucosa, and play a vital role in innate host defence. Activated MCs release a wide variety of bioactive mediators. These include preformed mediators stored in the granules (e.g. histamine and tryptase) and newly synthesised mediators (e.g. prostaglandins, leukotrienes and cytokines). MCs are present in all layers throughout the gastrointestinal (GI) tract and there is a close bi-directional connection between MCs and enteric nerves that is of vital importance in the regulation of GI functions. Some gain-of-function mutations in c-kit, encoding the tyrosine kinase- receptor for stem cell factor, are associated with the rare disease entity, systemic mastocytosis. These patients present symptoms arising from MC mediator release or infiltration. GI manifestations are common in this patient group, mainly abdominal pain and diarrhoea. Endoscopy with biopsies reveals MC infiltration in the mucosa. Other diagnostic tools include bone marrow biopsy and serum tryptase. Treatment is symptomatic with antihistamines or cromoglycate in mild cases, whereas severe cases need cytoreductive therapy that should be managed with expert haematologists. From a day-to-day clinical perspective, the important role of MCs in neuroimmune interaction has been implicated in the intestinal response to stress, in alterations of mucosal and neuromuscular function in irritable bowel syndrome or inflammatory bowel disease, and in the pathogenesis of non-erosive oesophageal reflux disease. Thus, MCs have important regulatory and protective roles in innate defence, in addition to being a potential mediator of mucosal pathophysiology in GI diseases. We need to learn how to balance the response of these volatile cells to be able to benefit from their versatility.

Case report of mastocytosis in an adult.

A case of adult-onset mastocytosis is presented to illustrate the classification, signs, symptoms, workup, treatment, and prognosis for this unusual condition. Although there is no cure for mastocytosis, symptoms of histamine release can be minimized with oral antihistamines. Ongoing surveillance of organ systems affected remains important. Our patient's mast cell disease predisposed him to bone loss, but there was no evidence of disease beyond the skin. He has done well with continued follow up monitoring his serum tryptase and oral antihistamine treatment.

[Mastocytosis--diagnostic criteria and treatment]. / Mastocytoza--rozpoznawanie i leczenie.

Mastocytosis is a heterogeneous group of rare diseases characterized by the proliferation and accumulation of mast cells in one or more organs such as the skin, bone marrow, liver, spleen, and lymph nodes. According to the WHO classification, mastocytosis is divided into seven subvariants. The symptoms are associated with mediator release and impaired organ function due to infiltration by neoplastic mast cells. There is a higher risk of anaphylactic shock; therefore education of the patients is very important. Patients may be asymptomatic. Symptomatic treatment is used in cutaneous mastocytosis and in indolent systemic mastocytosis. More aggressive subvariants of mastocytosis are treated with chemotherapy, targeted therapy, and bone marrow transplantation.

[Mastocytosis: when should it be considered?]. / Mastocytose: quand faut-il y penser?

Mast cell disorders are defined by the accumulation of mast cells in one or more organ systems. Cutaneous forms are mainly observed in children whereas systemic forms are predominant in adults. Mast cells cause symptoms by the release of proinflammatory mediators or by infiltration of various organs. The measurement of serum tryptase has opened the possibility of screening for mastocytosis, which must be taken into consideration in case of severe anaphylactic reactions. Definite diagnosis is established based on a biopsy of skin or bone marrow. An activating mutation of stem cell factor receptor c-kit is often found. Treatment is based on control of the symptoms triggered by mast cell degranulation. Moreover, novel treatment options targeting mast cell proliferation become available for clinical use.

Mayo alliance prognostic system for mastocytosis: clinical and hybrid clinical-molecular models.

Systemic mastocytosis (SM) is a clinically heterogeneous disease with prognosis chiefly assigned based on World Health Organization (WHO) morphologic subclassification. We assessed the feasibility of developing contemporary risk models for SM based on clinical and integrated clinical-genetics information. Diagnosis of SM was per WHO criteria, and karyotype and next-generation sequencing data were available in a subset of the total 580 patients (median age, 55 years; range, 18-88 years) seen at the Mayo Clinic between 1968 and 2015. Morphologic subcategories were indolent/smoldering in 291 (50%) and "advanced" in 289 (50%): SM with an associated hematological neoplasm in 199, aggressive SM in 85, and mast cell leukemia in 5. Multivariable analysis of clinical variables identified age >60 years, advanced SM, thrombocytopenia <150 × 109/L, anemia below sex-adjusted normal, and increased alkaline phosphatase (ALP) as independent risk factors for survival; respective hazard ratios (HRs) 95% confidence intervals (95% CIs) were 2.5 (1.9-3.4), 2.7 (1.8-4.0), 2.5 (1.9-3.4), 2.2 (1.6-3.1), and 2.1 (1.5-3.0). In addition, ASXL1 (HR, 4.5; 95% CI, 2.6-7.6), RUNX1 (HR, 4.3; 95% CI, 1.3-10.8), and NRAS (HR, 5.0, 95% CI, 1.5-13.2) mutations were independently associated with inferior survival. Combined clinical, cytogenetic, and molecular risk factor analysis confirmed the independent prognostic contribution of adverse mutations (2.6, 1.6-4.4), advanced SM (4.0, 1.8-10.0), thrombocytopenia (2.8, 1.7-4.5), increased ALP (2.1, 1.2-4.0), and age >60 years (2.2, 1.3-3.6). These data were subsequently used to develop clinical and hybrid clinical-molecular risk models. The current study advances 2 complementary risk models for SM and highlights the independent prognostic contribution of mutations.