Interobserver variability in the classification of childhood maculopapular cutaneous mastocytosis.

BACKGROUND: Maculopapular cutaneous mastocytosis (MPCM) in children is classified in two variants: (i) monomorphic variant, presenting with the small macules or papules typically seen in adult patients; and (ii) polymorphic variant with larger lesions of variable size and shape, typically seen in children. The definition of polymorphic and monomorphic variants is mostly intuitive, and a validation of this classification has not been done. OBJECTIVE: To study interobserver variability in the classification of MPCM in two groups of observers: mastocytosis experts and general dermatologists. MATERIALS AND METHODS: Nineteen cases of childhood MPCM were shown blindly, for classification as monomorphic or polymorphic type, to 10 independent observers (eight dermatologists, one allergist and one haematologist) from Europe and North America with a vast experience in the management of paediatric mastocytosis. Also, the same cases were shown on a screen to 129 general dermatologists attending a meeting; their votes were registered by remote controls. The interobserver variability kappa coefficient (with 95% confidence interval) was calculated to measure the reliability of the correlation. RESULTS: The value of kappa interobserver variability coefficient for the group of 10 experts (95% confidence interval) was 0.39 (0.18-0.63), which is considered as 'fair'. The value of kappa interobserver variability coefficient for the group of 129 general dermatologists (95% confidence interval) was 0.17 (0.06-0.39), which is considered as 'slight'. A complete agreement of all 10 experts was achieved in only four of 19 cases (21.1%) The most voted choice was concordant between the two groups in only 11 of the 19 cases. CONCLUSIONS: We failed to validate the classification system of childhood MPCM in monomorphic and polymorphic types. While the rate of agreement was low for mastocytosis experts, it was nearly the agreement expected by chance in general dermatologists.

Clinical Approach to Mast Cell Activation Syndrome: A Practical Overview.

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.

Clinical Approach to Mast Cell ActivationSyndrome: A Practical Overview

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 (AU)

El diagnóstico de síndrome de activación mastocitaria (SAM) se basa en 3 criterios: 1) signos y síntomas específicos de activación mastocitaria aguda, recurrente y sistémica, 2) aumento de los valores de triptasa en un 20% + 2 ng/ml sobre el valor basal de cada individuo en el periodo comprendido entre 1-4 horas desde el inicio del cuadro agudo, y 3) resolución de los síntomas con tratamiento antimediador. Para realizar el diagnóstico de SAM, es preciso emplear métodos diagnósticos altamente sensibles y específicos capaces de detectar bajas cantidades de mastocitos en la médula ósea. El modelo predictivo de la Red Española de Mastocitosis (REMA score) resulta útil para identificar a los pacientes con mayor probabilidad de padecer una patología mastocitaria clonal y que, por tanto, requieren que se nealice un estudio de médula ósea en el proceso diagnóstico. En este artículo, proponemos un algoritmo diagnóstico para SAM y abordamos el manejo de estos pacientes desde un punto de vista práctico en la consulta alergológica (AU)

Characterization of CD34+ hematopoietic cells in systemic mastocytosis: Potential role in disease dissemination.

BACKGROUND: Recent studies show that most systemic mastocytosis (SM) patients, including indolent SM (ISM) with (ISMs+) and without skin lesions (ISMs-), carry the KIT D816V mutation in PB leukocytes. We investigated the potential association between the degree of involvement of BM hematopoiesis by the KIT D816V mutation and the distribution of different maturation-associated compartments of bone marrow (BM) and peripheral blood (PB) CD34+ hematopoietic precursors (HPC) in ISM and identified the specific PB cell compartments that carry this mutation. METHODS: The distribution of different maturation-associated subsets of BM and PB CD34+ HPC from 64 newly diagnosed (KIT-mutated) ISM patients and 14 healthy controls was analyzed by flow cytometry. In 18 patients, distinct FACS-purified PB cell compartments were also investigated for the KIT mutation. RESULTS: ISM patients showed higher percentages of both BM and PB MC-committed CD34+ HPC vs controls, particularly among ISM cases with MC-restricted KIT mutation (ISMMC ); this was associated with progressive blockade of maturation of CD34+ HPC to the neutrophil lineage from ISMMC to multilineage KIT-mutated cases (ISMML ). Regarding the frequency of KIT-mutated cases and cell populations in PB, variable patterns were observed, the percentage of KIT-mutated PB CD34+ HPC, eosinophils, neutrophils, monocytes and T cells increasing from ISMs-MC and ISMs+MC to ISMML patients. CONCLUSION: The presence of the KIT D816V mutation in PB of ISM patients is associated with (early) involvement of circulating CD34+ HPC and multiple myeloid cell subpopulations, KIT-mutated PB CD34+ HPC potentially contributing to early dissemination of the disease.

Actualización en mastocitosis. Parte 1: fisiopatología, clínica y diagnóstico / Update on Mastocytosis (Part 1): Pathophysiology, Clinical Features, and Diagnosis

Las mastocitosis constituyen un grupo heterogéneo de enfermedades caracterizadas por la proliferación clonal de mastocitos en distintos órganos, siendo la localización cutánea la más frecuente. Es «una enfermedad rara o poco frecuente», y afecta a todos los grupos de edad, si bien suele aparecer en la primera década de la vida o entre la segunda y la quinta década de la vida, con una distribución similar por sexos. En los últimos años se han realizado grandes avances en el conocimiento fisiopatogénico del trastorno: las mutaciones somáticas del gen c-kit y la presencia de alteraciones inmunofenotípicas en los mastocitos son elementos importantes en la fisiopatogenia de las mastocitosis. Las manifestaciones clínicas son variadas y las lesiones cutáneas son la clave diagnóstica en la mayoría de los pacientes

Mastocytosis is a term used to describe a heterogeneous group of disorders characterized by clonal proliferation of mast cells in various organs. The organ most often affected is the skin. Mastocytosis is a relatively rare disorder that affects both sexes equally. It can occur at any age, although it tends to appear in the first decade of life, or later, between the second and fifth decades. Our understanding of the pathophysiology of mastocytosis has improved greatly in recent years, with the discovery that somatic c-kit mutations and aberrant immunophenotypic features have an important role. The clinical manifestations of mastocytosis are diverse, and skin lesions are the key to diagnosis in most patient

Actualización en mastocitosis. Parte 2: categorías, pronóstico y tratamiento / Update on Mastocytosis (Part 2): Categories, Prognosis, and Treatment

Las mastocitosis constituyen un grupo heterogéneo de enfermedades caracterizadas por la proliferación clonal de mastocitos en distintos órganos, siendo la localización cutánea la más frecuente. La Organización Mundial de la Salud (OMS) clasifica las mastocitosis cutáneas en mastocitomas, mastocitosis máculo-papulosas y mastocitosis cutánea difusa, mientras que las formas sistémicas incluyen las mastocitosis indolentes, las agresivas, las asociadas a otra hematopatía monoclonal y la leucemia mastocitaria; el sarcoma mastocitario y el mastocitoma extracutáneo son variantes muy poco frecuentes. Aunque la evolución de la enfermedad en los niños es impredecible, con frecuencia las lesiones desaparecen durante la infancia; en los adultos la enfermedad tiende a persistir. El tratamiento se dirige a controlar las manifestaciones clínicas debidas a la acción de los mediadores mastocitarios, mientras que las formas agresivas requerirán de tratamientos dirigidos a reducir la masa mastocitaria

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 burd

Increased IL6 plasma levels in indolent systemic mastocytosis patients are associated with high risk of disease progression.

Systemic mastocytosis (SM) is a heterogeneous disease with altered interleukin (IL)-6 and IL13 plasma levels. However, no study has simultaneously investigated the plasma levels of IL1ß, IL6, IL13, CCL23 and clusterin in SM at diagnosis and correlated them with disease outcome. Here we investigated IL1ß, IL6, IL13, CCL23 and clusterin plasma levels in 75 SM patients--66 indolent SM (ISM) and 9 aggressive SM--and analyzed their prognostic impact among ISM cases grouped according to the extent of hematopoietic involvement of the bone marrow cells by the KIT D816V mutation. Although increased IL1ß, IL6 and CCL23 levels were detected in SM patients versus healthy controls, only IL6 and CCL23 levels gradually increased with disease severity. Moreover, increased IL6 plasma levels were associated with ISM progression to more aggressive disease, in particular among ISM patients with multilineal KIT mutation (ISM-ML), these patients also showing a higher frequency of organomegalies, versus other ISM-ML patients. Of note, all ISM patients who progressed had increased IL6 plasma levels already at diagnosis. Our results indicate that SM patients display an altered plasma cytokine profile already at diagnosis, increased IL6 plasma levels emerging as an early marker for disease progression among ISM cases, in particular among high-risk ISM patients who carry multilineage KIT mutation.

Update on Mastocytosis (Part 1): Pathophysiology, Clinical Features, and Diagnosis.

Mastocytosis is a term used to describe a heterogeneous group of disorders characterized by clonal proliferation of mast cells in various organs. The organ most often affected is the skin. Mastocytosis is a relatively rare disorder that affects both sexes equally. It can occur at any age, although it tends to appear in the first decade of life, or later, between the second and fifth decades. Our understanding of the pathophysiology of mastocytosis has improved greatly in recent years, with the discovery that somatic c-kit mutations and aberrant immunophenotypic features have an important role. The clinical manifestations of mastocytosis are diverse, and skin lesions are the key to diagnosis in most patients.

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.

Cutaneous and systemic mastocytosis in children: a risk factor for anaphylaxis?

Childhood mastocytosis is usually a clonal mast cell disease related to activating mutations in KIT. The symptoms in childhood mastocytosis are typically cutaneous in nature although systemic symptoms including anaphylaxis due to the release of mast cells (MC) mediators can also manifest. The prevalence of anaphylaxis reported in childhood mastocytosis is higher than the rates reported in the pediatric general population, but lower than the prevalence of anaphylaxis described in adult mastocytosis. An extensive cutaneous involvement was reported as a risk factor for anaphylaxis, and patients with diffuse cutaneous mastocytosis have been documented to have more severe anaphylaxis symptoms. Anaphylaxis due to unknown causes or idiopathic anaphylaxis was the primary etiology in pediatric mastocytosis, followed by foods as the most relevant identified trigger; however, hymenoptera stings are not a frequent trigger of anaphylaxis in children with mastocytosis in contrast to the adult patients.

Anaphylaxis as a clinical manifestation of clonal mast cell disorders.

Clonal mast cell disorders comprise a heterogeneous group of disorders characterized by the presence of gain of function KIT mutations and a constitutively altered activation-associated mast cell immunophenotype frequently associated with clinical manifestations related to the release of mast cells mediators. These disorders do not always fulfil the World Health Organization (WHO)-proposed criteria for mastocytosis, particularly when low-sensitive diagnostic approaches are performed. Anaphylaxis is a frequent presentation of clonal mast cell disorders, particularly in mastocytosis patients without typical skin lesions. The presence of cardiovascular symptoms, e.g., hypotension, occurring after a hymenoptera sting or spontaneously in the absence of cutaneous manifestations such as urticaria is characteristic and differs from the presentation of anaphylaxis in the general population without mastocytosis.

Increased serum baseline tryptase levels and extensive skin involvement are predictors for the severity of mast cell activation episodes in children with mastocytosis.

BACKGROUND: Despite the good prognosis of pediatric mastocytosis, some patients suffer from severe mast cell (MC) mediator-associated symptoms. The aim of this study was to identify predictors for severe MC mediator release symptoms in children with mastocytosis in the skin (MIS). METHODS: Serum baseline total tryptase (sbT) levels in 111 children with MIS - 80 maculopapular cutaneous mastocytosis/plaque mastocytosis, 22 nodular mastocytosis, and nine diffuse cutaneous mastocytosis - were investigated as a predictive biomarker for the occurrence of MC mediator-related signs and symptoms within the first 18 months after disease onset. RESULTS: Twelve children (11%) who showed extensive cutaneous disease involving >90% of body surface area (BSA) suffered from severe symptoms requiring hospitalization, with (n = 5) or without (n = 6) management in the intensive care unit (ICU) owing to life-threatening complications. The median sbT was significantly (P < 0.001) higher in patients with extensive cutaneous disease vs those with <90% of BSA involved (45.5 vs 5.2 µg/l, respectively), as well as in children with grade 4 (severe mastocytosis-related symptoms requiring emergency therapy and hospitalization) vs those with grade <4 (46.2 vs 5.2 µg/l, respectively). Receiver operating characteristics curve analyses showed that the optimal cutoff s for sbT to predict the need for daily antimediator therapy, hospitalization, and the management in an ICU were 6.6, 15.5, and 30.8 µg/l, respectively (sensitivity and specificity of 77% and 79%, 100% and 95%, and 100% and 96%, respectively). CONCLUSIONS: Increased sbT in association with extensive cutaneous involvement identifies patients at risk for severe MC activation events in pediatric mastocytosis.

Validation of the REMA score for predicting mast cell clonality and systemic mastocytosis in patients with systemic mast cell activation symptoms.

BACKGROUND: A variable percentage of patients with systemic mast cell (MC) activation symptoms meet criteria for systemic mastocytosis (SM). We prospectively evaluated the clinical utility of the REMA score versus serum baseline tryptase (sBt) levels for predicting MC clonality and SM in 158 patients with systemic MC activation symptoms in the absence of mastocytosis in the skin (MIS). METHODS: World Health Organization criteria for SM were applied in all cases. MC clonality was defined as the presence of KIT-mutated MC or by a clonal HUMARA test. The REMA score consisted of the assignment of positive or negative points as follows: male (+1), female (-1), sBt <15 µg/l (-1) or >25 µg/l (+2), presence (-2) or absence (+1) of pruritus, hives or angioedema and presence (+3) of presyncope or syncope. Efficiency of the REMA score for predicting MC clonality and SM was assessed by receiver operating characteristic (ROC) curve analyses and compared to those obtained by means of sBt levels alone. RESULTS: Molecular studies revealed the presence of clonal MC in 68/80 SM cases and in 11/78 patients who did not meet the criteria for SM. ROC curve analyses confirmed the greater sensitivity and a similar specificity of the REMA score versus sBt levels (84 vs. 59% and 74 vs. 70% for MC clonality and 87 vs. 62% and 73 vs. 71% for SM, respectively). CONCLUSIONS: Our results confirm the clinical utility of the REMA score to predict MC clonality and SM in patients suffering from systemic MC activation symptoms without MIS.

An immature immunophenotype of bone marrow mast cells predicts for multilineage D816V KIT mutation in systemic mastocytosis.

D816V KIT mutation of bone marrow (BM) mast cells (MC) is a common feature to systemic mastocytosis (SM) patients. Nevertheless, occurrence of the KIT mutation in BM cell compartments other than MC is associated with progression to more aggressive forms of the disease and poor outcome in indolent SM (ISM). Here, we assessed the potential association between the immunophenotype of MC and multilineage KIT mutation in the BM of SM patients through the investigation of the flow cytometric protein expression profile (PEP) of bone marrow mast cells (BMMC) from 70 control individuals and 206 SM patients, classified according to the WHO (World Health Organization), and the degree of involvement of BM hematopoiesis by the D816V KIT mutation; additionally, we developed a score-based class prediction algorithm for the detection of SM cases with multilineage mutation. Our results show that aberrant expression of CD25 with a FcɛRI(lo), FSC(lo), SSC(lo) and CD45(lo) immature phenotype of BMMC, in the absence of coexisting normal MC in the BM, was associated with multilineage involvement by the D816V KIT mutation, regardless of the diagnostic subtype of the disease (for example, indolent vs aggressive SM), which supports the utility of the immunophenotype of BMMC as a surrogate marker to screen for multilineage KIT mutation in ISM.

Evaluation of basophil activation in mastocytosis with Hymenoptera venom anaphylaxis.

BACKGROUND: Basophil activation tests (BATs) have been demonstrated to be useful in detecting IgE-mediated sensitization by measuring basophil activation surface markers (CD63 and CD203c). Hymenoptera venom is one of the best known mediators-release trigger in patients with systemic mastocytosis (SM). The aim of this study was to investigate the use of BATs as an additional diagnostic tool in patients with mastocytosis suffering from hymenoptera venom anaphylaxis (HVA). METHODS: A total of 22 patients with history of HVA and SM, together with a group of 11 patients with HVA in whom SM was ruled out after a complete bone marrow study, were analyzed. RESULTS: Among 11 SM patients who had specific serum IgE (sIgE) against hymenoptera venom and an evaluable BAT, a positive BAT was found in nine. Additionally, a positive BAT was detected in three of seven patients who had no sIgE. These three patients had low levels of total IgE compared with control population (mean of 20 vs. 78 IU/mL); one had discontinued immunotherapy after 5 years, when sIgE levels had turned negative, and, in the other two patients, BAT identified the culprit insect. CONCLUSIONS: BAT is a useful complementary diagnostic tool to sIgE in mastocytosis patients with HVA, and it may contribute to predict or confirm these nearly fatal reactions, especially before discontinuing venom immunotherapy in patients who are negative for skin tests or sIgE or display low total IgE levels; in such cases, it also provides evidence on the culprit insect prompting HVA.