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Background: Cutaneous lesions of mastocytosis (CLM) are often subtle and may require biopsy. However, dermatohistopathological criteria for CLM remain undefined. Objectives: To establish criteria for CLM by validating histological and molecular parameters. Methods: In skin samples from Caucasian patients with CLM and controls (atopic dermatitis, chronic urticaria, pruritus, tissue from tumor safety margin excisions), mast cell (MC) numbers, size, shape, distribution, immunostainability with a large panel of markers, pigmentation and presence of KIT D816V mutation were analysed. Results: Forty‐seven CLM patients (32 maculopapular cutaneous mastocytosis (MPCM), 15 mastocytomas) and 36 controls were included. Mastocytomas were easily identified by densely packed cuboidal MCs. In MPCM, skin MC density in CD117 stains was higher in CLM patients than in controls (P < 0.0001) and values correlated closely (r = 0.65, P < 0.0001) to results in tryptase stains. The optimized upper dermis cut‐off number of 62 MC/mm2 had a sensitivity and specificity of 92% in both stainings, corresponding to approximately 12 MC/high power field (HPF). MC size was larger in MPCM than in controls (P = 0.01). Interstitial (= not perivascular or periadnexal) MCs and stronger basal pigmentation of the epidermis were indicative of MPCM (P < 0.0001 each) and clusters of >3 nucleated MC/HPF exclusively found in MCPM. Surface markers CD2, CD25 and CD30 stained T‐lymphocytes, but only negligibly CLM MC. The KIT D816V mutation in formalin fixed paraffin embedded (FFPE) skin was evaluable in 87.5% of MCPM patients and had both 100% sensitivity and specificity. Conclusions: MPCM can be predicted by major and minor criteria combined in a scoring model. Presence of D816V mutation in FFPE skin and MC density > 27/HPF are >95%‐specific major criteria for MPCM. MC densities 12/HPF, interstitial MC, clusters and basal pigmentation are minor criteria. [ABSTRACT FROM AUTHOR]

Background Treatment failure during venom immunotherapy ( VIT) may be associated with a variety of risk factors, of which the relative importance is unknown. Objective Our aim was to evaluate the association of baseline serum tryptase concentration ( BTC), mastocytosis in the skin ( MIS) and of other parameters with the frequency of objective systemic reactions during in-hospital sting challenge ( SC). Methods In this observational retrospective study, we enrolled 1532 patients (1609 cases due to double SC) with established honeybee or vespid venom allergy who had undergone VIT and a subsequent SC. Data were collected on various putative risk factors. Adult-onset MIS and/or a BTC > 20.0 μg/L was defined as clinical indicators of systemic mastocytosis. Relative rates were calculated with logistic regression models. Results Ninety-eight patients (6.4%) presented with MIS and/or BTC > 20.0 μg/L. 104 cases (6.5%) developed objective generalized symptoms during SC. In the absence of MIS, a BTC ≤ 20 μg/L did not increase the risk for VIT failure. The most important factors associated with a worse outcome were ACE inhibitor medication ( OR 5.24, 95% CI 1.83-13.00, P < 0.001), honeybee venom allergy ( OR 5.09, 95% CI 3.17-8.15, P < 0.001), systemic allergic reaction during VIT ( OR 3.07, 95% CI 1.79-5.14, P < 0.001), and a substantial likelihood to suffer from SM ( OR 2.74, 95% CI 1.37-5.22, P = 0.003), whereas a double VIT ( OR 0.51, 95% CI 0.27-0.90, P = 0.027) and a longer duration of therapy ( OR 0.68 per treatment month, 95% CI 0.50-0.93, P = 0.017) reduced the failure rate. Conclusion The magnitude of therapeutic success correlates with type of venom, duration of therapy, and venom dose. Adult-onset MIS and/or a BTC > 20 μg/L is a significant, albeit not the strongest determinant for VIT failure. According to its odds ratio, ACE inhibitor therapy appears to be associated with the highest risk for VIT failure. [ABSTRACT FROM AUTHOR]

Background Chronic eosinophilic leukemia ( CEL) is a myeloproliferative neoplasm characterized by expansion of neoplastic eosinophils, tissue infiltration, and organ damage. In a subset of these patients, the FIP1L1/ PDGFRA (F/P) oncoprotein is detectable. F/P exhibits constitutive tyrosine kinase activity and activates a number of signaling pathways. So far, however, little is known about the role of F/P-dependent proteins in the pathogenesis of CEL. Methods A screen for F/P-dependent cytokines was performed in growth factor-dependent human cell lines lentivirally transduced with F/P. Signal transduction pathways were characterized in Ba/F3 cells with doxycycline-inducible expression of F/P and in EOL-1 cells. Cytokine expression was confirmed in patients' material by immunohistochemistry, immunofluorescence, and confocal microscopy. Gene expression analysis, proliferation assays, and chemotaxis assays were used to elucidate paracrine interactions between neoplastic eosinophils and stromal cells. Results We show that F/P upregulates expression of oncostatin M ( OSM) in various cell line models in a STAT5-dependent manner. Correspondingly, neoplastic eosinophils in the bone marrow were found to overexpress OSM. OSM derived from F/P + cells stimulated proliferation of stromal cells. Moreover, OSM-containing supernatants from F/P + cells were found to upregulate production of stromal cell-derived factor-1 (SDF-1)/CXCL12 in human fibroblasts. SDF-1, in turn, induced migration of EOL-1 cells in a dose-dependent manner. Conclusions We have identified a F/P-driven paracrine interaction between neoplastic eosinophils and stromal cells that may contribute to tissue fibrosis and accumulation of neoplastic eosinophils in CEL. [ABSTRACT FROM AUTHOR]

Although a classification for myelodysplastic syndromes (MDS) has been proposed by several working groups and by the World Health Organization (WHO), with criteria useful to discriminate between disease variants, the important issue of minimal diagnostic criteria of MDS has only recently been addressed. In the current article, proposed minimal diagnostic criteria for MDS are discussed together with two conditions that do not meet these criteria, although cytopenia or dysplasia is present. These two conditions, idiopathic cytopenia of unknown significance and idiopathic dysplasia of unknown significance should be kept in mind as a provisional (potential) diagnosis in patients with suspected MDS. Both conditions can progress to frank MDS over time. Therefore, once diagnosed, these patients should have a haematological follow-up. The diagnosis MDS, on the other hand, needs to be based on robust criteria and exclusion of all other causes of cytopenia and dysplasia, which requires detailed and sometimes extensive investigations, including a bone marrow biopsy, cytogenetic analyses, molecular studies and flow cytometry. [ABSTRACT FROM AUTHOR]

Several emerging treatment concepts for myeloid neoplasms are based on novel drugs targeting cell surface antigens, signalling pathways, or critical effector molecules. Systemic mastocytosis is a haematopoietic neoplasm that behaves as an indolent myeloproliferative disease in most patients, but can also present as aggressive disease or even as an acute leukaemia. In patients with aggressive disease or mast cell leukaemia, the response to conventional therapy is poor in most cases, and the prognosis is grave. Therefore, a number of attempts have been made to define novel treatment strategies for these patients. One promising approach may be to identify novel targets and to develop targeted drug therapies. In this article, we support the notion that neoplastic mast cells indeed express a number of potential molecular targets including immunoreactive CD antigens, the microphthalmia transcription factor (MITF), and members of the Bcl-2 family. In addition, the tyrosine kinase receptor KIT and downstream signalling pathways have been proposed as targets of a specific pharmacological intervention. A particular challenge is the disease-related D816V-mutated variant of KIT, which is resistant against diverse tyrosine kinase inhibitors including STI571, but may be sensitive to more recently developed targeted compounds. The therapeutic potential of target-specific approaches in malignant mast cell disorders should be evaluated in forthcoming clinical trials in the near future. Eur J Clin Invest 2004; 34 (Suppl. 2): 41–52 [ABSTRACT FROM AUTHOR]

Reports the very rare case of a primary malignant mixed Mullerian tumors (MMMT) arising in the rectosigmoid. Information on the case of a 79-year-old female patient presented with rectal bleeding and a history of weight loss diagnosed with polypoid ulcerating tumor of the rectosigmoid colon diffusely infiltrating the mesocolon; Histogenesis of MMMT.

The article discusses close association of ectopic intrathyroidal parathyroid gland and papillary microcarcinoma of the thyroid. A bilateral nodal goiter had been removed from a 41 year old woman. Clinically, an adenoma was suspected within the left lobe, and the right lobe showed a nodule with decreased hormonal function on scintigraphic evaluation. There was no history of hyperparathyroidism. On gross examination, the largest diameters of the two roughly spindle-shaped thyroid lobes were 62 and 48mm. Cut surfaces revealed multiple nodules measuring upto 25 mm in largest diameter.

The article presents excerpts from research articles found in scientific and medical journals. Some of the articles listed include "Mastocytosis: reactive or neoplastic," "HIV-1 detection by nested PCR and viral culture in fresh or cryopreserved postmortem skin: potential implications for skin handling and allografting," "Overcoming the obstacles of gene therapy," "Nonviral strategies for gene therapy," "The promise and problems of meta-analysis," and others.

Mastocytosis is an emerging differential diagnosis in patients with more or less specific mediator-related symptoms. In some of these patients, typical skin lesions are found and the diagnosis of mastocytosis can be established. In other cases, however, skin lesions are absent, which represents a diagnostic challenge. In the light of this unmet need, we developed a diagnostic algorithm for patients with suspected mastocytosis. In adult patients with typical lesions of mastocytosis in the skin, a bone marrow (BM) biopsy should be considered, regardless of the basal serum tryptase concentration. In adults without skin lesions who suffer from mediator-related or other typical symptoms, the basal tryptase level is an important parameter. In those with a slightly increased tryptase level, additional investigations, including a sensitive KIT mutation analysis of blood leucocytes or measurement of urinary histamine metabolites, may be helpful. In adult patients in whom (i) KIT D816V is detected and/or (ii) the basal serum tryptase level is clearly increased (>25-30 ng/ml) and/or (iii) other clinical or laboratory features suggest the presence of 'occult' mastocytosis or another haematologic neoplasm, a BM investigation is recommended. In the absence of KIT D816V and other signs or symptoms of mastocytosis or another haematopoietic disease, no BM investigation is required, but the clinical course and tryptase levels are monitored in the follow-up. In paediatric patients, a BM investigation is usually not required, even if the tryptase level is increased. Although validation is required, it can be expected that the algorithm proposed herein will facilitate the management of patients with suspected mastocytosis and help avoid unnecessary referrals and investigations., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Chronic eosinophilic leukemia (CEL) is a myeloproliferative neoplasm characterized by expansion of neoplastic eosinophils, tissue infiltration, and organ damage. In a subset of these patients, the FIP1L1/PDGFRA (F/P) oncoprotein is detectable. F/P exhibits constitutive tyrosine kinase activity and activates a number of signaling pathways. So far, however, little is known about the role of F/P-dependent proteins in the pathogenesis of CEL., Methods: A screen for F/P-dependent cytokines was performed in growth factor-dependent human cell lines lentivirally transduced with F/P. Signal transduction pathways were characterized in Ba/F3 cells with doxycycline-inducible expression of F/P and in EOL-1 cells. Cytokine expression was confirmed in patients' material by immunohistochemistry, immunofluorescence, and confocal microscopy. Gene expression analysis, proliferation assays, and chemotaxis assays were used to elucidate paracrine interactions between neoplastic eosinophils and stromal cells., Results: We show that F/P upregulates expression of oncostatin M (OSM) in various cell line models in a STAT5-dependent manner. Correspondingly, neoplastic eosinophils in the bone marrow were found to overexpress OSM. OSM derived from F/P + cells stimulated proliferation of stromal cells. Moreover, OSM-containing supernatants from F/P + cells were found to upregulate production of stromal cell-derived factor-1 (SDF-1)/CXCL12 in human fibroblasts. SDF-1, in turn, induced migration of EOL-1 cells in a dose-dependent manner., Conclusions: We have identified a F/P-driven paracrine interaction between neoplastic eosinophils and stromal cells that may contribute to tissue fibrosis and accumulation of neoplastic eosinophils in CEL., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A subset of patients with systemic mastocytosis (SM) develop acute myeloid leukaemia (AML). However, little is known about the biology of such leukaemias and their relationship to the mast cell (MC) lineage. We report on two female patients who suffered from SM and AML. According to FAB criteria, the leukaemias were classified as AML-M4 (patient 1) and AML-MO (patient 2). The coexistence of the two distinct neoplasms (AML and SM) was demonstrable by immunostaining of serial bone marrow (BM) sections with monoclonal antibodies (mAb). In particular, the MC infiltrates were found to react with mAb against MC-tryptase and MC growth factor receptor c-kit (CD117), but not with mAb to CD15 or CD34. In contrast, the AML blasts were immunoreactive for CD15 (patient 1) or CD34 (patient 2), but did not express tryptase. The c-kit point mutation Asp-->Val at codon 816, considered to play a role in the transformation of MC progenitors, was detected in patient 1 in a BM cell fraction containing 4% MC. However, no c-kit mutation was found in pure AML blasts (<1% MC). These findings argue against an evolution of the AML clone from neoplastic MC or MC-committed progenitors.

Problem: The functional role of the leukocytes in the decidual is not clear. They may regulate the maternal immune response to the fetal allograft. However, the factors controlling maternal and fetal communication have not yet been identified., Method: A comparative analysis of the phenotypes of decidual and peripheral blood large granular lymphocytes (LGLs) and T lymphocytes in early human pregnancy was performed on decidual tissue and blood samples obtained from ten patients at therapeutic abortion., Results: Whereas most of the decidual LGLs were found to have a CD56bright++ phenotype, most of the peripheral blood NK cells (90%) showed the classical CD56dim+ phenotype, and only a small proportion were CD56bright+ cells. Another striking difference was found in the expression of very late antigen 1 (VLA-1, CD49a): Almost all the decidual CD56bright++ LGLs, but virtually none of the peripheral blood CD56+ NK cells expressed this antigen. Further differences were found in the expression of CD16, CD44, CD45RA, CD54, and CD57. There were also differences in phenotype between T cells derived from decidual tissue and those derived from peripheral blood. Approximately 31% of the CD3+ decidual T cells expressed VLA-1, but this antigen was virtually absent on peripheral blood T cells. A further difference was seen in the expression of HLA-DR. This activation antigen was found on 32 +/- 13% of the decidual T cells but only 8 +/- 5% of the peripheral blood T cells. Additionally, the proportion of cells expressing CD38 was higher among decidual than peripheral blood T cells., Conclusion: The findings suggest that both decidual LGLs and a subset of decidual T cells are activated and possibly play a role in the control of trophoblast growth and placental development.

The decidua apparently plays a major role in immune tolerance to the semiallogeneic embryo. In the present study we applied the immunohistochemical ABC method to investigate the expression of CD3, TCR alpha/beta and TCR gamma/delta molecules on intradecidual T cells with a panel of mAbs. Whereas intradecidual T cells expressed readily detectable amounts of CD3, they lacked immunohistochemically detectable amounts of either alpha/beta or gamma/delta TCR heterodimers on their cell surface. Peripheral blood smears of the same patients showed normal expression of alpha/beta and gamma/delta TCR on CD3+ T cells. The specific absence of (alpha/beta or gamma/delta) TCR molecules on the surface of intradecidual T cells could be one of the decisive factors in tolerance of the maternal immune system towards the fetus.

Systemic mastocytosis (SM) can be regarded as a tumorous proliferation of tissue mast cells (TMC) involving various organs, particularly the bone marrow. The infiltrates, however, are by no means composed exclusively of TMC, but also contain eosinophils and lymphocytes. The varying composition of the TMC infiltrates and the immunohistological characteristics of the lymphatic cells were the main subjects of investigation in this study. Three different types of bone marrow infiltrates could be identified: (1) A pure mastocytic infiltrate. (2) A mixed mastocytic/lymphocytic infiltrate. (3) A predominantly lymphocytic infiltrate containing loosely-scattered TMC. The mixed mastocytic/lymphocytic infiltrate seems to be a unique finding confined to the bone marrow in cases of SM, and is not detected in this conformation in other tissue sites normally involved in SM (spleen, liver, lymph nodes and skin), nor in cases of malignant mastocytosis. The lymphoid cells could be identified immunohistologically as being an admixture of T lymphocytes and B lymphocytes, while NK cells were virtually absent from the composite nodules. The TMC reacted strongly with antibodies (monoclonal or polyclonal) against vimentin, common leucocyte antigen, lysozyme, alpha 1-antichymotrypsin and alpha 1-antitrypsin, but were negative with a variety of other antibodies tested (UCHL1, MB1, Ki-B3, Leu-7, KL1, desmin, S-100 protein, F VIII-related antigen and chromogranin A).