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 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 Systemic mast cell activation disorders (MCADs) are characterized by severe and systemic mast cell (MC) mediators–related symptoms frequently associated with increased serum baseline ...tryptase (sBt). Objective To analyze the clinical, biological, and molecular characteristics of adult patients presenting with systemic MC activation symptoms/anaphylaxis in the absence of skin mastocytosis who showed clonal (c) versus nonclonal (nc) MCs and to provide indication criteria for bone marrow (BM) studies. Methods Eighty-three patients were studied. Patients showing clonal BM MCs were grouped into indolent systemic mastocytosis without skin lesions (ISMs- ; n = 48) and other c-MCADs (n = 3)—both with CD25++ BM MCs and either positive mast/stem cell growth factor receptor gene ( KIT ) mutation or clonal human androgen receptor assay (HUMARA) tests—and nc-MCAD (CD25-negative BM MCs in the absence of KIT mutation; n = 32) and compared for their clinical, biological, and molecular characteristics. Results Most clonal patients (48/51; 94%) met the World Health Organization criteria for systemic mastocytosis and were classified as ISMs- , whereas the other 3 c-MCAD and all nc-MCAD patients did not. In addition, although both patients with ISMs- and patients with nc-MCAD presented with idiopathic and allergen-induced anaphylaxis, the former showed a higher frequency of men, cardiovascular symptoms, and insect bite as a trigger, together with greater sBt. Based on a multivariate analysis, a highly efficient model to predict clonality before BM sampling was built that includes male sex ( P = .01), presyncopal and/or syncopal episodes ( P = .009) in the absence of urticaria and angioedema ( P = .003), and sBt >25 μg/L ( P = .006) as independent predictive factors. Conclusions Patients with c-MCAD and ISMs- display unique clinical and laboratory features different from nc-MCAD patients. A significant percentage of c-MCAD patients can be considered as true ISMs- diagnosed at early phases of the disease.
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.
Bone Marrow Expression of Mast Cell Disorders Sánchez-Muñoz, Laura; Henriques, Ana Filipa; Alvarez-Twose, Iván ...
Immunology and allergy clinics of North America,
08/2018, Letnik:
38, Številka:
3
Journal Article
Recenzirano
Mast cell disorders comprise a heterogeneous group of rare diseases, the diagnosis of which still remains a challenge. Bone marrow analysis constitutes the most appropriate site for screening ...systemic involvement in mastocytosis. Morphologic, immunohistochemical, flow cytometric immunophenotyping, and molecular studies should be routinely performed for diagnostic/prognostic purposes in experienced reference centers during the diagnostic workup in suspected systemic mastocytosis. The authors review the most relevant characteristics of bone marrow expression of mast cell disorders as well as the different methodological approaches to be applied to perform an objective and reproducible diagnosis and classification of mastocytosis and other mast cell disorders.
A preferential association between systemic mastocytosis (SM) and hymenoptera allergy (HVA) has been observed. Patients with both diseases are at risk for more severe reactions, and venom ...immunotherapy (VIT) may represent a life-saving treatment, but the use of VIT in such patients raised concerns about its safety.
We evaluated a large population of patients with SM and HVA who received VIT.
This prospective study was performed in Italy and Spain. A diagnosis of SM and HVA and a VIT prescription were made according to international recommendations. The patients were carefully followed up during VIT, with special attention to field stings.
A total of 84 patients (70 men, 14 women; mean age 52.1 years) were included, 81% with grade IV reaction, 91% with indolent SM. No difference was seen between the Italian and Spanish patients. There were 10 adverse reactions during the induction phase: 3 with the conventional induction and 7 with the rush-modified induction, none resulted in epinephrine administration and/or hospitalization. Fifty patients had one or more field re-sting (95 episodes), none during induction. The time elapsed from starting VIT and first re-sting was 2 months to 7 years, and the number of re-stings per patient was 1-6. Of the 50 patients who were re-stung, 43 (86%) resulted in being fully protected. Seven patients had reactions, and the maintenance dose was safely increased to 200 mcg. The maintenance dose interval was not different between patients with and those without reactions at re-stings.
VIT is well tolerated, safe, and effective in patients with SM.
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