scholarly journals Systemic mastocytosis with subcutaneous hemorrhage and edema in a Greyhound dog: case report and review of diagnostic criteria

2020 ◽  
Vol 33 (1) ◽  
pp. 95-100
Author(s):  
Alexander Aceino ◽  
Unity Jeffery ◽  
Julie Piccione ◽  
Carolyn L. Hodo
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Diagnostic Criteria ◽  
Complete Blood Count ◽  
Systemic Mastocytosis ◽  
Mast Cell Tumors ◽  
Multiple Organs ◽  
Subcutaneous Edema ◽  
Diagnostic Framework ◽  
Criteria For Diagnosis

Systemic mastocytosis, characterized by infiltration of multiple organs by neoplastic mast cells, is a well-described entity in human medicine with specific criteria for diagnosis, but is ill defined in veterinary literature. Hemostatic disorders are reported in humans affected by systemic mastocytosis but have not been well described in veterinary literature. A 5-y-old, spayed female Greyhound dog had a 1-mo history of progressive ventral cutaneous edema, hemorrhage, and pain. Cytology of an antemortem aspirate from the subcutis of the ventral abdomen was suggestive of mast cell neoplasia, but no discrete mass was present. The dog was euthanized and submitted for autopsy; marked subcutaneous edema and hemorrhage were confirmed. The ventral abdominal panniculus and dermis superficial to the panniculus carnosus were infiltrated by a dense sheet of neoplastic mast cells. The neoplastic cells contained toluidine blue–positive granules and formed aggregates within the bone marrow and several visceral organs, including the liver, spleen, heart, and kidney. Diffuse edema and hemorrhage is an unusual presentation of mast cell tumors in dogs. Antemortem tests, including complete blood count, coagulation profile, and viscoelastic coagulation testing, were suggestive of a primary hemostatic defect. We discuss here the diagnostic criteria used in humans, how these can be applied to veterinary patients, and the limitations of the current diagnostic framework.

scholarly journals Suppressible and nonsuppressible autocrine mast cell tumors are distinguished by insertion of an endogenous retroviral element (IAP) into the interleukin 3 gene.

1993 ◽  
Vol 178 (2) ◽  
pp. 403-411 ◽  
Author(s):  
H H Hirsch ◽  
A P Nair ◽  
C Moroni
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Gene Transcription ◽  
Class Ii ◽  
Class I ◽  
Ras Oncogene ◽  
Interleukin 3 ◽  
Mast Cell Tumors ◽  
Intracisternal A Particle

After v-H-ras expression, the interleukin 3 (IL-3)-dependent PB-3c mast cells progress in vivo to two different classes of IL-3 autocrine tumors. Class I tumors show a germline configuration of the IL-3 gene and represent more than 90% of tumors analyzed so far. Somatic cell fusion of class I tumor lines with the nontumorigenic parental PB-3c resulted in loss of oncogenic IL-3 expression by a posttranscriptional mechanism with concomitant tumor suppression. Class II tumors arise rarely and contain an insertion in one IL-3 allele. This alteration was linked to enhanced IL-3 gene transcription. For one tumor, the insertion was shown to be an endogenous retroviral element (intracisternal A-particle). Cell hybrids of class II tumors with PB-3c remained IL-3 independent, expressed IL-3, and formed tumors rapidly. These results suggest that the v-H-ras oncogene synergizes with a recessive and a dominant lesion in class I and II tumors, respectively, both of which lead to the autocrine production of IL-3.

Imatinib Mesylate in the Treatment of Systemic Mastocytosis, a Phase I/II Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1516-1516 ◽  
Author(s):  
H.J. Droogendijk ◽  
J.C. Kluin-Nelemans ◽  
P.L.A van Daele
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Mast Cell ◽  
Mast Cells ◽  
Imatinib Mesylate ◽  
Systemic Mastocytosis ◽  
Skin Lesions ◽  
Tissue Response ◽  
Serum Tryptase ◽  
Kit Receptor

Abstract Introduction: mastocytosis comprimes a group of diseases characterized by abnormal proliferation and accumulation of mast cells in one or more organs. A cutaneous and systemic form of mastocytosis is distinguished. Systemic mastocytosis defines the disease process in which mast cell proliferation exceeds the skin. The clinical manifestations of systemic mastocytosis depend on the tissues involved and the tissue response to the accumulation of mast cells. Although in general the disease progresses slowly, it may develop into a malignant disease. Currently there is no cure for systemic mastocytosis. Mast cells develop from pluripotent bone marrow progenitor cells that express CD34 antigen and are dispersed as precursors which undergo proliferation and maturation in different tissues. Normal mast cell development involves the action of stam cell growth factor and c-kit receptors, which are expressed by mast cells at their different developmental stages. Deregulation and/or abnormalities of the c-kit receptor are assumed to play a causal role in disordered mast-cell proliferation. In most patients a mutation in the gene for c-kit exists. One of the mutations is the D816V mutation. Aim of the study:imatinib mesylate, formerly called ST1571, is a potent inhibitor of c-kit receptor tyrosine kinase activity. In this study, we evaluate whether imatinib mesylate is safe and effective in the treatment of patients with systemic mastocytosis. Primary end-points of study are reduction in urinary N-methylhistamine excretion, serum tryptase activity, skin lesions, number of mast cells in sections of bone marrow, hepato-and/or splenomegaly and symptoms.Adverse effects on therapy are also considered. Results: up to now, 10 patients with systemic mastocytosis are treated with 400 mg of imatinib mesylate orally once daily. During the first 2 weeks of the study the patients also received 30 mg of prednisolone daily. In general imatinib mesylate is well tolerated. The first results show a 38–80% reduction in urinary N-methylhistamine excretion and 30–66% reduction in serum tryptase activity. Skin lesions diminish in two of the six patients with cutaneous mastocytosis,. Number of mast cells in sections of bone marrow are reduced in 63% (5/8) of the patients. Hepato-and/or splenomegaly is slightly decreased in two of the three patients with organomegaly. Finally 60 % of all patients experiences relief of symptoms. In eight patients the D816V mutation was found. In contrast with former studies imatinib mesylate is also effective in these patients. Further results are to be awaited. Conclusion: imatinib mesylate is safe and seems effective in the treatment of patients with systemic mastocytosis (including patients with the D816V mutation).

Detection of Activated STAT5 in Neoplastic Mast Cells in Patients with Systemic Mastocytosis: Role of c-kit D816V.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3515-3515 ◽  
Author(s):  
Karoline Sonneck ◽  
Matthias Mayerhofer ◽  
Karoline V. Gleixner ◽  
Marc Kerenyi ◽  
Maria-Theresa Krauth ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Systemic Mastocytosis ◽  
Cell Leukemia ◽  
Oncogenic Signaling ◽  
Kit Mutation ◽  
Knock Out ◽  
Mast Cell Leukemia ◽  
Kit D816v

Abstract Recent data suggest that activated STAT5 contributes to growth and differentiation of mast cells (MC) and that STAT5-knock out mice are MC-deficient. We have recently shown that constitutively activated STAT5 acts as a potent oncogenic signaling molecule in hematopoietic progenitor cells (Cancer Cell2005;7:87–99). In the present study, we examined the expression of activated STAT5 in neoplastic MC in systemic mastocytosis (SM) and asked whether the SM-related oncogene c-kit D816V is involved in STAT5-activation. For the immunohistochemical detection of activated tyrosine phosphorylated STAT5 (P-Y-STAT5), we used the specific monoclonal antibody AX1 (Advantex) which does not react with inactive STAT5. In all patients with SM tested (indolent SM, n=11; smouldering SM, n=2; aggressive SM, n=1; mast cell leukemia, n=1; all exhibiting c-kit D816V), MC were found to display P-Y-STAT5. Expression of activated STAT5 was also demonstrable in the c-kit D816V-positive mast cell leukemia-derived cell line HMC-1. The reactivity of HMC-1 cells with AX1 antibody was abrogated by a STAT5-specific blocking-peptide. To define the role of c-kit D816V in STAT5-activation, Ba/F3 cells with doxycycline-inducible expression of c-kit D816V (Ton.kit) were employed. In these cells, induction of c-kit D816V was followed by a massive increase in phosphorylated STAT5 as determined by a specific DNA-binding assay, whereas the total amounts of STAT5-mRNA and of the STAT5-protein showed only a slight increase or remained unchanged. In summary, these data show that neoplastic MC in SM express activated STAT5 (P-Y-STAT5), and that the transforming c-kit mutation D816V leads to persistent activation of STAT5 in these cells.

Kit Signaling Regulates Mitf Expression in Mastocytosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3601-3601
Author(s):  
Youl-Nam Lee ◽  
Pierre Noel ◽  
Amir Shahlaee ◽  
Melody Carter ◽  
Reuben Kapur ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Systemic Mastocytosis ◽  
Tyrosine Kinase Receptor ◽  
Bone Marrow Biopsies ◽  
Activating Mutations ◽  
Cell Assays ◽  
Mast Cell Disease ◽  
Mitf Expression

Abstract Mastocytosis is a heterogeneous disease arising from abnormal proliferation of mast cells. Activating mutations in codon D816 of the tyrosine kinase receptor, c-kit, are found in the majority of adult patients with systemic mastocytosis, an aggressive form of the disease. Constitutive activation of the Kit signaling pathway is critical to the transformed phenotype, and thus understanding how this pathway regulates downstream events is of great importance. A number of transcription factors are also essential to mast cell development, including the Microphthalmia-associated transcription factor (Mitf). We examined Mitf expression in bone marrow biopsies from nine patients with systemic mastocytosis by immunohistochemistry; we found that Mitf is highly expressed in all cases with the D816V mutation. In contrast, Mitf is not highly expressed in non-malignant mast cells in the bone marrow from patients with aplastic anemia and leukemia, suggesting thatMitf expression is regulated by Kit-dependent signalsMitf may play a role in the transformed phenotype of mastocytosis.We show that in normal mast cells, Kit signaling markedly upregulates Mitf expression. In both normal and malignant mast cells, pharmacologic inhibitors of Kit, and the downstream kinase, PI3K, block Mitf expression. To examine whether Mitf is required for transformed phenotype from constitutive Kit signaling in mast cells, we have used a shRNA-expressing lentivirus to knockdown Mitf expression in mastocytosis cell lines. We found that silencing of Mitf markedly impaired growth in proliferation and colony forming cell assays. This work demonstrates a link between two critical factors, Kit and Mitf, in the development of malignant mast cell disease.

Change In Mast Cell Bone Marrow Burden and In Serum Tryptase Level Are Not Accurate Markers of Response In Patients with Systemic Mastocytosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3073-3073
Author(s):  
Alfonso QuintÁs-Cardama, ◽  
Matjaz Sever ◽  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Srdan Verstovsek
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Systemic Mastocytosis ◽  
Median Number ◽  
Response To Therapy ◽  
Serum Tryptase ◽  
Bone Marrow Biopsies ◽  
Tryptase Level ◽  
Bone Marrow Mast Cell

Abstract Abstract 3073 Background: Bone marrow involvement, with or without cutaneous or visceral involvement, is almost universal in patients with systemic mastocytosis (SM). The KITD816V mutation is present in most patients with SM, thus confirming its clonal nature. Patients with ASM are usually managed with cytoreductive agents such as hydroxyurea (HU), cladribine (2CDA), or interferon-alpha (IFN-α), although the activity of these therapies is limited as they do not target specifically the malignant clone. Response assessment in SM relies on symptom improvement and reduction in serum tryptase levels and visceral and/or bone marrow mast cell burden (percent mast cell involvement). We contend that the later two relatively objective metrics may not be appropriate markers of response because serum tryptase levels may vary significantly at different time-points in the same patient in the absence of intervention, do not correlate accurately with mast cell burden, and bone marrow mast cell burden determination is subject to sampling bias given the patchy infiltration observed in many cases of SM. Objectives: To assess the utility of bone marrow mast cell burden reduction and serum tryptase level reduction as criteria for response in patients with SM. Patients and Therapy: We studied a cohort of 50 patients with SM for whom at least 2 sequential bone marrow biopsies and 2 serum tryptase level determinations were available at our center. The KITD816V mutation was present in 20 (59%) of 34 assessable patients. No patient carried the JAK2V617F mutation or the FIP1L1-PDGFRA rearrangement. Patients had a diagnosis of indolent SM (ISM, n=25), aggressive SM (ASM, n=16), or SM-AHNMD (n=9). All but 1 patient received SM-directed therapy (median number of therapies 2, range 1–5), including: imatinib (n=16), dasatinib (n=23), RAD001 (n=8), denileukin diftitox (n=7). The median number of bone marrow biopsies available per patient was 4 (range, 2–14) and the median number of tryptase measurements was 6 (range, 2–18), which were obtained both on and off SM-directed therapies. Results: Four patients had a bone marrow complete response: 1 with imatinib, 2 with dasatinib, and 1 with decitabine (with SM-MDS). However none of the responders normalized their tryptase levels. We used the coefficient of variation (CV) as a normalized measure of dispersion of a probability distribution for the percentage of mast cells in bone marrow biopsies and serum tryptase levels. In this manner, the CV summarizes/describes the variation in tryptase levels and bone marrow mast cell percentage from the baseline (first recorded value) in the patients evaluated. We found that among the 49 treated patients, the percentage of bone marrow mast cells varied significantly with a CV ranging from 6 – 173% and an average of 65%. Forty-four percent of patients had a CV equal or higher to the average. Similar results were observed regarding tryptase levels, with an average CV of 19% that ranged from 0 to 96%. Thirty-six percent of patients had a CV higher than average. Conclusion: While most patients fail to respond to currently available SM-directed therapies, sequential bone marrow biopsies and tryptase level determinations exhibit remarkable variation both during and in the absence of SM-directed therapy. Therefore, it seems that single time point measurements of these values do not represent proper tools to assess accurately response to therapy. Disclosures: No relevant conflicts of interest to declare.

Anti CD-30 Antibody-Drug Conjugate Brentuximab Vedotin (ADCETRIS®) May Be a Promising Treatment Option for Systemic Mastocytosis (SM).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2857-2857 ◽  
Author(s):  
Amitkumar Mehta ◽  
Vishnu V B Reddy ◽  
Uma Borate
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Systemic Mastocytosis ◽  
White Male ◽  
Brentuximab Vedotin ◽  
Antibody Drug Conjugate ◽  
Antimitotic Agent ◽  
Drug Conjugate ◽  
Tryptase Level ◽  
Antibody Drug

Abstract Abstract 2857 Mastocytosis is a clonal proliferation of abnormal mast cells in single or multiple organs leading to clinical syndromes ranging from a benign self-resolving cutaneous disease to the highly aggressive malignancy, mast cell leukemia (MCL). Mastocytosis is categorized under myeloproliferative neoplasms in the 2008 World Health Organization (WHO) classification of hematopoietic and lymphoid diseases. In almost all cases of SM, the bone marrow (BM) is involved by atypical mast cells. The characteristic Asp816Val (D816V) mutation in the KIT gene present in most cases gives the atypical mast cells a survival advantage that leads to treatment resistance with tyrosine kinase inhibitor (TKIs) like imatinib. According to the 2008 WHO classification, 1 major and 1 minor or 3 minor criterion are required for the diagnosis of systemic mastocytosis (Fig. 1a). Systemic Mastocytosis (SM) is subcategorized into four distinct categories in order of indolent to highly aggressive disease: Indolent Systemic Mastocytosis (ISM), SM with an associated hematologic non-MC-lineage disease (SM-AHNMD), aggressive SM (ASM) and MCL. SM with C findings categorized as ASM (Fig. 1b) is treated with cytoreductive chemotherapy such as interferon 2α or 2-chlorodeoxyadenosine (2-CdA). The overall response rate (ORR) with these agents is 40–50% with significant chemotherapy-related toxicity and short durable responses. The majority of patients with ASM and MCL relapse within a year with a very poor prognosis. The CD30 (Ki-1) antigen is expressed in the majority of ASM cases. Thus, CD30 can serve as a potential therapeutic target as well as a reliable tumor marker to follow disease status. Brentuximab vedotin is an antibody-drug conjugate compound consisting of a chimeric monoclonal antibody against CD30 linked to the antimitotic agent monomethyl auristatin E (MMAE). Here we report evidence of anti-tumor activity in two patients with CD30-positive ASM treated with brentuximab vedotin. Case #1: A 62 year old white male with significant medical history of rheumatoid arthritis, diabetes mellitus and coronary artery disease was evaluated for pancytopenia and hepatomegaly. His initial BM aspiration and biopsy revealed multifocal dense mast cell infiltrate (30–40% involvement with tryptase and CD117 positivity). His initial serum tryptase level was 276 ng/ml. He was treated with 2-CdA continuous infusion for three cycles with no significant response and substantial toxicities. He was subsequently enrolled in a clinical trial with brentuximab vedotin given every 3 weeks at 1.8 mg/kg after confirmation of CD30 positivity on BM aspirate and biopsy (Fig. 2). His peripheral blood counts started to improve after the 5thcycle and he had a durable partial response as assessed by his peripheral blood counts and BM biopsies (Fig 2). Importantly, his sequential bone marrow biopsies showed a decrease in mast cell involvement and CD30 intensity with improved normal marrow cellularity (Fig 2). His only treatment-related toxicities were grade II neuropathy and neutropenia for which his dose was reduced to 1.2 mg/kg. He is currently asymptomatic with ECOG performance status of 0 and does not require any growth factor support at Cycle 12 of this regimen. Case #2: A 79 yr old white male with significant medical history of hypertension, obstructive sleep apnea, coronary artery disease s/p CABG was referred for new diagnosis of ASM on BM biopsy (60–70% marrow involvement with 3+ mast cell density). His initial tryptase level was 224ng/ml. He was enrolled on the same clinical protocol as described above. His sequential BM biopsies revealed significant reduction in mast cell density with mild improvement in overall normal cellularity after 3 cycles of treatment. (Fig 3). Conclusion: Brentuximab vedotin is a promising targeted therapy for SM and needs to be confirmed further by a prospective multicenter clinical trial. In two patients reported here treatment is well tolerated, targets the malignant mast cells and seems to prevent disease progression in a rare disorder with few treatment options and limited response rates. Disclosures: Off Label Use: Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate compound consisting of a chimeric monoclonal antibody against CD30 linked to the antimitotic agent monomethyl auristatin E (MMAE). It is not FDA approved for use in Mastocytosis.

scholarly journals Chymase and tryptase in dog mastocytoma cells: asynchronous expression as revealed by enzyme cytochemical staining.

1988 ◽  
Vol 36 (8) ◽  
pp. 1053-1060 ◽  
Author(s):  
G H Caughey ◽  
N F Viro ◽  
L D Calonico ◽  
D M McDonald ◽  
S C Lazarus ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Staining Technique ◽  
Staining Intensity ◽  
Cell Development ◽  
Cytochemical Staining ◽  
Mast Cell Tumors ◽  
General Utility ◽  
Developmental Relationship ◽  
Mastocytoma Cells

Mast cell populations can be distinguished by differences in the content and substrate specificity of their two major cytoplasmic granule proteases, the chymases and the tryptases. To explore the origins of differences in the types of proteases present in mast cells, we used a double cytochemical staining technique to reveal both chymase and tryptase in cells from four lines of dog mast cell tumors containing both enzymes. We expected that if chymase and tryptase were expressed together during cell development the relative staining intensity of chymase compared to tryptase would be constant among different cells of each tumor. Instead, we found substantial variation in the relative intensity of chymase and tryptase staining among cells of a given mastocytoma line, each of which contained cells presumed to be monoclonal in origin but heterogeneous with respect to cell development. The overall staining intensity for chymase or tryptase correlated with the amount of protease activity in extracts of tumor homogenates. Staining specificity was established by use of selective inhibitors and competitive substrates and was tested on various types of dog cells obtained by bronchoalveolar lavage. The results suggest that active chymase and tryptase may be expressed differently during mast cell differentiation and support the possibility of a close developmental relationship between mast cells differing in protease phenotype. Moreover, the success of the staining procedures applied to mastocytoma cells suggests that they may be of general utility in phenotyping of mast cells according to the protease activities present in their granules.

Mast cell leukemia

Blood ◽  
2013 ◽  
Vol 121 (8) ◽  
pp. 1285-1295 ◽  
Author(s):  
Sophie Georgin-Lavialle ◽  
Ludovic Lhermitte ◽  
Patrice Dubreuil ◽  
Marie-Olivia Chandesris ◽  
Olivier Hermine ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
De Novo ◽  
Systemic Mastocytosis ◽  
Mast Cell Activation ◽  
Cell Leukemia ◽  
Mast Cell Leukemia ◽  
Kit D816v

Abstract Mast cell leukemia (MCL) is a very rare form of aggressive systemic mastocytosis accounting for < 1% of all mastocytosis. It may appear de novo or secondary to previous mastocytosis and shares more clinicopathologic aspects with systemic mastocytosis than with acute myeloid leukemia. Symptoms of mast cell activation—involvement of the liver, spleen, peritoneum, bones, and marrow—are frequent. Diagnosis is based on the presence of ≥ 20% atypical mast cells in the marrow or ≥ 10% in the blood; however, an aleukemic variant is frequently encountered in which the number of circulating mast cells is < 10%. The common phenotypic features of pathologic mast cells encountered in most forms of mastocytosis are unreliable in MCL. Unexpectedly, non-KIT D816V mutations are frequent and therefore, complete gene sequencing is necessary. Therapy usually fails and the median survival time is < 6 months. The role of combination therapies and bone marrow transplantation needs further investigation.

scholarly journals Cutaneous Mastocytosis in a 61-year-old Female from a Dermatological and Histopathological Perspective

2020 ◽  
pp. 01-06
Author(s):  
Erisa Kola ◽  
Jorida Memini ◽  
Ina Kola ◽  
Daniela Nakuci ◽  
John Ekladous ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Lymph Nodes ◽  
Systemic Mastocytosis ◽  
World Health ◽  
Systemic Involvement ◽  
Cutaneous Mastocytosis ◽  
Health Organization ◽  
Cell Disorder

First described by Nettleship et al. in 1869 [1], mastocytoses are a heterogeneous group of disorders characterized by the pathologic accumulation of mast cells in various tissues [2-5]. Mastocytosis can be confined to the skin as in cutaneous mastocytosis (CM), or it can involve extracutaneous tissues such as the liver, spleen, bone marrow and lymph nodes, as in systemic mastocytosis [6]. Mastocytosis is a World Health Organization-defined clonal mast cell disorder characterized by significant clinicopathologic heterogeneity [7]. Keywords: Cutaneous mastocytosis; Systemic mastocytosis; Systemic involvement; Mast cells; Mastocytosis.

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