Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized and disseminated forms. Although a classification and criteria for cutaneous mastocytosis (CM) have ...been proposed, there remains a need to better define subforms of cutaneous manifestations in patients with mastocytosis. To address this unmet need, an international task force involving experts from different organizations (including the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology) met several times between 2010 and 2014 to discuss the classification and criteria for diagnosis of cutaneous manifestations in patients with mastocytosis. This article provides the major outcomes of these meetings and a proposal for a revised definition and criteria. In particular, we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 variants, namely a monomorphic variant with small maculopapular lesions, which is typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, which is typically seen in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. This delineation might have important prognostic implications, and its implementation in diagnostic algorithms and future mastocytosis classifications is recommended. Refinements are also suggested for the diagnostic criteria of CM, removal of telangiectasia macularis eruptiva perstans from the current classification of CM, and removal of the adjunct solitary from the term solitary mastocytoma.
Background Indolent systemic mastocytosis is a group of rare diseases for which reliable predictors of progression and outcome are still lacking. Objective Here we investigate the prognostic impact ...of the clinical, biological, phenotypic, histopathological, and molecular disease characteristics in adults with indolent systemic mastocytosis, who were followed using conservative therapy. Methods A total of 145 consecutive patients were prospectively followed between January 1983 and July 2008; in addition, from 1967 to 1983, 20 patients were retrospectively studied. Results Multivariate analysis showed that serum β2-microglobulin ( P = .003) together with the presence of mast/stem cell growth factor receptor gene ( KIT ) mutation in mast cells plus myeloid and lymphoid hematopoietic lineages ( P = .02) was the best combination of independent parameters for predicting disease progression (cumulative probability of disease progression of 1.7% ± 1.2% at 5-10 years and of 8.4% ± 5.0% at 20-25 years). Regarding overall survival, the best predictive model included age >60 years ( P = .005) and development of an associated clonal hematological non–mast cell disorder ( P = .03) with a cumulative probability of death of 2.2% ± 1.3% at 5 years and of 11% ± 5.9% at 25 years. Conclusions Indolent systemic mastocytosis in adults has a low disease progression rate, and the great majority of patients have a normal life expectancy, with the presence of KIT mutation in all hematopoietic lineages and increased serum β2-microglobulin the most powerful independent parameters for predicting transformation into a more aggressive form of the disease.
Background Well-differentiated systemic mastocytosis (WDSM) is a rare variant of systemic mastocytosis (SM) characterized by bone marrow (BM) infiltration by mature-appearing mast cells (MCs) often ...lacking exon 17 KIT mutations. Because of its rarity, the clinical and biological features of WDSM remain poorly defined. Objective We sought to determine the clinical, biological, and molecular features of a cohort of 33 patients with mastocytosis in the skin in association with BM infiltration by well-differentiated MCs and to establish potential diagnostic criteria for WDSM. Methods Thirty-three patients with mastocytosis in the skin plus BM aggregates of round, fully granulated MCs lacking strong CD25 and CD2 expression in association with clonal MC features were studied. Results Our cohort of patients showed female predominance (female/male ratio, 4:1) and childhood onset of the disease (91%) with frequent familial aggregation (39%). Skin involvement was heterogeneous, including maculopapular (82%), nodular (6%), and diffuse cutaneous (12%) mastocytosis. KIT mutations were detected in only 10 (30%) of 33 patients, including the KIT D816V (n = 5), K509I (n = 3), N819Y (n = 1), and I817V (n = 1) mutations. BM MCs displayed a unique immunophenotypic pattern consisting of increased light scatter features, overexpression of cytoplasmic carboxypeptidase, and aberrant expression of CD30, together with absent (79%) or low (21%) positivity for CD25, CD2, or both. Despite only 9 (27%) of 33 patients fulfilling the World Health Organization criteria for SM, our findings allowed us to establish the systemic nature of the disease, which fit with the definition of WDSM. Conclusions WDSM represents a rare clinically and molecularly heterogeneous variant of SM that requires unique diagnostic criteria to avoid a misdiagnosis of cutaneous mastocytosis per current World Health Organization criteria.
Background Systemic mastocytosis (SM) is a heterogeneous group of disorders with distinct clinical and biological behavior. Despite this, little is known about the immunophenotypic features of the ...distinct diagnostic categories of SM. Objective To analyze the immunophenotypic characteristics of bone marrow (BM) mast cells (MCs) of different subtypes of SM. Methods Bone marrow samples from 123 patients with different subtypes of SM and 92 controls were analyzed for a broad panel of immunophenotypic markers by flow cytometry. Results Three clearly different maturation-associated immunophenotypic profiles were found for BMMCs in SM. These different profiles were associated with both genetic markers of the disease and its clinical behavior. BMMCs from poor-prognosis categories of SM (aggressive SM and MC leukemia) typically showed an immature phenotype with clonal involvement of all myeloid lineages by the D816V stem cell growth factor receptor gene ( KIT ) mutation. In turn, a mature activated versus resting BMMC immunophenotype was commonly found among patients with good-prognosis subtypes of SM depending on whether they carried (indolent SM and clonal MC activation disorders) or not (well differentiated SM) the D816V KIT mutation. Conclusion Bone marrow MCs from SM show 3 different maturation-related immunophenotypic profiles that are associated with both the genetic markers of the disease and its clinical behavior.
Background Despite the fact that a great majority (>90%) of patients with systemic mastocytosis (SM) carry a common genetic lesion, the D816V KIT mutation, little is known regarding the molecular and ...biological pathways underlying the clinical heterogeneity of the disease. Objective We sought to analyze the gene expression profile (GEP) of bone marrow mast cells (BMMCs) in patients with SM and its association with distinct clinical variants of the disease. Methods GEP analyses were performed by using DNA-oligonucleotide microarrays in highly purified BMMCs from patients with SM carrying the D816V KIT mutation (n = 26) classified according to the diagnostic subtype of SM versus normal/reactive BMMCs (n = 7). Validation of GEP results was performed with flow cytometry in the same set of samples and in an independent cohort of 176 subjects. Results Overall, 758 transcripts were significantly deregulated in patients with SM, with a common GEP (n = 398 genes) for all subvariants of SM analyzed. These were characterized by upregulation of genes involved in the innate and inflammatory immune response, including interferon-induced genes and genes involved in cellular responses to viral antigens, together with complement inhibitory molecules and genes involved in lipid metabolism and protein processing. Interestingly, aggressive SM additionally showed deregulation of apoptosis and cell cycle–related genes, whereas patients with indolent SM displayed increased expression of adhesion-related molecules. Conclusion BMMCs from patients with different clinical subtypes of SM display distinct GEPs, which might reflect new targetable pathways involved in the pathogenesis of the disease.
Background Indolent systemic mastocytosis (ISM) without skin lesions (ISMs− ) shows a higher prevalence in males, lower serum baseline tryptase levels, and KIT mutation more frequently restricted to ...bone marrow (BM) mast cells (MCs) than ISM with skin lesions (ISMs+ ). Interestingly, in almost one-half of ISMs− patients, MC-mediator release episodes are triggered exclusively by insects. Objective We aimed to determine the clinical and laboratory features of ISMs− associated with insect-induced anaphylaxis (insectISMs− ) versus other patients with ISM. Methods A total of 335 patients presenting with MC activation syndrome, including 143 insectISMs− , 72 ISMs− triggered by other factors (otherISMs− ), 56 ISMs+ , and 64 nonclonal MC activation syndrome, were studied. Results Compared with otherISMs− and ISMs+ patients, insectISMs− cases showed marked male predominance (78% vs 53% and 46%; P < .001), a distinct pattern of MC-related symptoms, and significantly lower median serum baseline tryptase levels (22.4 vs 28.7 and 45.8 μg/L; P ≤ .009). Moreover, insectISMs− less frequently presented BM MC aggregates (46% vs 70% and 81%; P ≤ .001), and they systematically showed MC-restricted KIT mutation. Conclusions ISMs− patients with anaphylaxis triggered exclusively by insects display clinical and laboratory features that are significantly different from other ISM cases, including other ISMs− and ISMs+ patients, suggesting that they represent a unique subgroup of ISM with a particularly low BM MC burden in the absence of adverse prognostic factors.
Background Anaphylaxis after Hymenoptera sting has been described in patients with mastocytosis. Venom immunotherapy (VIT) is a safe and effective way to treat patients with Hymenoptera anaphylaxis, ...but few studies have addressed its usefulness in patients with systemic mastocytosis. Objective To study the effectiveness and safety of VIT in patients with systemic mastocytosis having anaphylaxis after Hymenoptera sting. Methods A total of 21 mastocytosis patients—4 women (19%) and 17 men (81%) with a median age of 50 years (range, 29-74 years)—with Hymenoptera sting anaphylaxis who were treated with VIT and followed for a median of 52 months (range, 2-250 months) were studied. Results In 18 of 21 patients—16 of them lacking skin involvement—anaphylaxis was the presenting symptom. Six patients (29%) experienced adverse reactions during VIT, 3 during initiation and 3 during maintenance. Twelve patients (57%) were restung while undergoing VIT; 9 (75%) presented local reactions and 3 (25%) systemic reactions, 1 of which required intubation. The Hymenoptera specific IgE decreased from 4.15 kU/L (range, 0.44-100 kU/L) before immunotherapy to 1.2 kU/L (range, 0.34-69.4 kU/L) after 4 years ( P < .003). Conclusion Venom immunotherapy is effective to treat IgE-mediated Hymenoptera anaphylaxis in patients with mastocytosis. Its use is recommended despite a relatively high risk of adverse reactions during the build-up phase because it provides protection from anaphylaxis in around 3/4 of the patients.
Conversely, they did not screen for mastocytosis in their series, and the potential association between the absence of hives during anaphylaxis and mastocytosis was supported only by studies ...including a limited number of cases, most of which had urticaria pigmentosa (UP). Because of this, we call the authors' and readers' attention to several previous studies that have investigated the association between anaphylaxis and mastocytosis.
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