Differential Diagnoses of Systemic Mastocytosis in Routinely Processed Bone Marrow Biopsy Specimens: A Review

Diagnosis of systemic mastocytosis (SM) is mainly based on the morphological demonstration of compact mast cell infiltrates in various tissue sites. In almost all patients such infiltrates are detected in the bone marrow. Reliable immunohistochemical markers for the diagnosis and grading of SM have been established, but various differential diagnoses including myeloproliferative neoplasms, basophilic and eosinophilic leukemias may be very difficult to delineate. Even more challenging is the recognition of hematological neoplasms with signs of mast cell differentiation but not fulfilling diagnostic criteria for SM, especially the rare myelomastocytic leukemia. It is also important to separate the reactive state of mast cell hyperplasia from indolent variants of SM, especially those with a very low degree of bone marrow infiltration and absence of compact mast cell infiltrates. When the lymphocytic component of the SM infiltrate is very prominent, SM may be confused with an indolent lymphoma, especially lymphoplasmacytic lymphoma which almost always shows a marked reactive increase in mast cells. In aggressive and leukemic variants of SM, mast cells may be very atypical and devoid of metachromatic granules. This hypogranulation can be regarded as cellular atypia and may lead to the misdiagnosis aspect of monocytic leukemia or histiocytic neoplasm. Regarding immunohistochemical anomalies, mast cells in aggressive and leukemic SM have been found to express CD30 (Ki1-antigen). Thus, anaplastic large cell lymphoma or Hodgkin's disease may first be considered rather than SM. There is increasing evidence that most patients with long-standing adult-type urticaria pigmentosalike skin lesions have in fact indolent SM. Therefore, such skin lesions are an important clue to the correct diagnosis in these patients. However, in aggressive or leukemic SM skin lesions are usually absent and then the correct diagnosis relies on an appropriate investigation of bone marrow biopsy specimens using both SM-related immunohistochemical markers (tryptase, KIT, CD25, CD30) but also markers excluding potential differential diagnoses. Investigation for presence of the activating KIT point mutation D816V is very helpful to establish a correct diagnosis of SM in all the difficult cases exhibiting a low degree of bone marrow infiltration or puzzling morphological findings. Copyright (C) 2010 S. Karger AG, Base

Histological investigations on the thyroid glands of marine mammals (Phoca vitulina, Phocoena phocoena) and the possible implications of marine pollution

In 1988 and 1989, thousands of harbor seals (Phoca vitulina) died in the North Sea from phocine distemper infection. The morphology of thyroid glands from 40 harbor seals found dead on the North Sea coastlines of Schleswig-Holstein, Federal Republic of Germany, during an epizootic of phocine distemper, was compared with the morphology of thyroid glands from five healthy harbor seals collected in Iceland. Thyroid glands from seven harbor porpoises (Phocoena phocoena) found dead in 1990 on the North Sea coastlines also were evaluated. Colloid depletion and fibrosis were found in the thyroid glands of harbor seals which died during the epizootic, but not in animals from Iceland. Thyroid glands of the porpoises showed similar lesions, but to a lesser degree, than those observed in the North Sea seals

KITD816V+ systemic mastocytosis associated with KITD816V+ acute erythroid leukaemia: first case report with molecular evidence for same progenitor cell derivation

Toll-like receptor (TLR)-9 recognizes CpG motifs in microbial DNA. TLR9 signalling stimulates innate antimicrobial immunity and modulates adaptive immune responses including autoimmunity against chromatin, e.g., in systemic lupus erythematosus (SLE). This review summarizes the available data for a role of TLR9 signalling in lupus and discusses the following questions that arise from these observations: 1) Is CpG-DNA/TLR9 interaction involved in infection-induced disease activity of lupus? 2) What are the risks of CpG motifs in vaccine adjuvants for lupus patients? 3) Is TLR9 signalling involved in the pathogenesis of lupus by recognizing self DNA

Systemic mastocytosis with associated myeloproliferative disease and precursor B lymphoblastic leukaemia with t(13;13)(q12;q22) involving FLT3.

Systemic mastocytoses represent neoplastic proliferations of mast cells. In about 20% of cases systemic mastocytoses are accompanied by clonal haematopoietic non-mast cell-lineage disorders, most commonly myeloid neoplasms. A case of systemic mastocytosis carrying the characteristic mutation at codon 816 (D816V) in the KIT gene of mast cells, with two concurrent accompanying clonal haematopoietic non-mast cell-lineage disorders, chronic myeloproliferative disease, unclassifiable and precursor B lymphoblastic leukaemia is documented. Both accompanying clonal haematopoietic non-mast cell-lineage disorders carried the wild-type KIT gene, but had a novel t(13;13)(q12;q22) involving the FLT3 locus at 13q12. The chronic myeloproliferative disease, unclassifiable and the precursor B lymphoblastic leukaemia were cured by syngenous stem cell transplantation, but the systemic mastocytosis persisted for more than 10 years. The additional impact of molecular techniques on the correct diagnosis in haematological malignancies is highlighted, and evidence is provided that, apart from internal tandem duplications and mutations, FLT3 can be activated by translocations

Evaluation of Mast Cell Activation Syndromes: Impact of Pathology and Immunohistology

Mast cell activation syndromes (MCAS) are clinically defined disease states with a largely unknown morphological background. Since mastocytosis may be associated with MCAS, it is crucial in every patient to document or exclude mastocytosis by appropriate histological, molecular, and serological investigations of tissues/organs that are commonly involved in mastocytosis like skin, mucosa of the gastrointestinal tract and bone marrow. Accordingly, histopathological investigation including immunohistological stains is crucial to reach the final diagnosis in such patients and to classify MCAS into primary MCAS, which can present with or without evidence of overt mastocytosis, or secondary MCAS, where an underlying disease with or without tissue inflammation is detected. Cases without evidence of mastocytosis, monoclonal mast cells, or any underlying disease should be termed idiopathic MCAS. When the activating point mutant KIT D816V is detectable but criteria for diagnosis of mastocytosis are not completely met, a so-called (mono)clonal MCAS as a subvariant of primary MCAS should be diagnosed. Copyright (C) 2012 S. Karger AG, Base

Title: Ex vivo coronary stent implantation evaluated with digital image correlation

Abstract: Intracoronary stenting (PCI) has become standard revascularization technique to reopen blocked arteries. Although significant progress in stenting technology and implantation techniques has been made a number of problems remain. Specifically, stent sizing and inflation pressures are still a matter of scientific debates. Despite a large number of biomechanical computational simulations experimental data are rare, likely due to technical difficulties to measure dilatation pressures and coronary dimensions in the same settings. Our study shows that valuable data can be obtained by employing digital image correlation for 3D strain measurement during stent inflation ex-vivo that can provide further insight into the stent-artery wall interactions. Keywords: Artery wall-stent interaction; coronary stent; digital image correlation; experimental implantation; strain. 3 Abstract/Introduction Intracoronary stenting (PCI) has become standard revascularization technique to reopen blocked arteries. Although significant progress in stenting technology and implantation techniques has been made a number of problems remain Despite a large number of biomechanical computational simulations [3, Methods Stent and PCI equipment The balloon-expandable CoCr coronary stent Kaname TM (Terumo Corporation, Tokyo, Japan) with nominal diameter 3.5 mm, and length 15 mm (at pressure 0.9 MPa; and diameter 3.73 mm at 1.6 MPa) was used in this study. The stent was premounted on PCI dilatation catheter RX-2 (Terumo Corporation). Sample The sample of the main branch of the left coronary artery was obtained from autopsy. The male donor was 40 years old and atherosclerotic lesions were presented inside the sample. The experiment was performed 70 hours post mortem. Experiment The sample was mounted into the experimental setup ( Displacement measurement was based on 3D digital image correlation (DIC) conducted with commercial system Dantec Q-450 (Dantec Dynamics, Ulm, Germany). 4 DIC is non-contact optical method based on the stereoscopic principle which is becoming more popular especially within the strain measurement of geometrically nonuniform objects. The algorithm identifies material points on the object surface and the correlation between consecutive images allows material point tracking. Detailed description can be found in the literature The artery was recorded with two digital cameras (NanoSens Mk III, Dantec Dynamics; 1MPx CCD chip; lens Sigma EX, 105 mm, 1:2.8 D Macro) during the balloon expansion (sampling rate 25 Hz). In fully expanded state, the object ROI approx. 18*3 mm*mm was projected onto 600*300 px*px (in each camera). RX2 manometer was recorded with another camera to obtain time course of change of the balloon distending pressure (pressure transducer connected with PC was not available at the time of experiment). The stent was deployed within manual pressurization up to 1.6 MPa which spanned approximately 42 seconds. Results DIC revealed significant overloading of the artery by the expanded stent. The results are depicted in Principal strains' distribution (Green-Lagrange strain is considered within this study) shows artery response within maximally expanded stent. Principal vectors are predominantly aligned with the circumferential and longitudinal direction which is supposed to be the consequence of the cylindrical stent expansion. Circumferential deformation attains 0.5 mm/mm at the peak value which is far beyond physiological situation. The circumferential strain concentration appears non-symmetrically with respect to the length of the sample which is supposed to be the result of irregular reference geometry (an asymmetrical partially occluded lumen of the artery). Six points (P1-6) were chosen to illustrate specific strain values resulting from different loading conditions and atherosclerotic specimen in our experiment. Discussion This is a preliminary report concerning a stent implantation in ex-vivo settings employing a human coronary artery harvested from autopsy. The results suggest that 3D DIC is promising tool suitable for the evaluation of ex-vivo stent implantation potentially useful for validation of computational models and clinical considerations. Presented results suggest that overexpansion of a stent during deployment may overstretch the target site potentially resulting in implantation injury associated with restenosis and/or intimal tears associated with dissections. To obtain exact intraluminal dimensions during stent deployment optical coherence tomography or intravascular ultrasound (IVUS) would be required, currently not available in our laboratory. Nevertheless we plan to combine IVUS with 3D DIC in future experiments

Influence of the substrate-induced strain and irradiation disorder on the Peierls transition in TTF-TCNQ microdomains

The influence of the combined effects of substrate-induced strain, finite size and electron irradiation-induced defects have been studied on individual micron-sized domains of the organic charge transfer compound tetrathiafulvalene-tetracyanoquinodimethane (TTF-TCNQ) by temperature-dependent conductivity and current-voltage measurements. The individual domains have been isolated by focused ion beam etching and electrically contacted by focused ion and electron beam induced deposition of metallic contacts. The temperature-dependent conductivity follows a variable range hopping behavior which shows a crossover of the exponent as the Peierls transition is approached. The low temperature behavior is analyzed within the segmented rod model of Fogler, Teber and Shklowskii, as originally developed for a charge-ordered quasi one-dimensional electron crystal. The results are compared with data obtained on as-grown and electron irradiated epitaxial TTF-TCNQ thin films of the two-domain type

Splenomegaly, elevated alkaline phosphatase and mutations in the SRSF2/ASXL1/RUNX1 gene panel are strong adverse prognostic markers in patients with systemic mastocytosis

We evaluated the impact of clinical and molecular characteristics on overall survival (OS) in 108 patients with indolent (n=41) and advanced SM (advSM, n=67). Organomegaly was measured by magnetic resonance imaging (MRI)-based volumetry of liver and spleen. In multivariate analysis of all patients, an increased spleen volume greater than or equal to450?ml (hazard ratio [HR], 5.2; 95% confidence interval [CI], [2.1–13.0]; P=0.003) and an elevated alkaline phosphatase (AP; HR 5.0 [1.1–22.2]; P=0.02) were associated with adverse OS. The 3-year OS was 100, 77, and 39%, respectively (P<0.0001), for patients with 0 (low-risk, n=37), 1 (intermediate-risk, n=32) or 2 (high-risk, n=39) parameters. For advSM patients with fully available clinical and molecular data (n=60), univariate analysis identified splenomegaly greater than or equal to1200?ml, elevated AP and mutations in the SRSF2/ASXL1/RUNX1 (S/A/R) gene panel as significant prognostic markers. In multivariate analysis, mutations in S/A/R (HR, 3.2 [1.1–9.6]; P=0.01) and elevated AP (HR 2.6 [1.0–7.1]; P=0.03) remained predictive adverse prognostic markers for OS. The 3-year OS was 76% and 38%, respectively (P=0.0003), for patients with 0-1 (intermediate-risk, n=28) or 2 (high-risk, n=32) parameters. We conclude that splenomegaly, elevated AP and mutations in the S/A/R gene panel are independent of the WHO classification and provide the most relevant prognostic information in SM patient

Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal

Activation of tissue mast cells (MCs) and their abnormal growth and accumulation in various organs are typically found in primary MC disorders also referred to as mastocytosis. However, increasing numbers of patients are now being informed that their clinical findings are due to MC activation (MCA) that is neither associated with mastocytosis nor with a defined allergic or inflammatory reaction. In other patients with MCA, MCs appear to be clonal cells, but criteria for diagnosing mastocytosis are not met. A working conference was organized in 2010 with the aim to define criteria for diagnosing MCA and related disorders, and to propose a global unifying classification of all MC disorders and pathologic MC reactions. This classification includes three types of `MCA syndromes' (MCASs), namely primary MCAS, secondary MCAS and idiopathic MCAS. MCA is now defined by robust and generally applicable criteria, including (1) typical clinical symptoms, (2) a substantial transient increase in serum total tryptase level or an increase in other MC-derived mediators, such as histamine or prostaglandin D 2, or their urinary metabolites, and (3) a response of clinical symptoms to agents that attenuate the production or activities of MC mediators. These criteria should assist in the identification and diagnosis of patients with MCAS, and in avoiding misdiagnoses or overinterpretation of clinical symptoms in daily practice. Moreover, the MCAS concept should stimulate research in order to identify and exploit new molecular mechanisms and therapeutic targets. Copyright (C) 2011 S. Karger AG, Base

Microscopic examination of bone marrow aspirates in malignant disorders of haematopoiesis—a comparison of two slide preparation techniques

It is mandatory to perform microscopic examinations of bone marrow aspirates during the diagnosis of many neoplastic haematopoiesis disorders. In 2008, The International Committee for Standardization in Hematology recommended the use of two types of slides for the microscopic evaluation of bone marrow: wedge-spread film and crush film slides. Because these techniques have not yet been compared, we performed such a comparison. Routine bone marrow samples from 250 patients diagnosed due to different neoplastic haematological disorders were evaluated. The major differences between the two compared techniques were identified in 13 patients with non-Hodgkin’s lymphoma, seven patients with systemic mastocytosis and 11 patients with acute leukaemias or myelodysplastic syndromes or chronic myelomonocytic leukaemia. Differences were noted also in many patients with multiple myeloma, but the clinical significance of these discrepancies was rather modest. The major causes of the differences observed seemed to be the dilution of marrow with blood cells and the focal growth of many neoplastic cells. We believe that the crush technique is more advantageous compared to the wedge-spread films. Therefore, we recommend the use of crush films as the primary method for establishing a diagnosis or for making therapeutic decisions based on the microscopic examination of bone marrow