Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis

Abstract

Mastocytosis is an emerging differential diagnosis in patients with more or less specific mediator-related symptoms. In some of these patients, typical skin lesions are found and the diagnosis of mastocytosis can be established. In other cases, however, skin lesions are absent, which represents a diagnostic challenge. In the light of this unmet need, we developed a diagnostic algorithm for patients with suspected mastocytosis. In adult patients with typical lesions of mastocytosis in the skin, a bone marrow (BM) biopsy should be considered, regardless of the basal serum tryptase concentration. In adults without skin lesions who suffer from mediator-related or other typical symptoms, the basal tryptase level is an important parameter. In those with a slightly increased tryptase level, additional investigations, including a sensitive KIT mutation analysis of blood leucocytes or measurement of urinary histamine metabolites, may be helpful. In adult patients in whom (i) KIT D816V is detected and/or (ii) the basal serum tryptase level is clearly increased (>25-30 ng/ ml) and/or (iii) other clinical or laboratory features suggest the presence of 'occult' mastocytosis or another haematologic neoplasm, a BM investigation is recommended. In the absence of KIT D816V and other signs or symptoms of mastocytosis

Detection of the KIT D816V mutation in peripheral blood of systemic mastocytosis: diagnostic implications

“…Moreover, virtually all aggressive systemic mastocytosis cases, as well as around one-fourth of indolent systemic mastocytosis patients, 6 present multilineage involvement of bone marrow cell compartments other than mast cells by the KIT mutation, 11,12,25,26 this being considered as the most powerful prognostic factor for disease progression among adult indolent systemic mastocytosis patients. 7,10,27 Recently, several groups 9,13,14 have confirmed the feasibility of detecting the KIT mutation in peripheral blood leukocytes; consequently, sensitive allele-specific oligonucleotide-qPCR approaches for peripheral blood detection of the KIT D816V mutation 13,28 have been included in recent consensus diagnostic algorithms 18 owing to the less invasive diagnostic approach in peripheral blood vs bone marrow. However, careful analysis of the literature shows discrepant results regarding both the frequency of systemic mastocytosis cases who are KIT D816V + in peripheral blood and the prognostic impact of the KIT D816V allele burden.…”

“…Altogether, these results support the recent consensus proposal, to introduce the use of allele-specific oligonucleotide-qPCR analysis of peripheral blood leukocytes in the diagnostic screening of systemic mastocytosis. 9,18 However, caution should be taken in systemic mastocytosis cases presenting with mast cell activation-associated symptoms (e.g., anaphylaxis) in the absence of skin lesions if the mutation is not detected, because around one-third of indolent systemic mastocytosis without skin lesions cases carrying the KIT D816V mutation in bone marrow cells this mutation could not be detected in peripheral blood by either of the methods. More importantly, no clear association was found between the qualitative allele-specific oligonucleotide-qPCR method and multilineage involvement of bone marrow hematopoiesis using the presence of the mutation in peripheral blood; in contrast, the KIT allele burden by (quantitative) allele-specific oligonucleotide-qPCR and the detection of the KIT D816V + mutation in peripheral blood cells by the peptide nucleic acid-mediated PCR method were both highly predictive for multilineage involvement of bone marrow hematopoiesis.…”

“…These 192 KIT D816V + cases were selected from a series of 456 consecutively diagnosed systemic mastocytosis patients, of whom 417 (91%) had the KIT D816V mutation, 9 (2%) had other exon 17 KIT mutations, 5 (1%) had KIT mutations in exons other than exon 17 and 25 (6%) had no detectable KIT mutations. 18 and REMA guidelines, 3 with the following distribution: indolent systemic mastocytosis with skin lesions, 135 cases; indolent systemic mastocytosis without skin lesions, 44 cases; aggressive systemic mastocytosis, 9 cases; systemic mastocytosis with an associated hematological non-mast cells lineage disease, 2 cases, and; monoclonal mast cell activation syndrome, 2 patients. Paired peripheral blood and bone marrow samples from all cases were analyzed by the peptide nucleic acid-mediated PCR method; 17 all such peripheral blood samples were analyzed in parallel by the allele-specific oligonucleotide-qPCR method.…”

Clinical presentation and management practice of systemic mastocytosis. A survey on 460 Italian patients

“…Minor criteria for SM are: a spindle shaped appearance of mast cells in the BM; aberrant expression of CD2 and/or CD25 by mast cells; mutation of the codon 816 of cKIT gene, in most cases D816V; serum tryptase level >20 ng/mL, except for patients with associated hematologic disorders where tryptase levels do not count as a criterion. Diagnosis of SM is established when the major plus one minor criterion, or three minor criteria, are satisfied [2,3]. The WHO 2008 classification of SM recognizes different subgroups that have important prognostic correlates: indolent systemic mastocytosis (ISM), including smoldering systemic mastocytosis (SSM) and isolated bone marrow mastocytosis (iBMM); aggressive SM (ASM); SM associated with an hematological clonal non-MC lineage disease (SM-AHNMD); mast cell leukemia (MCL).…”

Diagnosis and management of mastocytosis: an emerging challenge in applied hematology

“…With regard to diagnostic algorithms, assays, and standard procedures, we refer to the available literature. 12,14,24,25 A simplified version of a diagnostic algorithm is shown in Figure 1. The most important screen parameter in suspected SM remains the basal serum tryptase.…”