Different patterns of spleen involvement in systemic and malignant mastocytosis

Summary Three cases of splenic involvement in three different types of generalized mastocytosis (systemic mast cell disease) are reported. The macroscopic, histological and ultrastructural modifications of the spleen are described. Each case exhibited a different morphological pattern. Giemsa staining, fluorescence after acridine orange staining and naphthol ASD chloracetate esterase reaction are shown to be valuable for diagnosis. By comparison, immunohistochemistry seemed not to be very useful, because no specific antigens are expressed. These findings are compared to previously published cases. Their value for the diagnosis and the prognosis are discussed.     

Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis

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.     

Systemic mastocytosis in association with chronic lymphocytic leukemia and plasma cell myeloma

Systemic mastocytosis with associated clonal haematological non-mast cell lineage disease (SM-AHNMD) is a heterogeous group of mast cell disorders with different clinical, pathologic and underlying molecular characteristics. While myelomonocytic/myeloid neoplasia overwhelmingly predominates the AHNMD component, lymphoproliferative disorders rarely occur as an AHNMD component of SM-AHNMD. Here we report two cases of SM-AHNMD, in which the AHNMD component is chronic lymphocytic leukemia in one case, and concurrent chronic lymphocytic leukemia as well as plasma cell myeloma in another case. To the best of our knowledge, this is the first case report of SM-AHNMD with chronic lymphocytic leukemia and plasma cell dyscrasia simultaneously.     

Trypanosomiasis leads to extensive proliferation of B, T and null cells in spleen and bone marrow

Changes in the distribution of T, B and null cells in the spleen and bone marrow have been studied in inbred mice infected with Trypanosoma brucei. Immunofluorescent staining combined with a ³H-thymidine pulse and autoradiography showed activation of all three cell types. A transient increase in splenic T cells was followed by dramatic increases in B cells (2·5-fold) and in null cells (35-fold). By day 12, after the first peak of parasitaemia, nearly half the spleen cells were dividing. In the bone marrow, very large blast cells appeared within a week of infection.     

Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis,heritability and diagnostics

Despite increasing understanding of its pathophysiology, the aetiology of systemic mast cell activation disease (MCAD) remains largely unknown. Research has shown that somatic mutations in kinases are necessary for the establishment of a clonal mast cell population, in particular mutations in the tyrosine kinase Kit and in enzymes and receptors with crucial involvement in the regulation of mast cell activity. However, other, as yet undetermined, abnormalities are necessary for the manifestation of clinical disease. The present article reviews molecular genetic research into the identification of disease‐associated genes and their mutational alterations. The authors also present novel data on familial systemic MCAD and review the associated literature. Finally, the importance of understanding the molecular basis of inherited mutations in terms of diagnostics and therapy is emphasized.     

Enhancement of terminal B lymphocyte differentiation in vitro by fibroblast-like stromal cells from human spleen

Stromal elements are major components of lymphoid tissues contributing to both tissue architecture and function. In this study we report on the phenotype and function of fibroblast-like stromal cells obtained from human spleen. These cells express high levels of CD44 and ICAM-1 and moderate levels of VLA-4, VCAM, CD40 and CD21. They fail to express endothelial, epithelial, lymphocyte and monocyte/macrophage markers. We show that these cells interact with B cell blasts induced in vitro by anti-CD40 and anti-μ stimulation. As a result of these interactions both IL-6 and IgG secretion into culture medium is increased. The enhanced secretion of IgG is partly inhibited by abolishing B cell blast-stromal cell contact or by anti-IL-6, anti-VCAM or anti-CD49d antibodies. Our studies also suggest that the ability of stromal cells to promote B cell survival is most likely the underlying mechanism of the enhanced immunoglobulin secretion. Comparison of stromal cells from different lymphoid and non-lymphoid organs revealed that bone marrow- and spleen-derived stromal cells are the most effective in promoting B cell blast differentiation.     

Autoimmune bone marrow environment severely inhibits B cell development by inducing extensive cell death and inhibiting proliferation

Plasmacytoid dendritic cell (PDC) is a Th2-type dendritic cell precursor. It is an important professional effector cell characterized by its capacities to produce large amount of alpha interferon and to differentiate into dendritic cell. PDCs are scarce in normal condition. They circulate in the blood as veiled cells and enter the lymph node and mucosal site in response to immune stimulation. Besides the recent and wide-open field of the implication of PDCs in inflammatory diseases and in the microenvironment of solid or lymphoid tumours it has also been observed that PDCs can also be tumoral cells. In this paper, the authors present the different tumours thought to be originating from tumoral PDCs. To date, two kinds of tumoral conditions are recognized: the so-called PDCs proliferations in patients with myeloid disorders and the blastic plasmacytoid dendritic cell neoplasm. These two entities are exposed and discussed.     

不同细胞因子诱导的小鼠骨髓树突状细胞亚群与小鼠脾脏树突状细胞亚群的比较

目的对粒-单集落刺激因子(GM-CSF)/白介素4(IL-4)或脱氧氟胸腺嘧啶配体(Flt3-L)体外诱导的小鼠骨髓来源树突状细胞(BMDC)亚群和正常小鼠脾脏DC亚群进行比较,探索诱生DC的特性。方法分离Balb/c小鼠骨髓细胞,分别加入含GM-CSF/IL-4或Flt3-L的培养液,体外培养7d,倒置显微镜观察细胞形态,并用流式细胞术检测CD11c、MHCⅡ、CD4、CD8α、CD45RA及Sirp-α分子;利用免疫磁珠从小鼠脾脏细胞中分离DC。结果两组细胞因子均可在体外诱导小鼠骨髓细胞分化发育为未成熟的DC;倒置显微镜下观察可见BMDCs表面有树突状突起,具有典型的DC形态学特点,与Flt3-L诱导的BMDC相比GM-CSF/IL-4诱导的DC体积大,树突长;但是,流式细胞术检测发现Flt3-L体外诱导的BMDCs与小鼠脾脏DC亚群更为相似。结论 GM-CSF/IL-4及Flt3-L均可在体外诱导小鼠骨髓细胞分化发育为DC,且Flt3-LDC亚群与脾脏DC亚群相似,有可能成为体外研究脾脏来源DC的一种方法。     

T lymphocyte subpopulations and B lymphocyte cells in caecum and spleen of chicks infected with Salmonella enteritidis

The effect of low and high doses of Salmonella enteritidis PT4 (SE) on immunocompetent cells in caecum and spleen of one-day-old chicks was investigated. Subsets of T lymphocytes positive for CD3, CD4, CD8 and B lymphocytes (Bu1b-positive cells) were counted in the caecum after immunohistochemical staining and the relative percentage of these cells in the spleen was analysed using a FACScan cytometer on days 7, 10, 14, 21, and 27 post-inoculation (pi). In the low dose group, the number of CD3+ and CD4+ cells in the caecum had significantly increased at day 10 pi. Both CD8+ and Bu1b+ cells were significantly higher on day 14 pi in this group. In the high-dose group, the number of CD4+ cells had significantly increased at day 7 pi. CD3+, CD8+, and Bu1b+ cells showed prolonged proliferation at days 7 up to 21 pi. Splenic lymphocytes demonstrated significant changes only in the high dose group. The percentage of splenic CD4+ cells was decreased at day 7 pi. A decrease in CD3+ and CD8+ cells was found at day 14 pi in this group.     

Expression of the c-kit gene product in normal and neoplastic mast cells but not in neoplastic basophil/mast cell precursors from chronic myelogenous leukaemia

The expression of the c-kit gene product has been examined in normal mast cells, mast cell neoplasms, and basophil/mast cell precursors obtained from patients with chronic myelogenous leukaemia (CML). Formalin-fixed, paraffin-embedded sections or smears fixed with formalin vapour were studied by immunohistochemical methods, using a polyclonal antibody against the c-kit gene product. Normal and neoplastic mast cells showed a positive immunoreaction for c-kit gene product, but neoplastic basophil/mast cell precursors from CML patients lacked c-kit gene product by immunohistochemical and flow cytometric methods, even in cells having mast cell granules, together with or without basophil granules. Mast cell tryptase was, however, expressed in normal and neoplastic mast cells and basophil/mast cell precursors containing mast cell granules. In addition, cells of monocyte/macrophage lineage lacked c-kit gene product. These findings indicate that the c-kit gene product may play an important role in the development and function of mast cell but not of cell of basophil and monocyte/macrophage lineage.     

Large B cell lymphoma presenting initially in bone marrow, liver and spleen: an aggressive entity associated frequently with haemophagocytic syndrome

Yeh Y‐M, Chang K‐C, Chen Y‐P, Kao L‐Y, Tsai H‐P, Ho C‐L, Wang J‐R, Jones D & Chen T‐Y
(2010) Histopathology 57, 785–795 Large B cell lymphoma presenting initially in bone marrow, liver and spleen: an aggressive entity associated frequently with haemophagocytic syndrome Aims: To describe diffuse large B cell lymphoma (DLBCL) presenting initially in bone marrow, liver and spleen (BLS‐type) without lymphadenopathy. Methods and results: The clinicopathological and cytogenetic features of 11 such cases (eight men, three women; mean age: 62.7 years are described). Usually presenting with fever and haemophagocytic syndrome suggesting infection and complicating timely diagnosis, bone marrow examination showed patchy and interstitial infiltration of large tumour cells without sinusoidal involvement. All cases had a high Ki‐67 index (≥90%), commonly a non‐germinal centre/activated B cell immunophenotype and were negative for Epstein–Barr virus and human herpesvirus 6 and 8. The more frequent cytogenetic changes involved chromosomal loci 14q32 and 9p24, as well as del(3)(q21), add(7)(p22), t(3;6), del(8)(p22), +18 and add(19)(p13). Clinical behaviour was very aggressive, with a 2‐year survival rate of 18% (45% of patients died within 3 weeks). High‐dose chemotherapy with haematopoietic stem cell transplantation prolonged survival in one patient. Conclusions: Although it shares with intravascular LBCL a subtle presentation and an aggressive clinical course, this primary BLS large cell lymphoma variant is distinguished by lacking an intravascular component and having different cytogenetic findings.