Aberrant CpG island methylation contributes to the pathogenesis of various malignancies. However, little is known about the association of epigenetic abnormalities with multistep tumorigenic events in adult T cell leukemia/lymphoma (ATLL). To determine whether epigenetic abnormalities induce the progression of ATLL , we analyzed the methylation profiles of the SHP1 , p15 , p16 , p73 , HCAD, DAPK , hMLH-1, and MGMT genes by methylation specific PCR assay in 65 cases with ATLL patients. The number of CpG island methylated genes increased with disease progression and aberrant hypermethylation in specific genes was detected even in HTLV-1 carriers and correlated with progression to ATLL. The CpG island methylator phenotype (CIMP) was observed most frequently in lymphoma type ATLL and was also closely associated with the progression and crisis of ATLL. The high number of methylated genes and increase of CIMP incidence were shown to be unfavorable prognostic factors and correlated with a shorter overall survival by Kaplan-Meyer analysis. The present findings strongly suggest that the multistep accumulation of aberrant CpG methylation in specific target genes and the presence of CIMP are deeply involved in the crisis , progression , and prognosis of ATLL , as well as indicate the value of CpG methylation and CIMP for new diagnostic and prognostic biomarkers.
Polycomb group (PcG) proteins are important for the regulation of hematopoiesis by regulating chromatin compaction and silencing genes related to differentiation and cell cycle. Overexpression of enhancer of zeste homologue 2 (Ezh2) and Bmi-1/PCGF4 has been implicated in solid organ cancers, while Mel-18/PCGF2 has been reported as a tumor suppressor. Detailed expression profiles of PcG proteins and their diagnostic significance in malignant lymphomas are still unknown. In this study, we analyzed the expression levels of Ezh2, Bmi-1, Mel-18, and Ki67 in 197 Hodgkin's and non-Hodgkin's lymphoma patient samples and in lymphoma cell lines using immunohistochemistry, fluorescent immunocytochemistry, and Western blotting. Immunohistochemical staining showed that Ezh2 expression was significantly increased in aggressive compared to indolent subtypes of B cell neoplasms (P = 0.000-0.030), while no significant differences in Bmi-1 expression were found between these subtypes. Compared to the normal counterpart, T cell lymphomas showed significant overexpression of Bmi-1 (P = 0.011) and Ezh2 (P = 0.000). The Ki67 labeling index showed a positive correlation with Ezh2 expression in B cell lymphomas (correlation coefficient (Co) = 0.983, P = 0.000) and T/NK cell lymphomas (Co = 0.629, P = 0.000). Fluorescent immunohistochemical staining showed coexpression of Ezh2 and Ki67 in the same tumor cells, indicating that Ezh2 expression correlates with cell proliferation. Both B and T/NK cell neoplasms showed low expression of Mel-18 and high expression of both Bmi-1 and Ezh2. In conclusion, in aggressive lymphoma variants, Ezh2 is strongly expressed and polycomb repressive complex PRC1.4 dominates over PRC1.2. Coexpression of Bmi-1 and Ezh2 is a characteristic of aggressive lymphomas. Ezh2 correlates with the proliferation and aggressive nature of non-Hodgkin's lymphomas.
Histiocytosis X of the stomach of a 47‐year‐old Japanese woman, who underwent subtotal gastrectomy following a clinical diagnosis of scirrhous carcinoma, was studied by light and electron microscopy as well as by immuno‐histochemistry. The histiocytoid cells proliferated monotonously in the lamina propria mucosae of the atrophied mucosa covering the body and fornix. They were arranged in a sheet‐ or pavement stone‐pattern and included some giant cells. The histiocytoid cells had a reniform to irregularly indented nucleus and conspicuous cytoplasm. Ultrastructurally, they were characterized by interdigitating cytoplasmic extensions and abundant tubulovesicular structures including Langerhans granules. S‐100 protein, α1‐antitrypsin, and α1‐antichymo‐trypsin were immunohistochemically identified in the cytoplasm. Endoscopic biopsies of the extragastric digestive tract, a biopsy of the lymph node, and bone marrow aspiration excluded a systemic disorder. The case is regarded as benign localized histiocytosis X of the stomach, a previously undescribed gastric lesion.
Thymic carcinoma (TC) is often very difficult to distinguish from type B3 thymoma and lung squamous cell carcinoma (L-SCC) involving the anterior mediastinum. The present study evaluated the usefulness of immunohistochemical markers including c-Kit, CD5, glucose transporter-1 (GLUT-1), claudin-1 (CLDN-1), thymoproteasome β5t, p53 and Ki-67 (MIB-1) and thymic cortical environmental marker cells, cortical thymocytes (c-Thy) and thymic cortical dendritic macrophages (TCDMs) in distinguishing thymic carcinoma (TC) from type B3 thymoma or lung squamous cell carcinoma (L-SCC) using 17 cases of type B3 thymoma, 18 cases of TC and 12 cases of L-SCC. The results indicated that c-Kit and CD5 are very useful markers for TC, while GLUT-1, CLDN-1, p53 and Ki-67 are not. Thymic cortical microenvironmental marker cells, especially TCDMs, and thymic cortical epithelial cell-marker β5t are also useful for distinguishing TC from type B3 thymoma. Although none of these markers are adequate for making a distinction when used alone, the plural use of c-Kit, CD5, β5t thymic cortical environmental marker cells, c-Thys and TCDMs may therefore lead to a correct distinction between TC and type B3 thymoma or L-SCC. [J Clin Exp Hematop 53(1) : 9-19, 2013].
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