Case Of Indolent Systemic Mastocytosis Research Articles

A case of indolent systemic mastocytosis with extensive cutaneous involvement

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Distinct Diagnostic and Clinical Features of Bone Marrow Mastocytosis: A Study of the Registry of the European Competence Network on Mastocytosis (ECNM)

Abstract Background. Bone marrow mastocytosis (BMM) is characterized by accumulation of neoplastic mast cells (MC) in the bone marrow (BM), absence of skin lesions and lack of overt infiltration of other extra-cutaneous organs by neoplastic MC. Although clinically relevant due to its association with life-threatening anaphylaxis, BMM is considered a provisional sub-entity of indolent systemic mastocytosis (ISM) in the 2016 WHO classification. Aims and methods. To define clinical and biological features of BMM we evaluated 1,343 adult patients (pts) with non-advanced systemic mastocytosis (SM) enrolled in the European Competence Network on Mastocytosis (ECNM) registry. The following characteristics were compared between pts with BMM (n=260), ISM (n=1,027) and smouldering SM (SSM, n=56): age, gender, diagnostic criteria, biochemical parameters at diagnosis [blood counts, albumin, alkaline phosphatase (AP), lactate dehydrogenase, tryptase], presence of mediator-related symptoms (diarrhea, flushing, headache, pruritus, hypotension, blistering, cramping, bone pain) and their severity (classified according to Valent P. et al. Eur J Clin Invest. 2007;37:435-53), constitutional symptoms, osteoporosis/osteopenia and allergy. The Student- t and the χ2 tests were used to assess the statistical significance of differences for continuous and categorical variables, respectively. Event-free survival (EFS) was calculated from diagnosis to progression into more severe SM (i.e. SSM, aggressive SM, SM associated with another hematological neoplasm or mast cell leukemia) or death. Results. Median age at diagnosis was 53 years (yrs) (range 19-83) for BMM vs 46 yrs (range 19-82) for ISM vs 52 yrs (range 25-79) for SSM (p 20 ng/mL at diagnosis, while 77% of ISM and 100% of SSM pts fulfilled this criterion. If performed, atypical MC morphology in BM smears, aberrant MC immunophenotype (i.e. CD25 and/or CD2 expression) and KIT D816V mutation were demonstrable in the majority of pts (CD25 and/or CD2-positive BM MC: n=918, 95%; KIT D816V positive: n=910, 86%), without differences between the three groups. As a consequence, in 31% of BMM and 11% of ISM cases the diagnosis was made on the basis of minor criteria only. BMM pts had significantly higher hemoglobin levels compared to pts with ISM/SSM (median 14.5 vs 13.9 g/dL, respectively, p BMM pts had less frequent and less severe (grade 0-2) mediator-related symptoms as compared to ISM/SSM, except for hypotension, mainly due to the association of BMM with severe allergic reactions. Indeed, 76% of the BMM pts had a history of anaphylaxis, a significant difference compared to ISM or SSM pts (34% and 31%, respectively; p Long-term prognosis was similar for all groups, even though SSM tended to a less favourable course: EFS at 10 years was 88.9% (95%CI: 73.6-95.6) for BMM, 88.1% (95%CI: 83.4-91.6) for ISM and 78.8% (95%CI:55.7-90.8) for SSM (p=0.2). Conclusions. BMM is a distinct subgroup of non-advanced SM characterized by male predominance, low burden of neoplastic MC, low level of serum tryptase and AP, limited frequency and severity of mediator-related symptoms, except hypotension, and a striking association with anaphylaxis, mainly triggered by hymenoptera. These data support the proposal of considering BMM as a distinct variant of mastocytosis. Disclosures Bonifacio: Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Hadzijusufovic: Novartis: Honoraria. Gotlib: Promedior: Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Promedior: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding. Sperr: Meda: Research Funding; Phadia: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Novartis: Other: Register; Teva: Honoraria. Valent: Teva: Honoraria; BMS: Honoraria; Deciphera: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Blueprint: Research Funding; Pfizer: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Incyte: Honoraria. Zanotti: Deciphera: Consultancy.

KIT D816V–mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression

AbstractMultilineage involvement of bone marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult indolent systemic mastocytosis (ISM) patients in association with a poorer prognosis. Here, we investigated the potential involvement of BM mesenchymal stem cells (MSCs) from ISM patients by the KIT D816V mutation and its potential impact on disease progression and outcome. This mutation was investigated in highly purified BM MSCs and other BM cell populations from 83 ISM patients followed for a median of 116 months. KIT D816V–mutated MSCs were detected in 22 of 83 cases. All MSC-mutated patients had multilineage KIT mutation (100% vs 30%, P = .0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P = .03) and a polyclonal pattern of inactivation of the X-chromosome of KIT-mutated BM mast cells (64% vs 0%; P = .01) vs other multilineage ISM cases. Moreover, presence of KIT-mutated MSCs was associated with more advanced disease features, a greater rate of disease progression (50% vs 17%; P = .04), and a shorter progression-free survival (P ≤ .003). Overall, these results support the notion that ISM patients with mutated MSCs may have acquired the KIT mutation in a common pluripotent progenitor cell, prior to differentiation into MSCs and hematopoietic precursor cells, before the X-chromosome inactivation process occurs. From a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a significantly greater risk for disease progression and a poorer outcome.

KIT D816V Mutation Positive Bone Marrow Mesenchymal Stem Cells in Indolent Systemic Mastocytosis Are Associated with Disease Progression

PURPOSEMultilineageinvolvement of bone marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult indolent systemic mastocytosis (ISM) patients in association with a poorer prognosis. Here we investigated the potential involvement of BM mesenchymal stem cells (MSC) from ISM patients by the KIT D816V mutation and its potential impact on disease progression and outcome. METHODSThe KIT D816V mutation was investigated in highly-purified BM MSC and other BM cell populations from 83 ISM patients followed for a median of 116 months. MC clonality was further evaluated in female patients by the pattern of inactivation of the X chromosome (XCIP). RESULTSKIT D816V-mutated MSC were detected in 22/83 (27%) ISM patients. All MSC-mutated patients had multilineage KIT mutation (100% vs. 30%, p=0.0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P =.03) and a polyclonal XCIP of the KIT- mutated BM MC (64% vs 0%; P =0.01) vs other multilineage ISM cases. Moreover, presence of KIT D816V-mutated MSC was associated with more advanced disease features of ISM, a greater rate of disease progression (50% vs 17%; P =.04) and a shorter progression-free survival at 10, 20 and 30 years (P ≤.003). CONCLUSIONOverall, these results support the notion that ISM patients with mutated MSC may have acquired the KIT mutation in a common pluripotent progenitor cell, prior to differentiation into MSC and hematopoietic precursor cells, before the X-chromosome inactivation process occurs. From a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a significantly greater risk for disease progression and a poorer outcome. DisclosuresNo relevant conflicts of interest to declare.

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 IL1β, IL6, IL13, CCL23 and clusterin in SM at diagnosis and correlated them with disease outcome. Here we investigated IL1β, 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 IL1β, 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.

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.

Nonaggressive systemic mastocytosis (SM) without skin lesions associated with insect-induced anaphylaxis shows unique features versus other indolent SM

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. We aimed to determine the clinical and laboratory features of ISMs(-) associated with insect-induced anaphylaxis (insectISMs(-)) versus other patients with ISM. 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. 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. 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.

Indolent systemic mastocytosis limited to the bone: a case report and review of the literature

CONTEXT Systemic mastocytosis is defined as a clonal disorder of mast cells and their precursor cells and is currently classified as a myeloproliferative neoplasm. Its clinical course has a wide spectrum, ranging from indolent disease, with normal life expectancy, to highly aggressive disease, associated with multisystemic involvement and poor overall survival. The aim of this study was to report a case of indolent systemic mastocytosis, focusing on the diagnostic challenges, with a review of the literature. CASE REPORT A 79-year-old Caucasian woman with osteoporosis was evaluated at the Emergency Department because of complaints of low back pain. Before this, she had consulted an orthopedist and had undergone some imaging examinations, namely a bone scan that revealed a "superscan" pattern. Due to her pain complaints and these test results, the patient was admitted to the Department of Internal Medicine. After undergoing several analytical tests and some additional imaging examinations to rule out some important differential diagnoses, she then underwent bone marrow biopsy, which made it possible to identify indolent systemic mastocytosis. CONCLUSION Systemic mastocytosis is a rare entity that is difficult to diagnose. Its symptoms are often unspecific and frequently ignored. Skeletal changes may be the first and only manifestation of the disease and in some cases, like this one, the diagnosis is made only after histological examination. The key point for the diagnosis is to contemplate the possibility of systemic mastocytosis.

Indolent systemic mastocytosis associated with light chain deposition disease

Systemic mastocytosis (SM) is characterized by infiltration of neoplastic mast cells in one or more organ systems. SM in association with plasma cell dyscrasia is very rare. We report a first case of indolent SM (ISM) associated with light chain deposition disease (LCDD) in a kidney biopsy from a 59-year-old female presenting with skin rash, elevated serum creatinine, hematuria and mild proteinuria. Subsequent workup demonstrated IgG kappa monoclonal protein in serum and urine. A bone marrow biopsy revealed neoplastic mast cells involving bone marrow without evidence of clonal myeloid or lymphoid proliferation. Kidney biopsy demonstrated modest mesangial expansion detected by light microscopy and unequivocal evidence of monoclonal kappa light chain deposition within glomerular capillaries, tubular basement membranes and vascular walls detected by immunofluorescence and/or electron microscopy, along with equivocal evidence of light chain cast nephropathy. Despite treatment with bortezomib and dexamethasone, her renal function was progressively declined over the next 6 months. This case is a reminder that SM can coincide with LCDD, which requires clinical suspicion and multimodality workup on a kidney biopsy including immunofluorescence and electron microscopy to reach the correct diagnosis.