Well-differentiated Systemic Mastocytosis Research Articles

The 2023 Updated Classification and Diagnostic Criteria of Mastocytosis

Mastocytosis is an uncommon hematologic malignancy characterized by accumulation of abnormal mast cells in various organs or tissues. A somatic point mutation in the KIT gene at codon 816 is detected in more than 90% of patients with systemic Masto cytosis (SM). The 2022 WHO classification continues to recognize three disease types: systemic mastocytosis, cutaneous mastocytosis and mast cell sarcoma. Bone marrow mastocytosis is a new separate subtype of SM. The classification also recognizes well-differentiated systemic mastocytosis, a morphologic pattern that can occur in any SM subtype. Diagnostic criteria for SM have been modified. The expression of CD30 and the presence of any KIT mutation causing ligand-independent activation have been accepted as minor diagnostic criteria. Classical B-findings and C-findings have undergone minor refinements. Most notably, variant allele frequency of D816V mutation ≥ 10% in bone marrow cells or peripheral blood leukocytes is qualified as a B-finding.

A rare case of well-differentiated systemic mastocytosis

A rare case of well-differentiated systemic mastocytosis

Systemic Mastocytosis and Other Entities Involving Mast Cells: A Practical Review and Update.

Simple SummaryIn this article, we outline recent updates in systemic mastocytosis (SM) classification, including the bone marrow mastocytosis subtype; and discuss the mast cell leukemia subtype (acute or chronic), the rare variant of SM known as well-differentiated SM (morphologic variant), and other diseases involving mast cells (i.e., myelomastocytic leukemia and mast cell activation syndrome) that may be diagnostically challenging. We also provide a concise clinical update of new adjusted risk stratification models and overview new treatments that were approved for advanced SM (midostaurin, avapritinib).Evidence in the recent literature suggests that the presentation spectrum of mast cell neoplasms is broad. In this article, we elaborate on recent data pertaining to minor diagnostic criteria of systemic mastocytosis (SM), including sensitive testing methods for detection of activating mutations in the KIT gene or its variants, and adjusted serum tryptase levels in cases with hereditary α-tryptasemia. We also summarize entities that require differential diagnosis, such as the recently reclassified SM subtype named bone marrow mastocytosis, mast cell leukemia (an SM subtype that can be acute or chronic); the rare morphological variant of all SM subtypes known as well-differentiated systemic mastocytosis; the extremely rare myelomastocytic leukemia and its differentiating features from mast cell leukemia; and mast cell activation syndrome. In addition, we provide a concise clinical update of the latest adjusted risk stratification model incorporating genomic data to define prognosis in SM and new treatments that were approved for advanced SM (midostaurin, avapritinib).

Tyrosine kinase inhibitors for the treatment of indolent systemic mastocytosis: Are we there yet?

Indolent systemic mastocytosis (ISM) is the most prevalent form of systemic mastocytosis. Many patients with ISM suffer from mast cell (MC) mediator-related symptoms. In a small number of patients, hematologic progression is seen in the follow-up. In some patients with ISM, symptoms arising from MC-derived mediators including gastrointestinal symptoms, anaphylaxis, and neuropsychiatric symptoms are kept under control with conventional mediator-targeting drugs or MC-stabilizing agents. However, in a substantial number of patients, the symptoms are refractory to such conventional therapy. For these patients, novel drugs and targeted approaches are considered. One reasonable approach may be to apply tyrosine kinase inhibitors directed against KIT and other key kinase targets expressed in neoplastic MCs in ISM. Because MCs in more than 90% of all patients with typical ISM display the KIT D816V mutant receptor, clinically effective KIT-targeting drugs have to be active against this mutant form of KIT. The 2 such most effective and well-studied agents currently available are midostaurin and avapritinib. Other KIT-targeting drugs, such as imatinib or masitinib, are less effective or even noneffective against KIT D816V and are thus recommended for use only in patients with other KIT mutant forms (noncodon 816 mutations) or with wild-type KIT. In the present article, we review the current state in the treatment of ISM with tyrosine kinase inhibitors, with special emphasis on treatment responses and potential adverse effects. In fact, all of these agents also have unique and common adverse effects, and their use to treat patients with ISM should be balanced against their toxicity and short- and long-term safety.

Well-differentiated systemic mastocytosis with KIT K509I mutation and uterus infiltration in an Asian woman with good response to imatinib

Well-differentiated systemic mastocytosis with KIT K509I mutation and uterus infiltration in an Asian woman with good response to imatinib

Bone Marrow Mast Cell Antibody-Targetable Cell Surface Protein Expression Profiles in Systemic Mastocytosis

Despite recent therapeutic advances, systemic mastocytosis (SM) remains an incurable disease due to limited complete remission (CR) rates even after novel therapies. To date, no study has evaluated the expression on SM bone marrow mast cells (BMMC) of large panel of cell surface suitable for antibody-targeted therapy. In this study, we analyzed the expression profile of six cell-surface proteins for which antibody-based therapies are available, on BMMC from 166 SM patients vs. 40 controls. Overall, variable patterns of expression for the markers evaluated were observed among SM BMMC. Thus, CD22, CD30, and CD123, while expressed on BMMC from patients within every subtype of SM, showed highly variable patterns with a significant fraction of negative cases among advanced SM (aggressive SM (ASM), ASM with an associated clonal non-MC lineage disease (ASM-AHN) and MC leukemia (MCL)), 36%, 46%, and 39%, respectively. In turn, CD25 and FcεRI were found to be expressed in most cases (89% and 92%) in virtually all BMMC (median: 92% and 95%) from both indolent and advanced SM, but with lower/absent levels in a significant fraction of MC leukemia (MCL) and both in MCL and well-differentiated SM (WDSM) patients, respectively. In contrast, CD33 was the only marker expressed on all BMMC from every SM patient. Thus, CD33 emerges as the best potentially targetable cell-surface membrane marker in SM, particularly in advanced SM.

Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature.

Resistance to imatinib has been recurrently reported in systemic mastocytosis (SM) carrying exon 17 KIT mutations. We evaluated the efficacy and safety of imatinib therapy in 10 adult SM patients lacking exon 17 KIT mutations, 9 of which fulfilled criteria for well-differentiated SM (WDSM). The World Health Organization 2008 disease categories among WDSM patients were mast cell (MC) leukemia (n = 3), indolent SM (n = 3) and cutaneous mastocytosis (n = 3); the remainder case had SM associated with a clonal haematological non-MC disease. Patients were given imatinib for 12 months −400 or 300 mg daily depending on the presence vs. absence of > 30% bone marrow (BM) MCs and/or signs of advanced disease–. Absence of exon 17 KIT mutations was confirmed in highly-purified BM MCs by peptide nucleic acid-mediated PCR, while mutations involving other exons were investigated by direct sequencing of purified BM MC DNA. Complete response (CR) was defined as resolution of BM MC infiltration, skin lesions, organomegalies and MC-mediator release-associated symptoms, plus normalization of serum tryptase. Criteria for partial response (PR) included ≥ 50% reduction in BM MC infiltration and improvement of skin lesions and/or organomegalies. Treatment was well-tolerated with an overall response rate of 50%, including early and sustained CR in four patients, three of whom had extracellular mutations of KIT, and PR in one case. This later patient and all non-responders (n = 5) showed wild-type KIT. These results together with previous data from the literature support the relevance of the KIT mutational status in selecting SM patients who are candidates for imatinib therapy.

Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis

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. 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. 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. 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. WDSM represents a rare clinically and molecularly heterogeneous variant of SM that requires uniquediagnostic criteria to avoid a misdiagnosis of cutaneousmastocytosis per current World Health Organization criteria.

CD30 expression by bone marrow mast cells from different diagnostic variants of systemic mastocytosis

CD30 expression by bone marrow (BM) mast cells (MC) has been reported recently in systemic mastocytosis (SM) patients. The aim of this study was to investigate the potential diagnostic and prognostic value of CD30 expression in SM as assessed by multiparameter flow cytometry. A total of 163 consecutive BM samples corresponding to 142 SM patients and 21 non-mastocytosis cases were studied. CD30 was positive in most SM patients (80%), but in only one non-mastocytosis case (4.8%). When combined with CD25, CD30 contributed to an improved accuracy over that of CD25 alone (98% versus 93%) mainly because most (eight of nine) of the well-differentiated SM (WDSM), who lacked CD25, were CD30(+). Similar levels of expression of CD30 were observed among all different subgroups of SM except mast cell leukaemia; among indolent SM (ISM) patients, no significant association was observed between the levels of CD30 expression and other clinical and biological features of the disease. The increased expression of CD30 associated with absence of CD25 contributes to the diagnosis of WDSM and its distinction from other subtypes of SM. By contrast, CD30 expression did not contribute either to prognostic stratification of ISM or to the differential diagnosis between ISM and aggressive SM cases.

Complete Response After Imatinib Mesylate Therapy in a Patient With Well-Differentiated Systemic Mastocytosis

Complete Response After Imatinib Mesylate Therapy in a Patient With Well-Differentiated Systemic Mastocytosis

Clinical, Biological, and Molecular Characteristics of Well-Differentiated Systemic Mastocytosis: a study in 18 Patients by Spanish Network on Mastocytosis (REMA)

BACKGROUND: Well-differentiated systemic mastocytosis (WDSM) has recently been described as a novel form of mast cell disease. WDSM is characterized by a marked increase of bone marrow (BM) mast cells, usually with compact aggregates, with normal phenotype and morphology as well as the absence of the typical D816V somatic KIT mutation.OBJECTIVE: To describe and compare clinical, morphological, biological and molecular characteristics in a group of 18 patients who fullfilled criteria for WDSM with a group of 32 patients with indolent systemic mastocytosis (ISM).PATIENTS AND METHODS: All the patients were diagnosed on the basis of BM aspirate and biopsy findings after they were thought to have a systemic mastocytosis. A rigorous skin examination together with a clinical work-up and a complete laboratory analysis including peripheral blood count, routine biochemistry and serum tryptase levels were performed. The Mann-Whitney U and the chi-square tests were used to assess the statistical differences of continuous and categorical variables, respectively.RESULTS: WDSM patients were 4 males and 14 females with a median (range) age of 24 years (2–72) at diagnosis. Median (range) age at the time of the first observation of skin lesions was 2 years (0–41). In 16 of the 18 patients (89%), skin lesions appeared under the age of 14, five of them being younger than 1 year old. All the WDSM patients had skin involvement but the typical maculo-papular lesions were found only in 18% of patients while in the remaining 82% of cases, cutaneous lesions were plaques or nodules. Interestingly, 78% of WDSM patients had cutaneous neck involvement in contrast with only 13% in the ISM group (p<0.001). There were no significant differences in mast cell mediators-related symptoms such as pruritus, flushing, abdominal pain or diahrrea between the two groups while anaphylactic reactions were significantly more frequent in the WDSM group than in the ISM group (59% vs 19%, p=0.004). Overall, bone loss was found in 38% and 37% of WDSM and ISM patients, respectively. Among all the biochemical parameters analyzed, only median serum cholesterol (mg/dL), ferritin (ng/mL) and tryptase levels (ng/mL) were significantly lower in patients with WDSM when compared to ISM patients (150 vs 168.5, p=0.043; 31.3 vs 56.6, p=0.004; 11 vs 31.6, p<0.001; respectively). There were no significant differences in the median percentage of mast cells in the BM study as assesed by flow cytometry between both groups (0.055% in WDSM group and 0.08% in ISM group). In contrast, the presence of both fibrosis and lymphoid aggregates in the BM biopsy were more frequent in patients with ISM than in patients with WDSM (52% vs 0%, p<0.001; 55% vs 14%, p=0.01; respectively). Somatic KIT mutation at codon 816 was found in 31 of the 32 ISM patients (97%) while only in one (6%) WDSM patient (p<0.001). Additionally, 2 WDSM patients were found to carry variant mutations at codons other than at codon 816 (N819Y and I817V, respectively). From the remaining 15 WDSM patients, clonality of mast cell population was demonstrated by human androgen receptor (HUMARA) assay in the 5 female patients in whom the assay was made.CONCLUSIONS: WDSM is a variant of systemic mastocytosis with several characteristics that are distinguishable from ISM, such as:early onset of skin lesions,atypical skin involvement (plaques or nodules and cutaneous neck involvement),frequent anaphylactic episodes,lower serum tryptase levels than ISM despite no differences in BM mast cell infiltration, andinfrequent detection of typical activating D816V KIT mutation.

KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients

AbstractDespite the relevance of the c-kit/stem cell factor (SCF) signaling pathway in mast cell (MC) diseases, the exact frequency of KIT mutations in different compartments of bone marrow (BM) hematopoietic cells of individuals with systemic mastocytosis (SM), and its different diagnostic categories, remains unknown. In this study, we prospectively analyzed the presence of KIT mutations in fluorescence-activated cell-sorting (FACS)– purified populations of BM MCs (n = 113) and other BM cell compartments (n = 67) from adults with SM. Our results show the presence of D816V KIT mutation in virtually all adults (93%) with indolent and aggressive forms of SM, except well-differentiated SM (29%), while other KIT mutations were rarely (< 3%) detected. In around one-third of patients with mutated MCs, the KIT mutation was also detected in CD34+ hematopoietic cells and eosinophils, and, to a lesser extent, in monocytic, neutrophil-lineage BM precursor cells and lymphocytes. Most patient with poor-prognosis SM (81%) carried the KIT mutation in 2 or more BM myeloid cell populations, while this was detected in a smaller proportion (27%) of indolent cases. These results would support the notion that KIT mutation is a hallmark of adult SM where it targets a pluripotent hematopoietic stem cell, and may contribute to explaining previously observed discrepancies in the literature.

The tryptase positive compact round cell infiltrate of the bone marrow (TROCI-BM): a novel histopathological finding requiring the application of lineage specific markers

Aims: Compact tryptase-positive round cell infiltrates of the bone marrow (TROCI-BM) are very rare histopathological findings and may pose challenging problems with regard to the cell type involved (either mast...

Well-differentiated systemic mastocytosis: A new disease variant with mature mast cell phenotype and lack of codon 816 c-Kit mutations

Rationale We reviewed clinical features and bone marrow pathology in 225 patients with mastocytosis referred to two major referral centers in the U.S. and Spain to identify histopathologic variants of disease, and describe their clinical features and response to therapy. Methods Bone marrow biopsy and aspirates were obtained after informed consent. Mast cells were examined by flow cytometry and mutational analysis of c-kit gene was performed. Results We identified six patients (5 females, 1 male, age range 10-73 years), whose mast cells had a unique mature phenotype with a round shape, fully granulated cytoplasm, and a centrally located round nucleus. None of the bone marrows had lymphoid aggregates or fibrosis commonly observed in classic forms of systemic mastocytosis. Flow cytometric analysis of the aspirate revealed mast cells to have an uncharacteristically normal surface immunophenotype with no detectable expression of CD2 and CD25 antigens. Five out of six patients had urticaria pigmentosa. Three had onset of disease during infancy, with bullous cutaneous disease. Common symptoms included pruritus and gastrointestinal complaints. Splenomegaly was present in two patients resulting hypersplenism in one. Serum tryptase levels ranged from 13.6 to 271 ng/ml. Codon 816 c-kit mutations, commonly associated with systemic mastocytosis, were undetectable in all bone marrow samples studied. A trial with the tyrosine kinase inhibitor imatinib resulted in a dramatic improvement of mast cell infiltration and symptoms in the one patient treated. Conclusions Well-differentiated systemic mastocytosis is a rare disease variant which should be recognized because of its potential to response to curative therapy.