Clonal Proliferation Of Mast Cells Research Articles

Diagnosis and management of systemic mastocytosis in a community hematology setting.

Systemic mastocytosis (SM) is a rare and potentially severe hematologic disorder characterized by the clonal proliferation of mast cells (MCs) into various organs. The clinical manifestations of advanced SM are caused by the uncontrolled release of cytokines and vasoactive amines from MC and disease-induced organ dysfunction. Patients with SM typically present with symptoms such as flushing, pruritus, diarrhea, and headaches, but outcomes following active treatment have not been well characterized. In this study, the clinical characteristics, treatment patterns, and natural history of an SM patient cohort diagnosed and treated within a community hematology network in the United States is described. We identified 105 patients who were diagnosed and managed in one of 19 community hematology clinics up to an index date of 1 October 2022. Data collection included patient and disease characteristics, baseline biochemistry and hematology, SM diagnostic criteria being met, biomarkers tested, CD2 and/or CD25 expression in MCs as well as serum tryptase levels at presentation. Data abstraction also included supportive care drugs and anticancer therapy used, treatment response, reason for discontinuation, and overall survival by disease subtype. A total of 105 SM patients were identified who met the inclusion criteria. The specific SM subtypes were indolent (47.6%), aggressive (9.5%), SM with an associated hematological neoplasm (19.0%), MC leukemia (1.9%), and subtype not documented (21.9%). Regardless of subtype, approximately 62% of patients did not receive SM-directed active therapy. Only 26% of patients with indolent systemic mastocytosis (ISM) received treatment compared to 65.6% with advanced subtypes. Relative to ISM cohort, the relative risk of death in patients with the advanced SM subtypes was approximately 15 times greater (hazard ratio = 15.0; 95% confidence interval: 3.3 to 66.5). SM patients present with multiple underlying symptoms, within various disease subtypes that are difficult to diagnose in a timely manner. As a result, many patients do not receive active drug therapy for their disease. Therefore, greater disease awareness is required as well as new tools for earlier disease detection.

Safety of COVID-19 mRNA vaccination and effects of SARS-CoV-2 infection in children and adults with mast cell disorders.

Mastocytosis is characterized by abnormal clonal mast cell proliferation. Given the paucity of data in patients with mastocytosis, it is crucial to assess the safety of COVID-19 vaccines in this population. We aimed to assess the risk of allergic reactions and the effect of COVID-19 infection among patients with mastocytosis. Participants were recruited from Canada and Israel between December 2021 and May 2022. Consenting participants were administered standardized questionnaires querying whether they were infected with COVID-19, if they received the first and second dose vaccines, and post-vaccination side effects including allergic reactions (urticaria/angioedema, current rash flaring, need for updosing medications, or respiratory symptoms) and common side effects including injection site reaction (ISR) and flu-like symptoms. Forty participants with mastocytosis were administered a standardized questionnaire (median age = 9, 59% male). Amongst all participants, 16 (39%) reported COVID-19 infection and most (75%) reported flu-like symptoms, 3 (19%) were asymptomatic, 1 suffered from shortness of breath/chest pain and 1 from facial flushing. Of the 25 participants who were eligible for vaccination (≥ 5years old), 80% received a first-dose vaccine and 68% received a second-dose vaccine. Of those who received the first-dose vaccine, most (60%) remained asymptomatic, 20% developed flu-like symptoms, 20% had an ISR, and 1 patient had an allergic reaction (urticaria and swelling). Of those who received the second-dose vaccine, most (53%) were asymptomatic, and 1 had an allergic reaction. No significant difference was found between side effects of both vaccine doses. No reactions fulfilled the criteria for anaphylaxis in either dose. This study reveals that among patients with mastocytosis, COVID-19 vaccine and infection were well-tolerated in the majority of cases.

Systemic mastocytosis in adults: 2023 update on diagnosis, risk stratification and management.

Systemic mastocytosis (SM) results from clonal proliferation of mast cells (MC) in extracutaneous organs. The major criterion is presence of multifocal MC clusters in the bone marrow and/or extracutaneous organs. Minor diagnostic criteria include elevated serum tryptase level, MC CD25/CD2/CD30 expression, and presence of activating KIT mutations. Establishing SM subtype as per the International Consensus Classification/World Health Organization classification systems is an important first step. Patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, including aggressive SM (ASM), SM with associated myeloid neoplasm (SM-AMN), and mast cell leukemia. Identification of poor-risk mutations (i.e., ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Several risk models are available to help assign prognosis in SM patients. Treatment goals for ISM patients are primarily directed toward anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to reverse disease-related organ dysfunction. Tyrosine kinase inhibitors (TKI) (midostaurin, avapritinib) have changed the treatment landscape in SM. While deep biochemical, histological and molecular responses have been documented with avapritinib treatment, its efficacy as monotherapy against a multimutated AMN disease component in SM-AMN patients remains unclear. Cladribine continues to have a role for MC debulking, whereas interferon-α has a diminishing role in the TKI era. Treatment of SM-AMN primarily targets the AMN component, particularly if an aggressive disease such as acute leukemia is present. Allogeneic stem cell transplant has a role in such patients. Imatinib has a therapeutic role only in the rare patient with an imatinib-sensitive KIT mutation.

Systemic mastocytosis: a (slightly) simplified diagnostic approach

This presentation which addresses changes and updates in mastocytosis is based on the recently published International Consensus Classification of myeloid neoplasms (Arber DA, Orazi A, Hasserjian RP, et al. Blood 2022; 140: 1200–1228). Mastocytosis is a neoplastic disease characterised by a clonal proliferation of mast cells, which accumulate in one or multiple organs. The disease includes three clinicopathologic types. It can be limited to the skin (cutaneous mastocytosis), a condition mostly occurring in childhood that usually behaves in a benign fashion. Adult patients usually present with systemic disease, i.e., systemic mastocytosis (SM). This includes indolent subtypes such as indolent SM, its subvariant termed bone marrow mastocytosis, and smoldering SM. Aggressive SM subtypes include aggressive SM and mast cell leukaemia. The latter represents a proliferation of immature and atypical mast cells (promastocytes, metachromatic blasts or pleomorphic poorly differentiated forms) which account for > 20% of the marrow aspirate cellularity. SM with an associated myeloid neoplasm represents the fifth subtype of SM. A separate type of mast cell neoplasm is mast cell sarcoma, a rare aggressive form of localised mast cell proliferation that can present in the skin, bone, and in other organs, and can progress to mast cell leukaemia. Reference 1. Leguit RJ, Wang SA, George TI, Tzankov A, Orazi A. The international consensus classification of mastocytosis and related entities. Virchows Arch 2022; doi: 10.1007/s00428-022-03423-3. Epub ahead of print. PMID: 36214901.

Systemic mastocytosis: a (slightly) simplified diagnostic approach

This presentation which addresses changes and updates in mastocytosis is based on the recently published International Consensus Classification of myeloid neoplasms (Arber DA, Orazi A, Hasserjian RP, et al. Blood 2022; 140: 1200–1228). Mastocytosis is a neoplastic disease characterised by a clonal proliferation of mast cells, which accumulate in one or multiple organs. The disease includes three clinicopathologic types. It can be limited to the skin (cutaneous mastocytosis), a condition mostly occurring in childhood that usually behaves in a benign fashion. Adult patients usually present with systemic disease, i.e., systemic mastocytosis (SM). This includes indolent subtypes such as indolent SM, its subvariant termed bone marrow mastocytosis, and smoldering SM. Aggressive SM subtypes include aggressive SM and mast cell leukaemia. The latter represents a proliferation of immature and atypical mast cells (promastocytes, metachromatic blasts or pleomorphic poorly differentiated forms) which account for > 20% of the marrow aspirate cellularity. SM with an associated myeloid neoplasm represents the fifth subtype of SM. A separate type of mast cell neoplasm is mast cell sarcoma, a rare aggressive form of localised mast cell proliferation that can present in the skin, bone, and in other organs, and can progress to mast cell leukaemia. Reference 1. Leguit RJ, Wang SA, George TI, Tzankov A, Orazi A. The international consensus classification of mastocytosis and related entities. Virchows Arch 2022; doi: 10.1007/s00428-022-03423-3. Epub ahead of print. PMID: 36214901.

The Use of Avapritinib in Advanced Systemic Mastocytosis: Report of an Open-Label Compassionate Use Program in the United Kingdom

Background: Advanced systemic mastocytosis (AdvSM) is a rare haematological neoplasm occurring due to clonal proliferation of mast cells in extracutaneous organs. In up to 95% of cases, the driver mutation is KIT D816V. AdvSM encompasses aggressive SM (ASM), mast cell leukaemia and SM with an associated haematological neoplasm (SM-AHN). In this latter, the AHN component often dictates the clinical course, being most frequently associated with chronic myelomonocytic leukaemia (CMML). Treatment for AdvSM has evolved recently with the introduction of targetted tyrosine kinase inhibitors (TKI). Avapritinib, a highly selective inhibitor for KIT and PDGFRA, produced robust responses in measures of mast cell/disease burden in the PATHFINDER trial, leading to approval in USA and Europe. We report the clinical experience of AdvSM patients who have received avapritinib at 11 centers in the United Kingdom via an open-label compassionate use program. Methods: Avapritinib was commenced in AdvSM patients with progressive disease-related symptoms and end-organ damage. The initial dose was adjusted according to tolerability and kept continuously until disease progression or unmanageable toxicity. Results: In a cohort of 13 patients, with an age average of 68.8 years (range 57-76), 11 patients (84.6%) were diagnosed with SM-AHN; 81.8% with a concomitant diagnosis of CMML. 2 patients (15.4%) were diagnosed with ASM. All patients harbored the D816V mutation and 8 patients (61.5%) presented with additional mutations; 5 with SRSF2 and 1 with ASXL1. On application of prognostic scores; International Prognostic Scoring system for Mastocytosis (IPSM) 10 patients (76.9%) were classified as AdvSM-3/4 and Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis (MARS) 7 patients (53.8%) were stratified as high risk. Treatment: 10 patients (76.9%) received avapritinib as a first-line regime, and 9 patients (69.2%) started at a dose of 200 mg od. Three patients were previously treated with other regimes - one patient with midostaurin, one with cladribine and one with azacytidine. Response: Median duration of treatment was 503.7 days (range 75 - 1168 days). Baseline median blood parameters for this cohort were tryptase level of 168 ng/mL (range 91-811), alkaline phosphatase (ALP) of 437 IU/L (range 127-1235), albumin of 34.5 g/L (range 24-48) and a spleen size of 16.4 cm (range 12-26), measured by radiologically. At response evaluation, 9 patients (69.2%) had a tryptase level <20 ng/mL and 11 patients (84.6%) had normalised their ALP and albumin levels. None of the patients had a clinically enlarged spleen, with 9 patients (69.2%) having a normal spleen size on abdominal ultrasound. 8 patients had a complete pathological remission. The overall response rate (using the modified IWG-ECNM-MRT criteria) was 76.9% with a complete response (CR) or CR with partial haematologic recovery in 53.8% of patients. At the last follow-up, 3 patients (23.1%) died; 1 from SM progression, 1 from haematemesis and 1 due to progression of the AHN component but had a partial response of the SM with avapritinib. Toxicities:10 patients (76.9%) had haematological toxicities. Bleeding was reported in 4 patients (30.8%); 3 patients with grade 1/2 (1 mucocutaneous and 2 mild gastrointestinal bleeds), and 1 fatal gastrointestinal bleed. No intracranial bleeds were reported. Fluid retention was noted in 3 patients (23.1%). Less frequent side effects noted were nausea/vomiting (2 patients) and skin/hair discoloration (1 patient). 11 patients (84.6%) needed dose reduction of avapritinib due to haematological toxicity with 8 patients (72.7%) remaining at 100 mg od. 4 patients (36.4%) had to intermittently stop treatment until haematological recovery. Avapritinib was stopped in 2 patients (15.4%) due to disease progression or unmanageable toxicity. Conclusion: This small cohort of patients reflects the clinical heterogeneity of AdvSM and mirrors the PATHFINDER trial outcomes in 'real world 'experience in the UK. Avapritinib as 1st line was tolerated, producing sustained clinical and pathological responses in the majority of this group of non-selected patients with AdvSM with high risk disease. Dose adjustments due to anticipated myelosuppression were made, with 72.2% of patients maintained on 100mg Avapritinib od. 2 patients with SM-AHN are referred for HSCT as a curative treatment as a result of achieving a CR with Avapritinib.

The international consensus classification of mastocytosis and related entities.

Mastocytosis is a neoplasm characterized by a clonal proliferation of mast cells, which accumulate in one or multiple organs, associated with an extremely heterogeneous clinical presentation. The disease can be limited to the skin (cutaneous mastocytosis) that is mostly seen in childhood and usually behaves in a benign fashion. Adult patients most often present with systemic disease with or without skin lesions. This includes indolent forms such as indolent systemic mastocytosis and its subvariant bone marrow mastocytosis, and smoldering systemic mastocytosis as well as aggressive forms including aggressive systemic mastocytosis, systemic mastocytosis with an associated myeloid neoplasm (previously called systemic mastocytosis with an associated hematologic neoplasm), and mast cell leukemia. In addition, mast cell sarcoma is a rare aggressive form of mastocytosis that can present in the skin as well as at extracutaneous sites. This review article focuses on the updates in mastocytosis of the 2022 international consensus classification (ICC).

Mastocytosis Colitis in 54 year old woman: A rare case report

Introduction: Mastocytosis is a rare disorder occurring due to neoplastic clonal proliferation of mast cells accumulating in one or more organ systems. Systemic mastocytosis is generally diagnosed after the second decade of life, reported male-to-female ratios range from 1:1 to 1:1.5. Case description : A 54-year-old woman came complaining weakness and diarrhea for the last 2 months. Symptoms are watery stools for 2-4 times a day and nausea. Physical examination found that the body temperature was 37.60C, tachycardia, increased bowel sounds, and tenderness on stomach. An endoscopic examination was performed with results: transverse colon appears with polyps with a size of 3 mm, with a mosaic pattern of mucosa. The mucosa of the ascending colon and caecum also appears to be a mosaic pattern. Biopsy was sent for histopathological examination. Morphological features show significant increase of eosinophils &amp; mast cells, differentially diagnosed with Mastocytosis colitis, Eosinophilic colitis, systemic mastocytosis with GI involvement. Methodology : Descriptive study of the case report type, data were obtained from the patient's record. Discussion and Conclusion : To rule out the differential diagnosis, an immunohistochemical examination and clinical correlation were performed. On histopathological examination, microscopic features showed the proliferation of mast cells in the aggregate only in the colon, without any other systemic manifestations, an increase in the number of mast cells &gt;20/HPF was found in the colonic mucosa. The staining of CD117 on cells in the superficial (1/3 top) of the lamina propria suspected of being a mastocyte, supporting mastocytosis colitis.

Cutaneous mastocytosis in childhood.

Mastocytoses are characterized by clonal proliferation of mast cells in various tissues. In childhood, cutaneous mastocytosis (CM) occurs almost exclusively. It is confined to the skin, and has a good prognosis. The most common form is the maculopapular cutaneous mastocytosis (MPCM), formerly called urticaria pigmentosa. A distinction is made between a monomorphic variant of MPCM with multiple small, roundish maculopapular skin lesions and the – more common – polymorphic variant with larger lesions of variable size. One quarter of CM diagnosed in childhood are mastocytomas, which often occur solitary or at multiple sites. The diffuse variant of CM (DCM), which affects 5% of children with CM, should be distinguished from these forms. Systemic mastocytoses (SM) with mast cell infiltrates in the bone marrow or other extracutaneous tissues, such as the gastrointestinal tract, occur predominantly in adults. The diagnosis of CM is usually made clinically: Manifestation in infancy, typical morphology and distribution, pathognomonic Darier sign. Basal serum tryptase is determined if DCM or systemic mastocytosis are to be diagnosed. Children with mastocytosis should be managed in a specialized outpatient clinic. For affected families, detailed information about the clinical picture including prognosis assessment is essential. Mast cell mediated symptoms are controlled by oral non-sedating antihistamines if needed.

The Role of Avapritinib for the Treatment of Systemic Mastocytosis.

Systemic mastocytosis is a rare hematologic disorder characterized by the clonal proliferation of mast cells in extra-cutaneous organs. This disease can be further subdivided into five different phenotypes: indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN) and mast cell leukemia (MCL). The tyrosine kinase inhibitor (and also potent KIT D816V inhibitor) avapritinib, initially approved for the treatment of gastrointestinal stromal tumors (GISTs) bearing a PDGFRA exon 18 mutation, also showed great promise in patients with systemic mastocytosis, a disease known to be driven by a mutation in KIT (D816V). We present an overview of this rare disorder, including a review of the current understanding of the genetic mechanisms which lead to the disease state, the action of the tyrosine kinase inhibitors, as well as the latest clinical trial data which led to the current recommendations for the use of avapritinib.

Cutaneous Mastocytosis in Childhood-Update from the Literature.

Mastocytosis (M) represents a systemic pathology characterized by increased accumulation and clonal proliferation of mast cells in the skin and/or different organs. Broadly, M is classified into two categories: Cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In children, CM is the most frequent form. Unfortunately, pathogenesis is still unclear. It is thought that genetic factors are involved, but further studies are necessary. As for features of CM, the lesions differ in clinical forms. The most important fact is evaluating a pediatric patient with CM. It must comprise laboratory exams (with baseline dosing of total serum tryptase), a skin biopsy (with a pathological exam and, if the diagnosis is unclear, immunohistochemical tests), and a complete clinical evaluation. It is also defining to distinguish between CM and other diseases with cutaneous involvement. As for the management of CM in children, the first intervention implies eliminating trigger factors. The available cures are oral H1 and/or H2 antihistamines, oral cromolyn sodium, oral methoxypsoralen therapy with long-wave psoralen plus ultraviolet A radiation, potent dermatocorticoid, and calcineurin inhibitors. In children, the prognosis of CM is excellent, especially if the disease’s onset is in the first or second years of life.

Detection of the germline KIT S476I mutation in a kindred with familial mastocytosis associated with gastrointestinal stromal tumors

Mastocytosis represents a rare disease characterized by clonal proliferation of mast cells (MCs).1 It mostly occurs sporadically as cutaneous or systemic mastocytosis due to somatic activating KIT mutations encoding the MC growth factor receptor KIT. A positive family history is rare and partly attributed to activating germline KIT mutations. Patients with familial mastocytosis (FM) may suffer in addition from gastrointestinal stromal tumors (GISTs), cutaneous hyperpigmentation, and/or dysphagia.

Clinicopathological profile of childhood onset cutaneous mastocytosis from a tertiary care center in South India

Background:Mastocytosis is characterized by clonal proliferation of mast cells in various organs and can have isolated cutaneous or systemic involvement. Childhood-onset mastocytosis (COM) is usually cutaneous and regresses spontaneously, while adult-onset mastocytosis (AOM) is often persistent with systemic involvement. There is limited data on COM from India.Objective:To elucidate the clinicopathological profile of COM.Methods:We conducted a retrospective chart review of all the patients with histologically proven COM (≤16 years), presenting over 11 years (January 2009 to December 2019) to the Dermatology Department. We compiled the demographic data, clinical characteristics (morphology, extent, distribution), laboratory investigations, histopathology findings, imaging (ultrasound abdomen), c-KIT mutation results, where available, and other associated abnormalities, and grouped them according to the WHO classification for mastocytosis.Results:Among the 66 patients with COM (M: F–1.6:1), 89.4% had onset before 2 years of age. The subtypes were: maculopapular cutaneous mastocytosis (MPCM: 44, 66.7%); mastocytoma of the skin (MOS: 19, 28.8%); diffuse cutaneous mastocytosis (DCM: 2, 3%) and indolent systemic mastocytosis (ISM: 1, 1.5%). Blistering was observed in 29 (43.9%) and Darier sign was elicited in 47 (71.2%) patients. Serum tryptase was elevated in 9/21 (42.9%) patients, but none had systemic mastocytosis. Three patients had c-KIT mutations (two in exon 8 and one in exon 17). Most patients were managed symptomatically and the patient with ISM improved with imatinib.Conclusion:MPCM is the most common variant of COM and most patients had a disease onset before 2 years. Overall, COM had a good prognosis with rare systemic involvement, mitigating the need for extensive evaluation routinely in children.

S2855 New Onset Gastrointestinal Involvement in Systemic Mastocytosis

INTRODUCTION: Mastocytosis is a rare hematopoietic disorder that results from abnormal clonal proliferation of mast cells. Bone marrow biopsy is a major criterion for diagnosis of systemic disease, with molecular markers fulfilling minor criteria. Mastocytosis can present with isolated cutaneous involvement, as solid tumors, or with systemic involvement. It can also have gastrointestinal (GI) involvement, however, non-specific clinical signs and subtle histological findings make it a challenging diagnosis. CASE DESCRIPTION/METHODS: A 33 year old female with a history of seasonal allergies and eczema initially presented to the dermatology clinic for urticaria pigmentosa that led to skin and bone biopsy confirming mild systemic mastocytosis. Six years later, she presented to the GI clinic with six months of non-radiating epigastric burning and gnawing pain, associated with bloating, minimal nausea and diarrhea, and twenty-pound unintentional weight loss. She had no dietary or appetite changes, no emesis or major bowel movement changes. At the time, she was not on any medications for mastocytosis. Serum serologies including CBC, CMP, TSH were within normal limits. Celiac panel was normal, but did show elevated immunoglobulin A of 344 mg/dL. Tryptase level was 18.9. CT abdomen pelvis with contrast did not reveal GI malignancies. Upper endoscopy was normal with biopsies taken. Pathology showed increased mast cells in the lamina propria of both the gastric and duodenal mucosa. Immunostains for CD117 and mast cell tryptase showed > 50/HPF mast cells in the lamina propria. Overall, findings are consistent with mastocytosis involving the GI tract. Patient was subsequently referred to immunology and started on cromolyn. DISCUSSION: The authors describe a case of GI infiltration of mastocytes in a patient with prior bone marrow biopsy confirmed systemic mastocytosis, previously only prescribed epinephrine for the feared complication of anaphylaxis. Her presentation to the GI clinic was highly suspicious for mastocyte extension to the GI tract; however a full workup to rule out malignancy was needed given her red flag symptoms. Pathology ultimately confirmed GI extension of mastocytosis. This case highlights the importance of interdisciplinary approach to systemic diseases. Although her GI complaints started more than five years after her initial diagnosis, high index of suspicion and thorough evaluation led to a timely unifying diagnosis that led to timely treatment and ultimately complete symptom resolution.Figure 1.: Duodenum, H&E 400x. Neoplastic mast cells are usually difficult to distinguish on H&E stained sections when not mass forming, but characteristic features include an elongate to ovoid nucleuscontaining smooth chromatin and inconspicousnucleoli, with a moderate amount of pale staining cytoplasm (arrows), distorting the normal mucosal architecture. They can be associated with an influx of eosinophils and/or plasma cells as well.Figure 2.: Immunohistochemistry staining of mucosa. Mast cells scattered throughout the mucosa in increased numbers without the formation of discreet and compact clusters that is typically seen in GI mastocytosis. Affected cells aberrantly co-express CD117 and CD25 to confirm diagnosis of systemic mastocytosis.

CUTANEOUS MASTOCYTOSIS IN THE ADULT: WHAT LIES BENEATH

Mastocytosis is a disorder characterized by clonal mast cell proliferation and accumulation within various organs, most commonly, the skin. Adult-onset mastocytosis is highly suggestive of a systemic involvement and the cases limited to the skin are uncommon. The authors report a 61-year-old male with pruritus associated with hyperpigmented maculopapular skin lesions and a positive Darier’s sign. The skin biopsy revealed spindle mast cells infiltrations. The bone marrow study was normal. He started on H1 antihistamines with significant clinical improvement

Flow-mediated dilation shows impaired endothelial function in patients with mastocytosis

Mastocytosis is a rare disease characterized by clonal proliferation of mast cells (MCs) in different organs. Clinical manifestations of mastocytosis are mostly due to release of mediators from MCs and, in many cases, such as urticaria, flushing, angioedema, and anaphylaxis, are an expression of the biological effects of mediators on endothelial cells. Chronic secretion of mediators in patients with mastocytosis can lead to alteration of endothelial function. We sought to investigate endothelial function in patients with mastocytosis using a noninvasive technique of flow-mediated dilation (FMD). Twenty-five adult patients with indolent and advanced forms of mastocytosis and 20 healthy control subjects were enrolled in the study. Ultrasound assessment of FMD was performed by measuring changes in the diameter of the brachial artery after 5minutes of arterial occlusion. Changes in FMD were correlated with clinical parameters and serum tryptase levels. Patients with mastocytosis had lower FMD compared with healthy control subjects (P<.001). Advanced and smoldering forms showed a lower FMD compared with indolent forms (P<.001). FMD inversely correlated with age and serum tryptase levels and directly with median arterial pressure and recurrent flushing episodes. No correlation was found between FMD and osteoporosis, recurrent anaphylaxis, presence of skin lesions, and long-term antihistamine treatment. Endothelial dysfunction, as demonstrated by FMD reduction, is detectable in patients with mastocytosis and is more severe in patients with high tryptase levels and advanced disease. Endothelial function appears to be negatively influenced by MC proliferation rather than by the severity of mediator-related symptoms.

Mastocytosis - pathogenesis, clinical manifestation and treatment.

The term mastocytosis designates a group of rare disorders characterized by typical skin lesions, frequently associated episodes of anaphylaxis, and clinical symptoms related to the release of various mediators. Dermatologists/allergists are frequently the first to establish the diagnosis. The condition is based on clonal mast cell proliferation, usually in the skin or bone marrow and only rarely in the gastrointestinal tract or other tissues. In general, mastocytosis has a good prognosis in terms of life expectancy. Rare variants - including mast cell leukemia, aggressive mastocytosis, and the exceedingly rare mast cell sarcoma - require cytoreductive therapy. In cases associated with hematological neoplasms, the prognosis depends on the underlying hematologic disorder.

Successful Treatment of Provisional Cutaneous Mastocytosis with Interferon Alpha.

Mastocytosis is a disorder characterized by the clonal proliferation of mast cells and their accumulation in skin, bone marrow, liver, and spleen. Cutaneous mastocytosis presents in children in over 90% of the cases and any cutaneous manifestation in an adult is the earliest sign of the systemic disease. A 45-year-old patient presented with itchy dark lesions over the body since childhood and Darier's sign was positive. Skin biopsy showed features of mastocytosis and immunohistochemistry was positive for CD34. Since the patient was refractory to treatment with antihistamines and psoralen-ultraviolet A therapy, injections of interferon alpha were given – 3 million IU twice weekly subcutaneously as they have been proven to improve constitutional symptoms. Very few reports of successful treatment of cutaneous mastocytosis using interferon alpha have been published.

Application of next generation sequencing in the diagnosis and management of mast cell leukemia.

Mast cell diseases are difficult to diagnose due to its protean symptoms and presence of coexisting conditions [1]. Symptoms are associated with clonal proliferation of mast cells and include from mild flushing to cardiac arrest following anaphylactic reaction [2]. In some cases, the patients are finally diagnosed with mast cell disease after several emergency room visits for cardiopulmonary resuscitations. Mast cell leukemia (MCL) is an extremely rare but aggressive subtype of systemic mastocytosis and the prognosis is just as abysmal with median survival of less than 6 months. Probably, some patients die even before a diagnosis is made if the physician was not aware of that there is link between the recurrent idiopathic anaphylaxis with mast cell leukemia and further evaluation for mast cell leukemia was not carried out. The evaluation algorism proposed for possible mastocytosis emphasizes testing for basal tryptase level greater or equal to 20.0 ng/mL or 20% above baseline after symptomatic event [1]. However, a recent study showed that a diagnosis of systemic mastocytosis cannot be ruled out by a normal serum tryptase level alone [3]. MCL is often characterized by somatically acquired activating mutations in the KIT receptor gene which causes uncontrolled ligand-independent signaling by KIT and increased proliferation of mast cells [4]. Studies have shown that the KIT D816V is the most frequently found mutation that also causes resistance to imatinib therapy in MCL. The presence of KIT D816V mutation has been included in the major diagnostic criteria of systemic mastocytosis by World Health Organization, and European Competence Network on Mastocytosis has recommended that KIT mutation should be evaluated using peripheral blood or bone marrow samples using more sensitive routine method that can detect low number of mast cells [5]. However, other mutations in SRSF2, ASXL1 and/or RUNX1 have also been found in the patients with KIT D816V positive systemic mastocytosis, indicating that mutations in more than one gene may be necessary for leukemogenesis [5,6]. In this issue of the Blood Research, Youk et al. [7] used next generation sequencing (NGS) to find mutations possibly causing the disease in a patient diagnosed with MCL. The whole exome sequencing revealed KIT S476I and whole transcriptome sequencing demonstrated possibly RARα-B2M fusion gene, and the authors used the results in personalized treatment. In addition, the RNA expression analysis revealed the upregulation of PI3K/AKT pathway downstream of mammalian target of rapamycin (mTOR). The all-trans retinoic acid (ATRA), dasatinib, and everolimus targeting mTOR pathway were used in sequence following the NGS data. Although the patient did not survive even after the tailored therapy, she survived longer than the median survival of MCL. The PI3K inhibitor could have been tried to prolong survival but was not available in Korea. This was the second exome sequencing study in MCL after a report by Spector et al., in which KIT V654A and MS4A2 L188F variants were found [8]. In both studies, KIT D816V was not detected, which is consistent with previous study showing that KIT D816V is not as frequent in MCL compared to other form of mast cell disorders [9]. Thus, more comprehensive method should be used to sequence KIT as well as finding other gene mutations possibly responsible for mast cell leukemogenesis to be measured for mutant allele burden in the follow up studies. Due to rarity of the disease and therefore lack of data, comprehensive molecular testing by NGS on more cases of MCL would be valuable to find new biomarkers and better treatment modalities including combination of drugs to cure such a devastating disease. Routine implementation of NGS testing still has some obstacles, such as limited ability to interpret techniques and high cost, but could be beneficial in molecular profiling of tumors for targeted therapies and promising approach in identifying novel genetic alteration of rare disease.

Update on Mastocytosis (Part 1): Pathophysiology, Clinical Features, and Diagnosis

Mastocytosis is a term used to describe a heterogeneous group of disorders characterized by clonal proliferation of mast cells in various organs. The organ most often affected is the skin. Mastocytosis is a relatively rare disorder that affects both sexes equally. It can occur at any age, although it tends to appear in the first decade of life, or later, between the second and fifth decades. Our understanding of the pathophysiology of mastocytosis has improved greatly in recent years, with the discovery that somatic c-kit mutations and aberrant immunophenotypic features have an important role. The clinical manifestations of mastocytosis are diverse, and skin lesions are the key to diagnosis in most patients.