Biomedical subjects

P Valent

Publications and source records attributed to P Valent.

At least 55 records · Page 3Linked to original sources

PubMed2001

Expression, epitope analysis, and functional role of the LFA-2 antigen detectable on neoplastic mast cells.

Recent data suggest that mast cells (MCs) in patients with systemic mastocytosis or mast cell leukemia express a CD2-reactive antigen. To explore the biochemical nature and function of this antigen, primary MCs as well as the MC line HMC-1 derived from a patient with mast cell leukemia were examined. Northern blot experiments revealed expression of CD2 messenger RNA in HMC-1, whereas primary nonneoplastic MCs did not express transcripts for CD2. In cell surface staining experiments, bone marrow (BM) MCs in systemic mastocytosis (n = 12) as well as HMC-1 cells (30%-80%) were found to express the T11-1 and T11-2 (but not T11-3) epitopes of CD2. By contrast, BM MCs in myelodysplastic syndromes and nonhematologic disorders (bronchiogenic carcinoma, foreskin phimosis, uterine myeomata ) were consistently CD2(-). All MC species analyzed including HMC-1 were found to express LFA-3 (CD58), the natural ligand of CD2. To study the functional role of CD2 on neoplastic MCs, CD2(+) and CD2(-) HMC-1 cells were separated by cell sorting. CD2(+) HMC-1 cells were found to form spontaneous aggregates and rosettes with sheep erythrocytes in excess over CD2(-) cells, and a T11-1 antibody inhibited both the aggregation and rosette formation. Moreover, exposure of CD2(+) HMC-1 cells to T11-1 or T11-2 antibody was followed by expression of T11-3. In addition, stimulation of neoplastic MCs through T11-3 and a second CD2 epitope resulted in histamine release. These data show that neoplastic MCs express functionally active CD2. It is hypothesized that expression of CD2 is associated with pathologic accumulation and function of MCs in systemic mastocytosis.

Animals↗

PubMed2001

Molecular and immunological characterization of arginine kinase from the Indianmeal moth, Plodia interpunctella, a novel cross-reactive invertebrate pan-allergen.

IgE recognition of indoor allergens represents a major cause of allergic asthma in atopic individuals. We found that 52 of 102 patients suffering from allergic symptoms indoors contained IgE Abs against allergens from the Indianmeal moth (Plodia interpunctella), a ubiquitous food pest. Using serum IgE from a moth-sensitized patient we screened an expression cDNA library constructed from P. interpunctella larvae. cDNAs coding for arginine kinase (EC 2.7.3.3), a 40-kDa enzyme commonly occurring in invertebrates that is involved in the storage of such high-energy phosphate bonds as phosphoarginine, were isolated. Recombinant moth arginine kinase, designated Plo i 1, was expressed in Escherichia coli as a histidine-tagged protein with enzymatic activity, and purified to homogeneity by nickel chelate affinity chromatography. Purified recombinant arginine kinase induced specific basophil histamine release and immediate as well as late-phase skin reactions. It reacted with serum IgE from 13 of the 52 (25%) moth-allergic patients and inhibited the binding of allergic patients' IgE to an immunologically related 40-kDa allergen present in house dust mite, cockroach, king prawn, lobster, and mussel. Our results indicate that arginine kinases represent a new class of cross-reactive invertebrate pan-allergens. Recombinant arginine kinase may be used to identify a group of polysensitized indoor allergic patients and for immunotherapy of these individuals.

Adolescent↗

PubMed2001

Detection of tryptase in cytoplasmic granules of basophils in patients with chronic myeloid leukemia and other myeloid neoplasms.

Tryptases are serine proteases primarily expressed in mast cells. Normal blood basophils express only trace amounts of the enzyme. However, recent immunohistochemical studies have raised the possibility that neoplastic basophils express significant amounts of tryptase. In this study, tryptase expression was analyzed in normal and neoplastic basophils by immunoelectron microscopy using antitryptase monoclonal antibody G3. Basophils were obtained from patients with chronic myeloid leukemia (CML), idiopathic myelofibrosis (IMF), and myelodysplastic syndrome (MDS), and from healthy donors. Tryptase-immunoreactive material was detected in cytoplasmic granules of basophils in CML, IMF, and MDS. By contrast, normal basophils did not contain significant amounts of tryptase by immunoelectron microscopy. As assessed by reverse transcription-polymerase chain reaction, neoplastic basophils contained messenger RNA (mRNA) for alpha-tryptase, but no beta-tryptase mRNA. In summary, these data provide evidence that neoplastic basophils in CML, IMF, and MDS can express detectable amounts of tryptase. Therefore, tryptase should not be regarded as specific for mast cells when neoplastic myeloid cells are analyzed.

Basophils↗

PubMed2001

Expression of mast cell tryptase by myeloblasts in a group of patients with acute myeloid leukemia.

alpha- and beta-tryptase genes encode serine proteases that are abundantly expressed by mast cells. Under physiologic conditions other myeloid cells are virtually tryptase negative. However, tryptases are also expressed in several myeloid leukemia cell lines. In this study, serum total tryptase levels were determined in 150 patients with acute leukemias (de novo acute myeloid leukemia [AML], n = 108; secondary AML, n = 25; acute lymphoid leukemia [ALL], n = 17) by fluoroenzyme immunoassay. In healthy subjects (n = 30), tryptase levels ranged between 2.0 and 12.6 ng/mL. Elevated tryptase levels (> 15) were detected in 42 (39%) of 108 patients with de novo AML and in 11 (44%) of 25 patients with secondary AML. No elevated tryptase levels were found in patients with ALL. In de novo AML, elevated tryptase levels were frequently detected in patients with French-American-British classification M0 (6 of 9), M2 (9 of 14), M3 (4 of 6), and M4eo (7 of 7), and less frequently in M1 (7 of 20), M4 (6 of 26), M5 (2 of 18), M6 (0 of 5), or M7 (1 of 3). The highest tryptase levels were found in M4eo. Immunohistochemical staining of bone marrow sections with anti-tryptase antibody as well as immunoelectron microscopy revealed tryptase expression in the cytoplasm of myeloblasts. As assessed by Northern blotting and reverse transcriptase-polymerase chain reaction, AML cells expressed alpha-tryptase messenger RNA (mRNA) but little or no beta-tryptase mRNA. In AML patients with elevated serum tryptase before chemotherapy, who entered complete remission, tryptase levels returned to normal or near normal values. Blast cell persistence or regrowth was associated with a persistently elevated level or recurrent increase of tryptase. Together, tryptase is expressed in myeloblasts in a group of AML and may serve as a useful disease-related marker.

Acute Disease↗

PubMed2001

Genetic engineering of a hypoallergenic trimer of the major birch pollen allergen Bet v 1.

An estimated 100 million individuals suffer from birch pollen allergy. Specific immunotherapy, the only curative allergy treatment, can cause life-threatening anaphylactic side effects. Here, we report the genetic engineering of a recombinant trimer consisting of three covalently linked copies of the major birch pollen allergen, Bet v 1. The trimer exhibited profoundly reduced allergenic activity but contained similar secondary structures such as Bet v 1 wild type, Bet v 1-specific B cell and T-cell epitopes, and induced Th1 cytokine release. As immunogen, rBet v 1 trimer induced IgG antibodies, which blocked patients' IgE binding to Bet v 1 and related allergens. Thus, rBet v 1 trimer represents a novel hypoallergenic vaccine prototype for treatment of one of the most frequent allergy forms.

Allergens↗

PubMed2001

Nonanaphylactic synthetic peptides derived from B cell epitopes of the major grass pollen allergen, Phl p 1, for allergy vaccination.

Worldwide more than 200 million individuals are allergic to group 1 grass pollen allergens. We have used the major timothy grass pollen allergen Phl p 1, which cross-reacts with most grass-, corn-, and monocot-derived group 1 allergens to develop a generally applicable strategy for the production of hypoallergenic allergy vaccines. On the basis of the experimentally determined B cell epitopes of Phl p 1, we have synthesized five synthetic peptides. These peptides are derived from the major Phl p 1 IgE epitopes and were between 28-32 amino acids long. We demonstrate by nuclear magnetic resonance that the peptides exhibit no secondary and tertiary structure and accordingly failed to bind IgE antibodies from grass pollen allergic patients. The five peptides, as well as an equimolar mixture thereof, lacked allergenic activity as demonstrated by basophil histamine release and skin test experiments in grass pollen allergic patients. When used as immunogens in mice and rabbits, the peptides induced protective IgG antibodies, which recognized the complete Phl p 1 wild-type allergen and group 1 allergens from other grass species. Moreover, peptide-induced antibodies inhibited the binding of grass pollen allergic patients IgE antibodies to the wild-type allergen. We thus demonstrate that synthetic hypoallergenic peptides derived from B cell epitopes of major allergens represent safe vaccine candidates for the treatment of IgE- mediated allergies.

Allergens↗

PubMed2001

The basophil activation marker defined by antibody 97A6 is identical to the ectonucleotide pyrophosphatase/phosphodiesterase 3.

It has recently been shown that monoclonal antibody (MoAb) 97A6 detects a surface antigen expressed on basophils and their CD34(+) precursor cells, as well as the basophil cell line KU-812. In this report the partial amino acid sequence of affinity chromatography- and sodium dodecyl sulfate-polyacrylamide gel electrophoresis-separated 97A6 antigen(s) from KU-812 lysates was determined. Sequence alignment of high-performance liquid chromatography-selected tryptic peptides from the resulting 130- and 150-kd bands revealed a 100% identity with amino acids 393 to 405 of ectonucleotide pyrophosphatase/phosphodiesterase-3 (E-NPP3; CD203c) but not of the related ectoenzyme PC-1 (E-NPP1). Moreover, MoAb 97A6 selectively recognized 293 cells transfected with human E-NPP3, but did not react with cells transfected with PC-1 or parental 293 cells. In addition, E-NPP3 messenger RNA expression was detected in basophils but not other peripheral blood cells. Finally, MoAb 97A6 immunoprecipitated phosphodiesterase activity from KU-812 cells and peripheral blood basophils, but not from other cell populations. These data demonstrate that MoAb 97A6 recognizes the functionally active type II transmembrane ectoenzyme E-NPP3.

Amino Acid Sequence↗

PubMed2001

Characterization of (123)I-vascular endothelial growth factor-binding sites expressed on human tumour cells: possible implication for tumour scintigraphy.

To explore the possibility of vascular endothelial growth factor (VEGF) receptor scintigraphy of primary tumours and their metastases, we analysed the binding properties of (123)I-labelled VEGF(165) ((123)I-VEGF(165)) and (123)I-VEGF(121) to human umbilical vein endothelial cells (HUVECs), several human tumour cell lines (HMC-1, A431, KU812, U937, HEP-1, HEP-G2, HEP-3B and Raji), a variety of primary human tumours (n = 40) and some adjacent non-neoplastic tissues as well as normal human peripheral blood cells in vitro. Two classes of high-affinity (123)I-VEGF(165)-binding site were found on the cell surface of HUVECs. In contrast, one class of high-affinity binding sites for (123)I-VEGF(165) was found on HMC-1, A431, HEP-1, HEP-G2, HEP-3B and U937 cells as well as many primary tumours. For (123)I-VEGF(121), a single class of high-affinity binding site was found on certain cell lines (HUVEC, HEP-1 and HMC-1) and distinct primary tumours (primary melanomas, ductal breast cancers and ovarian carcinomas as well as meningiomas). Tumour cells expressed significantly higher numbers of VEGF receptors compared with normal peripheral blood cells and adjacent non-neoplastic tissues. Immunohistochemical staining revealed that the VEGF receptor Flk-1 is expressed to a much higher extent within malignant tissues compared with neighbouring non-neoplastic cells. We observed significantly greater specific binding of (123)I-VEGF(165) and (123)I-VEGF(121) to a variety of human tumour cells/tissues compared with the corresponding normal tissues or normal peripheral blood cells. In comparison with (123)I-VEGF(121), (123)I-VEGF(165) bound to a higher number of different tumour cell types with a higher capacity. Thus, (123)I-VEGF(165) may be a potentially useful tracer for in vivo imaging of solid tumours.

Animals↗

PubMed2001

Effects of vasoactive intestinal peptide (VIP) and somatostatin (SST) on lipoprotein receptor expression by A431 tumor cells.

A variety of tumor cells have been shown to express lipoprotein receptors. Recent data suggest that lipoprotein receptors may play a regulatory role in the growth of certain tumor cells. We investigated the effects of vasoactive intestinal peptide (VIP) and somatostatin-14 (SST-14) on the binding of 111Indium-labeled lipoproteins [(111)In-low density lipoprotein ((111)In-LDL), (111)In-high density lipoprotein ((111)In-HDL) and (111)In-very low density lipoprotein ((111)In-VLDL)] onto the epidermoid mammary carcinoma cell line A431. Scatchard analyses of the binding data indicated one class of specific high affinity binding sites for LDL, HDL and VLDL expressed by A431 cells, respectively. VIP increased significantly the binding capacity for (111)In-LDL on A431 cells. The VIP-induced increase of (111)In-LDL binding sites was inhibited by SST-14. Furthermore, SST-14 inhibited VIP-induced 3H-thymidine incorporation and adenosine 3'-5' cyclic monophosphate (cAMP) formation in A431 cells with IC50 values in the range of 5-7 nM. However, SST-14 showed no effect on dibutyryl-cAMP-induced increase of (111)In-LDL binding sites expressed on A431 cells. In contrast to (111)In-LDL binding, no effects of VIP or SST-14 on HDL or VLDL binding to A431 tumor cells were found. Our results suggest a direct effect of VIP and SST-14 on LDL-binding onto tumor cells. The complex interactions between VIP and SST-14 on LDL receptor expression of tumor cells may play a role in tumor cell lipid metabolism.

Bucladesine↗

PubMed2001

Amplification of the AML1(CBFA2) gene on ring chromosomes in a patient with acute myeloid leukemia and a constitutional ring chromosome 21.

In the genesis of hematologic neoplasms gene amplification is a mechanism for illegitimate activation of proto-oncogenes. We report a phenotypically normal patient with a constitutional ring chromosome 21 who developed acute myeloid leukemia (AML). The leukemic cells revealed size-variable ring chromosomes 21 with amplification of the proto-oncogene AML1, located in the chromosomal band 21q22, within the rings. Hitherto, amplification of the proto-oncogene AML1-also in form of a ring chromosome-has been described recently only in one patient with myelodysplastic syndrome (MDS). In AML, gene amplification by ring formation has been demonstrated only in another three patients (amplification of the MLL gene in two cases and of the ETV6 gene in one case). Here we present the new evidence that the internal rearrangement of a constitutional ring chromosome 21 resulted in multiplication of a proto-oncogene in bone marrow cells and provided obviously a selective growth advantage. Moreover the amplification of ribosomal DNA was observed in the ring chromosomes of the tumor cells.

Acute Disease↗

PubMed2001

IgA cross-reactivity between a nuclear autoantigen and wheat proteins suggests molecular mimicry as a possible pathomechanism in celiac disease.

Celiac disease patients display IgA antibody reactivity to wheat as well as to human proteins. We used serum IgA from celiac patients and, for control purposes, from patients with Crohn's disease, ulcerative colitis and from healthy individuals to identify celiac disease-specific IgA autoantigens in nitrocellulose-blotted extracts from various human cell types (epithelial, endothelial, intestinal cells, fibroblasts). The pattern, recognition intensity and time course of IgA autoreactivity was monitored using serial serum samples obtained from celiac children before and under gluten-free diet. By immunoblot inhibition and subcellular (cytosolic, nuclear) cell fractionation we identified a 55 kDa nuclear autoantigen expressed in intestinal, endothelial cells and in fibroblasts which was recognized by IgA antibodies of approximately half of the celiac disease patients and cross-reacted with wheat proteins. IgA reactivity to the 55 kDa autoantigen disappeared during gluten-free diet and was inhibited after pre-absorption of sera with wheat proteins but not with tissue transglutaminase, previously reported as the unique celiac disease-specific autoantigen. In conclusion, we defined a novel 55 kDa celiac disease-specific nuclear IgA autoantigen which shares epitopes with wheat proteins and which is different from tissue transglutaminase and calreticulin. Although the newly defined autoantigen was recognized much less frequently than tissue transglutaminase, our data suggest molecular mimicry between wheat and human proteins as a possible pathomechanism for the induction and/or maintenance of mucosal tissue damage in celiac disease.

Adolescent↗

PubMed2001

Amplification of ribosomal RNA genes in acute myeloid leukemia.

Gene amplification is a relatively rare event in acute myeloid leukemia (AML). Double minutes (dmin) and homogeneously staining regions are well established phenomena as cytogenetic correlates of gene amplification. Recently, however, two additional mechanisms leading to gene amplification, i.e., segmental jumping translocations and formation of ring chromosomes, have been described. We report four patients with AML, in whom bone marrow cells exhibited amplifications of ribosomal RNA (rRNA) genes in the form of ring chromosomes or a hsr. In two patients, the MLL gene, and in one patient the CBFA2 gene were shown to be co-amplified with rRNA genes. In two of the four patients, multiple copies of alpha-satellite sequences of the centromeres 13 and 21, respectively, were also demonstrated. In three of the four patients, the clinical course was very aggressive, leading to death within 2-8 months. In these three patients, complex karyotype abnormalities were found, whereas the karyotype of Patient 4 was characterized only by supernumerary ring 21 chromosomes of different sizes and a trisomy 8 in half of the metaphases. Modes of origin and clinical significance of the amplification of rRNA genes are discussed.

Acute Disease↗

PubMed2001

Survival analysis and AML development in patients with de novo myelodysplastic syndromes: comparison of six different prognostic scoring systems.

A number of prognostic scoring systems for patients with myelodysplastic syndromes (MDS) have been introduced in the past. In the present study, survival and AML evolution were analyzed retrospectively in a total of 180 patients with de novo MDS (observation period: 1989-1999; median age: 71; range 27-93; f/m ratio: 1/1.2). Diagnoses were established according to FAB criteria (RARS, n=37; RA, n=53; RAEB, n=50; RAEB-t, n=19; CMML, n=21). Six different multiparameter scoring systems (the Mufti, Aul, Sanz, Morel, and Toyama scores, and the international prognostic scoring system [IPSS]) were applied. The Aul, Sanz, and Mufti scores were applied to all 180 patients, Morel and Toyama scores to 109 patients, and the IPSS to 102. As assessed by multivariate analysis, the percentage of bm-blasts, hemoglobin, platelet count, neutrophil count, LDH, and karyotype were found to be independent single variables for survival, and bm-blasts, neutrophil count, platelet count, and karyotype for AML evolution. All prognostic scoring systems applied appeared to be highly predictive for survival and AML development (P<0.001). The highest predictive values were found for the Aul, Sanz, and Toyama scores for overall survival, and the IPSS, Toyama, and Morel scores for AML-free survival. In summary, our data show that scoring systems are useful for predicting overall and AML-free survival in patients with MDS. Karyotype-based multiparameter systems appear to be particularly effective in defining MDS patients who are at high risk of transforming to leukemia.

Acute Disease↗

PubMed2001

Prognostic value of lactate dehydrogenase activity in myelodysplastic syndromes.

Several prognostic factors for patients with myelodysplastic syndromes (MDS) have been defined in the past. One of these factors appears to be the serum lactate dehydrogenase (LDH) activity. However, the precise predictive value of an elevated LDH level with regard to AML transformation remains uncertain. In this study, the prognostic value of the LDH activity was examined in a cohort of 180 patients with de novo MDS (median age 71 years [27-93]; f/m-ratio 1:1.2; RA: n=53; RARS: n=37; RAEB: n=50; RAEBT: n=19; CMML: n=21). Significant differences in LDH activities were found among FAB groups (P<0.05), and especially among IPSS groups (HIGH: 411+/-574; INT-2: 221+/-90; INT-1: 254+/-145; LOW: 192+/-47 U/l; P<0.05). An LDH level of >/=300 U/l was found to be associated with a significantly shorter median survival (10.3 months) when compared to <300 U/l (33.7 months; P<0.01). Moreover, an LDH activity of >/=300 U/l indicated a reduced AML-free survival in our MDS patients (P<0.01). As assessed by Cox regression, the inclusion of LDH as additional variable into the IPSS system resulted in an improved prediction concerning survival, but not with regard to AML evolution. Together, our data show that a serum LDH activity of >/=300 U/l in MDS is associated with a significantly shorter survival and higher risk to transform to AML. The LDH activity should be considered as an important prognostic factor in MDS.

Actuarial Analysis↗

PubMed2001

A case of 'smouldering' mastocytosis with high mast cell burden, monoclonal myeloid cells, and C-KIT mutation Asp-816-Val.

Mastocytosis is a term used for a group of disorders characterized by abnormal growth and accumulation of tissue mast cells (MC) in one or more organ systems. In patients with systemic mastocytosis (SM) the clinical course may be indolent or aggressive or even complicated by leukemic progression or an associated clonal hematologic non mast cell lineage disease (AHNMD). However, at first presentation (diagnosis) it may be difficult to define the category of disease and the prognosis. We report on a 48-year-old female patient with SM with urticaria pigmentosa-like skin lesions and mediator-related symptoms. She was found to have splenomegaly, a high infiltration grade (MC) in bone marrow biopsies (>30%), mild anemia, and a high serum tryptase level (>500 ng/ml). In addition, she exhibited discrete histologic signs of myeloproliferation in the 'non-affected' marrow and monoclonal blood cells established by C-KIT 2468A-->T mutation (Asp-816-Val) -analysis and HUMARA assay. Despite these findings, however, the clinical course was stable over years and no AHNMD or organ impairment developed. Because of the 'intermediate' clinical signs and absence of progression to aggressive disease, we proposed the term 'smouldering mastocytosis'.

Adult↗

PubMed2001

Diagnosis of mastocytosis: general histopathological aspects, morphological criteria, and immunohistochemical findings.

An increase in mast cell (MC) numbers in hemopoietic tissues may be associated with (a) primary neoplastic MC disease (mastocytosis); (b) non-mast cell lineage myelogenous disorders (myelodysplastic or myeloproliferative syndromes and myeloid leukemias); or (c) reactive, i.e. non-clonal states (MC hyperplasia and reactive mastocytosis). However, the histologic discrimination between hyperplastic states and neoplastic MC proliferative disorders is sometimes very difficult. MC hyperplasia is characterized by a diffuse increase in mature, round or spindle-shaped, metachromatic MC that are loosely scattered throughout the tissue and do not form dense focal infiltrates, even in states of marked hyperplasia. However, loosely scattered MC are also a prominent feature of many cases of myelodysplastic syndromes and acute leukemia involving the MC lineage. In contrast, the demonstration of dense, focal and/or diffuse MC infiltrates can be regarded as indicative of primary MC disease/mastocytosis. In addition to the highly diagnostic focal MC infiltrates, mastocytosis may also present with a predominantly diffuse or a mixed (diffuse and focal) infiltration pattern. The relatively rare diffuse pattern is usually dominated by atypical, often hypogranulated or even non-metachromatic MC and is associated with the aggressive or frankly malignant subtypes of systemic mastocytosis and MC leukemia. Although the demonstration of MC infiltrates in Giemsa-stained tissue sections is still very important for the diagnosis of mastocytosis, immunohistochemical techniques using antibodies against MC-associated antigens such as tryptase or c-kit (CD117) are essential for the identification of highly atypical, hypogranulated MC, especially in MC leukemia, and for the detection of small and even minute MC infiltrates.

Adult↗

PubMed2001

Diagnostic criteria and classification of mastocytosis: a consensus proposal.

The term 'mastocytosis' denotes a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells (MC) in one or more organ systems. Over the last 20 years, there has been an evolution in accepted classification systems for this disease. In light of such developments and novel useful markers, it seems appropriate now to re-evaluate and update the classification of mastocytosis. Here, we propose criteria to delineate categories of mastocytosis together with an updated consensus classification system. In this proposal, the diagnosis cutaneous mastocytosis (CM) is based on typical clinical and histological skin lesions and absence of definitive signs (criteria) of systemic involvement. Most patients with CM are children and present with maculopapular cutaneous mastocytosis (=urticaria pigmentosa, UP). Other less frequent forms of CM are diffuse cutaneous mastocytosis (DCM) and mastocytoma of skin. Systemic mastocytosis (SM) is commonly seen in adults and defined by multifocal histological lesions in the bone marrow (affected almost invariably) or other extracutaneous organs (major criteria) together with cytological and biochemical signs (minor criteria) of systemic disease (SM-criteria). SM is further divided into the following categories: indolent systemic mastocytosis (ISM), SM with an associated clonal hematologic non-mast cell lineage disease (AHNMD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL). Patients with ISM usually have maculopapular skin lesions and a good prognosis. In the group with associated hematologic disease, the AHNMD should be classified according to FAB/WHO criteria. ASM is characterized by impaired organ-function due to infiltration of the bone marrow, liver, spleen, GI-tract, or skeletal system, by pathologic MC. MCL is a 'high-grade' leukemic disease defined by increased numbers of MC in bone marrow smears (>or=20%) and peripheral blood, absence of skin lesions, multiorgan failure, and a short survival. In typical cases, circulating MC amount to >or=10% of leukocytes (classical form of MCL). Mast cell sarcoma is a unifocal tumor that consists of atypical MC and shows a destructive growth without (primary) systemic involvement. This high-grade malignant MC disease has to be distinguished from a localized benign mastocytoma in either extracutaneous organs (=extracutaneous mastocytoma) or skin. Depending on the clinical course of mastocytosis and development of an AHNMD, patients can shift from one category of MC disease into another. In all categories, mediator-related symptoms may occur and may represent a serious clinical problem. All categories of mastocytosis should be distinctively separated from reactive MC hyperplasia, MC activation syndromes, and a more or less pronounced increase in MC in myelogenous malignancies other than mastocytosis. Criteria proposed in this article should be helpful in this regard.

Adult↗

PubMed2001

Myelomastocytic overlap syndromes: biology, criteria, and relationship to mastocytosis.

Although mast cells (MC) appear to be myeloid cells, MC lineage involvement in myelogenous malignancies has been described only rarely. Based on clonal evolution, biology of afflicted cells, and disease criteria, three major groups of patients have been recognized: The first meets criteria for both diagnoses 'systemic mastocytosis' and 'associated hematologic clonal non-mast cell lineage disease (AHNMD)'. In such patients, myeloproliferative (MPS) or myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML) is diagnosed apart from mastocytosis. In a second group of patients, large numbers of very immature MC-lineage cells (metachromatically granulated blast-like cells) are detectable, but the criteria to diagnose mastocytosis are not met. These patients have advanced myeloid neoplasms (MDS or MPS with blast cell increase, or AML) and variably suffer from mediator-related symptoms (flush, GI-tract ulcer, diarrhoea, coagulopathy). In some cases, the disease mimics mast cell- or basophilic leukemia. In contrast to basophilic leukemia, however, the metachromatic cells are strongly KIT+ and tryptase+. In contrast to true mast cell leukemia (MCL), MC do not form multifocal dense infiltrates in the bone marrow. Also, MC lack CD2 and CD25, and the C-KIT mutation Asp-816-Val. We propose the term 'myelomastocytic leukemia' or 'myelodysplastic mast cell syndrome' for these cases. In a third group of patients, myeloid neoplasms (MDS, MPS, AML) show constitutive expression of MC-associated antigens (tryptase, histamine) or mastocytosis-related gene defects (mutated C-KIT) without significant increase in metachromatic cells or criteria of mastocytosis. Whether these neoplasms display aberrant gene expression (or gene defects) or represent 'pre-pre-mast cell leukemias', remains unknown.

Antigens, Differentiation↗