Death‐associated protein (DAP) kinase is a pro‐apoptotic serine/threonine kinase with a death domain, which is involved in apoptosis induced by interferon‐γ, tumor necrosis factor‐α, and Fas ligand. Down‐regulation of DAP kinase gene expression by hypermethylation of its promoter region might result in resistance to apoptotic cell death, and could provide a basis for tumor development. In the present study, we employed methylation‐specific polymerase chain reaction to examine the methylation status of CpG islands in the DAP kinase gene in 19 cases of T‐cell malignancies (including eight adult T‐cell leukemia/lymphoma), 24 of natural killer (NK)/T‐cell, and 34 of B‐cell. Frequency of methylation was significantly higher in B‐cell (27 of 34, 79.4%) than in T‐cell malignancies (nine of 19, 47.4%) (P<0.05). Fifteen of 24 (62.5%) NK/T‐cell lymphomas showed DNA methylation. One B‐cell lymphoma cell line with DNA methylation was resistant to apoptotic stimuli, and treatment of the cells with a demethylating agent restored apoptotic cell death. These findings suggested that suppression of DAP kinase expression by DNA methylation might play a substantial role in the development of not only B‐cell, but also T‐ and NK/T‐cell lymphomas. (Cancer Sci 2003; 94: 87–91)
Thrombopoietin (TPO) is widely used for ex vivo expansion of hematopoietic stem cells. Previously, we have reported that TPO induces a characteristic pattern of apoptosis, and the TPO-induced apoptosis is closely associated with megakaryocyte (MK) differentiation. In the present study, several cytokines, flt3-ligand, stem cell factor (SCF), interleukin-3 (IL-3), IL-6, IL-11, leukemia inhibitory factor, G-CSF, and erythropoietin, which are known to affect megakaryocytopoiesis, have been evaluated to elucidate their effects on the TPO-induced apoptosis. Measurement of apoptosis by flow cytometry revealed that only SCF absolutely reduced the TPO-induced apoptosis in MK fractions, particularly in the late phase of ex vivo expansion. Platelet production was demonstrated by electron microscopy in a later phase when SCF was added. Simultaneous measurement of DNA contents with immunophenotyping demonstrated a significant increase in polyploidization in the CD41+ cell fraction when cultured with SCF. These results suggested that SCF not only inhibited premature senescence but also enhanced maturation of the differentiating cells of MK lineage during ex vivo expansion using TPO.
A 22‐year‐old man had a subcutaneous nodule on the left thigh for 3 months. Physical examination showed an ulcerative nodule on the left thigh ( Fig. 1 ). He suffered from a fever for 1 week. Laboratory tests revealed a white blood cell count of 7180/mm 3 , with 22.4% neutrophils, 68.5% lymphocytes, 8.4% monocytes, 0.3% eosinophils, and 0.4% basophils. Hemoglobin was 9.0 g/dL, hematocrit was 28.1%, and the platelet count was 202 × 10 9 /L. Analysis of serum showed the following abnormal results: aspartate aminotransferase, 102 IU/L (normal, 13–37); alanine aminotransferase, 77 IU/L (normal, 7–43); alkaline phosphatase, 1296 (normal, 70–270); LDH, 1105 (normal, 120–520). Results of other laboratory tests including serum electrolytes, blood and tissue culture, and viral markers for hepatitis were negative or normal. Ultrasonography and computed tomography of abdomen and pelvis showed hepatosplenomegaly with ascites. Whole body bone scan showed an increased long bone activity of the left leg. Bone marrow aspiration was negative for neoplastic cells. Histologic examination from the thigh nodule revealed subcutaneous lymphoid infiltrates with involvement of the deep dermis. Examination at high power magnification showed small, medium, and large‐sized, pleomorphic lymphoid cells with hyperchromatic nuclei, nuclear debris, and phagocytic macrophages. Fat necrosis, partial rimming of fat spaces and clustering around blood vessels by pleomorphic lymphoid cells were also seen ( Fig. 2 ). The immunohistochemical studies on paraffin sections revealed that most of the infiltrated lymphoid cells positively stained for CD56 ( Fig. 3 ), granzyme B, TIA‐1, cytoplasmic CD3, and CD45RO, whereas CD4, CD8, CD20, and CD30 showed no immunoreactivity. Clonality of the infiltrate was analyzed by polymerase chain reaction (PCR). Nested PCR was performed using FR3A and VLJH as primers for IgH gene and Vγ – Jγ for T‐cell receptor γ chain gene. Polymerase chain reaction analysis showed a distinct band for TCR gene, confirming T‐cell monoclonality of infiltrating lymphocytes. EBV‐encoded small nuclear RNA was evident in lesional tissue by in situ hybridization. He was treated with two cycles of chemotherapy with CHOP‐BV (Cytoxan 735 mg, adriamycin 45 mg, vincristine 1.45 mg, prednisolone 75 mg, bleomycin 15 mg, VP‐16 150 mg). He died 5 days after chemotherapy. An ulcerative nodule on the left thigh image (a) Pleomorphic, small, medium and large‐sized lymphocytes with irregular hyperchromatic nuclei, nuclear debris, and phagocytic macrophages in the fat tissue. (b) A vascular involvement of pleomorphic lymphocytes and fat necrosis are seen (hematoxylin and eosin; original magnification × 100) image Positive immunohistochemical staining for CD56 in atypical tumor cells (original magnification × 400) image
Follicular dendritic cell (FDC) sarcomas, especially those of extranodal origin, are extremely rare, and this entity could easily be missed without a high index of suspicion. We report a case of FDC sarcoma presenting as a submucosal tumor of the stomach in a 45-year-old man. The mass was a spindle and epithelioid mesenchymal tumor with many individually scattered and perivascular aggregates of lymphocytes. Immunohistochemical and ultrastructural studies confirmed the diagnosis. Although more than 50 cases of this tumor have been documented in the English literature, to our knowledge the presentation of FDC sarcoma as a submucosal tumor of the stomach has never been recorded. This case highlights the occurrence of FDC sarcoma as a submucosal tumor of the gastrointestinal tract. We believe that FDC sarcoma should be included in the differential diagnosis of spindle or epithelioid cell tumors of the gastrointestinal hollow viscus to prevent this still under-recognized tumor from being overlooked.
Abstract Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare benign condition affecting principally the head and neck region of young females. We describe a 42‐year‐old female patient of ALHE showing the typical changes of endothelial cells and features similar to Kimura's disease in histologic and immunohistochemical findings.
BCL1/PRAD1 gene rearrangements involving the cyclin D1 gene are a feature of about 70% of centrocytic/mantlecell lymphomas (CC/MCL) but are identified in only a small proportion of other B-cell non-Hodgkin's lymphomas. Of 37 lymphomas found to have BCL1/cyclin D1 (PRAD1, CCND1) gene rearrangements, 30 fit the morphologic and immunophenotypic criteria for typical CC/MCL. Seven cases with morphologic features atypical for CC/MCL were identified. CD5+ monoclonal B cells were documented in all these cases. Six cases were subsequently stained for cyclin D1 protein, and all showed nuclear positivity. Five cases had variably sized foci of cells with moderately abundant pale cytoplasm resembling parafollicular/monocytoid B cells, marginal zone cells, hairy cells, or even proliferation centers. Transformed-appearing cells were also present in some lymphomas. In one case, striking follicular colonization created a markedly nodular growth pattern mimicking a follicular lymphoma. A sixth case had a marked predominance of small, round lymphocytes at some sites, mimicking a small lymphocytic lymphoma. Five of these six cases also had areas more typical of CC/MCL. The seventh case was a CD5-positive splenic marginal zone-like lymphoma (SMZL) with plasmacytic differentiation and circulating villous lymphocytes consistent with a splenic lymphoma with villous lymphocytes (SLVL). These cases illustrate the morphologic spectrum of small B-cell lymphoid neoplasms that have BCL1/cyclin D1 gene rearrangements and overexpression of cyclin D1. Despite the BCL1 translocation and cyclin D1 overexpression, the splenic lymphoma with plasmacytic differentiation was definitely not a CC/MCL and fit the clinicopathologic entity of SMZL/SLVL. The other six cases are best considered CC/MCL variants based on a combined morphologic, immunophenotypic, and genotypic evaluation. Genotypic or immunophenotypic studies to identify cyclin D1 rearrangements and overexpression, although not-pathognomonic, are useful in recognizing these variant CC/MCL cases, which can mimic almost any of the other well-described but more indolent low-grade B-cell lymphomas and leukemias. Some of the variant CC/MCL cases had features in common with the CD5 + cyclin D1 + SMZL/SLVL, suggesting a possible relationship between these two otherwise distinct entities.
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