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Notes: Five cases of a characteristic low-grade thymic epithelial tumour are described that we suggest calling metaplastic carcinoma of the thymus.〈section xml:id="abs1-2"〉〈title type="main"〉Methods and resultsThe patients' ages ranged from 44 to 71 (mean 56.2) years. Four of the patients were male. Three of five tumours showed invasion into mediastinal fat or pleura but, otherwise, all were well circumscribed. No metastases were present. Histologically, the tumours showed a biphasic pattern with solid carcinomatous areas merging gradually with a spindle cell component. Lymphocytes were rare. Cytological atypia and mitotic activity were variable in the solid areas, but slight or absent in the spindle cell component. On immunohistochemistry, the tumours showed expression of cytokeratin, vimentin and/or epithelial membrane antigen, both in the carcinomatous and spindle cell components. In two cases, actin expression was also present in both components. In one case, chromogranin, S100 protein, glial fibrillary acidic protein and neuron-specific enolase were expressed in at least some cells of both components. None of the patients had myasthenia gravis. All patients are alive without evidence of recurrence or metastasis.〈section xml:id="abs1-3"〉〈title type="main"〉ConclusionMetaplastic carcinoma of the thymus is a distinct clinicopathological entity that should be distinguished from the usually benign medullary thymomas and from the clinically aggressive carcinosarcomas and sarcomatoid carcinomas.

Notes: Multidrug resistance (MDR) is a major obstacle in the treatment of lymphoma. The expression of MDR-1 mRNA and P-glycoprotein (MDR-1/P-gp) has been linked to MDR. We aimed to investigate the expression of MDR-1/P-gp in B-cell lymphoma.Samples at diagnosis and relapse from 10 patients with B-cell lymphoma were obtained. We also obtained 14 unselected control cases of B-cell lymphoma at diagnosis. The expression of mRNA and protein were determined semiquantitatively by RT-PCR and immunohistochemistry. High MDR-1 and P-gp expressions were found in seven and seven of 10 samples obtained at diagnosis, eight and eight of 10 samples obtained at relapse, and three and four of 14 control cases at diagnosis, respectively. The results of RT-PCR paralleled those of immunohistochemistry. Concordance of high MDR-1/P-gp expression was noted in 27 of 34 samples (r = 0.73, P = 0.001). There were no significant changes in MDR-1/P-gp expression in all cases at relapse and during the clinical course following chemotherapy. In the 14 control cases, the average survival time was 12.7 months in MDR-1/P-gp positive cases and 29.0 months in the MDR-1/P-gp negative cases (P = 0.20).Our results showed that at least some B-cell lymphomas express MDR-1/P-gp, which could be detected by different methods, and suggested that high MDR-1/P-gp expression in tumour cells may be associated with a high probability of relapse and poor prognosis.

Notes: Evidence for local immunosuppression and demonstration of c-myc amplification in pyothorax-associated lymphoma Aims: Pyothorax-associated lymphoma (PAL) develops in the pleural cavity of patients with a long history of pyothorax. Epstein–Barr virus (EBV) is also involved in PAL, similar to lymphomas in immunodeficient patients. Here we examined T-lymphocyte subsets as well as c-myc and REL gene amplification in PAL tissues. Methods and results: We determined the number and distribution of CD4+ and CD8+ T-lymphocytes, to evaluate T-cells in the host immune reaction in seven cases of PAL. As controls, we also studied 10 cases of extranodal diffuse large B-cell lymphoma (DLBL) and 10 cases of nodal DLBL. Chromosomal imbalances in PAL were determined by using comparative genomic hybridization (CGH) analysis. The mean numbers of CD4+ and CD8+ and their ratio were significantly lower in PAL than in nodal DLBL. CGH analysis of PAL showed amplification of the 8q24 chromosomal region. In addition, c-myc amplification was found in four cases of PAL by Southern blot analysis. Conclusions: Our results suggest that the development of PAL may involve a local immunosuppressive environment and that amplification of c-myc might promote tumour progression, as has been described in the development of Burkitt’s lymphoma.

Notes: CD10 and Bcl10 expression in diffuse large B-cell lymphoma: CD10 is a marker of improved prognosis Aims: Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin’s lymphoma, is clinically and pathologically heterogeneous. The Bcl10 gene was recently isolated from the breakpoint region of t(1;14)(p22;q32) in mucosa-associated lymphoid tissue (MALT) lymphomas, and is considered to be an apoptosis-associated gene. CD10 is considered to be a marker of follicular centre B-cell differentiation. To assess the clinical significance and roles of CD10 and Bcl10 in DLBCL, we analysed 138 cases, using immunohistochemical methods. Methods and results: CD10 expression was limited to the cytoplasm, whereas Bcl10 expression was detected in the cytoplasm and/or nuclei. CD10 expression was detected in 39 of 138 cases (28.2%), cytoplasmic Bcl10 in 68 cases (49.2%), and nuclear Bcl10 in 34 cases (24.6%). Nuclear Bcl10 was detected in 14 of 28 cases (50%) of extranodal DLBCL, but only 20 of 110 cases (18.2%) of nodal DLBCL. Cytoplasmic Bcl10 was detected in 19 of 28 cases (67.8%) of extranodal DLBCL and 49 of 110 cases (44.5%) of nodal DLBCL. CD10 expression closely correlated with improved survival (68% overall survival (OS) vs. 48% OS), but not with site of disease. A high International Prognostic Index (IPI) was considered to be a poor prognostic factor associated with a shorter OS. CD10 expression was detected in 27 of 84 cases (32.1%) with low-risk IPIs, and in 12 of 54 cases (22.2%) with high-risk IPIs. In the low-risk group, cases expressing CD10 carried a better prognosis than CD10− cases (93% OS vs. 71% OS), whereas this was not the case in the high-risk group (25% vs. 20%). Conclusions: Bcl10 expression was associated with extranodal DLBCL, but not with prognosis. CD10 expression was closely associated with improved survival, but not with risk as predicted by IPI. Overall, our results suggest that CD10 expression may be useful, in combination with clinical parameters, for determining the prognosis of DLBCL.

Notes: Aims: Hodgkin's disease (HD) is characterized by the presence of Hodgkin and Reed–Sternberg (H–RS) cells against a hyperplastic background of reactive cells such as lymphocytes, histiocytes, plasma cells, eosinophils, neutrophils, and stromal cells. There is ample evidence to suggest that proliferation and survival of HD-derived cells is due to cytokine signalling. Recently, high expression of interleukin (IL)-13 was described in HD-derived cell lines. Here we investigated the possible involvement of IL-13 in the pathophysiology, especially autocrine pathways of H–RS cells.Methods and results: The expression of IL-13 and IL-13 receptor (IL-13R) was determined by immunostaining and reverse transcriptase-polymerase chain reaction in 39 cases of HD, including 17 cases with nodular sclerosis (NS) type, 19 cases with mixed cellularity (MC), and three cases with lymphocyte predominance (LP) type. Expression of IL-13 was confined to H–RS cells and a few lymphocytes. IL-13R was expressed in H–RS cells, lymphocytes, histiocytes, fibroblasts, and endothelial cells. H–RS cells of MC and NS types frequently expressed both IL-13 and IL-13R. However, the number of IL-13-positive H–RS cells was statistically higher in NS-type than in MC-type, but the number of IL-13R was similar. IL-13R-positive fibroblasts were frequently encountered in NS-type. H–RS cells of LP type rarely expressed IL-13.Conclusions: Our results suggest that IL-13 might be involved in autocrine pathways of H–RS cells and fibrosis at least in NS-type. Our results also indicated that in addition to the morphological and phenotypic differences, the neoplastic cells of LP type might be functionally different from H–RS cells of MC- and NS-types.

Notes: Accessory cell tumour: a clinicopathological study of 16 aggressive tumours containing EBV-positive Hodgkin and Reed–Sternberg-like giant cells Aims: Lymph nodes contain non-lymphoid accessory cells including follicular dendritic cells and interdigitating dendritic cells. Functionally, these cells belong to the category of immune accessory cells involved in antigen presentation to B or T-lymphocytes. Neoplastic proliferation of these cells is very uncommon. We present here the clinicopathological features of 16 cases of accessory cell tumour. Methods and results: We performed electron microscopic and immunohistochemical examinations, and used in-situ hybridization for EBV-encoded RNA (ISH-EBV) to detect the EBV genome in 11 cases, and Southern blot analysis to assess EBV clonality in two cases. Tumour cells were composed of oval-to-spindle cells arranged in diffuse, vague storiform, fascicular and sometimes whorled patterns in a background of small lymphocytes. In all cases, binucleated or multinucleated Hodgkin and Reed–Sternberg-like giant cells were encountered. Staining for CD68 was positive in all cases. CD21, CD35, Ki-M4p, Ki-FDC1p, and S100 exhibited variable reactivity. ISH-EBV yielded positive labelling in seven of 11 cases, of which five exhibited EBV only in Hodgkin and Reed–Sternberg-like giant cells. Southern blot analysis showed clonality of EBV terminal repeats (EBV-TR) in the two cases examined. Electron microscopic examination showed that many of the tumour cells had numerous interwoven long villous cell processes connected by occasional desmosomes. Many tumours were very refractory to chemotherapy and radiation, with a few exceptions, and half of the cases classified initially as stage IV. A short survival time, of 10 months or less, was observed in seven of 16 patients. Conclusions: Our study identified more aggressive behaviour of accessory cell tumours. Our results suggest that EBV may potentially induce activation of accessory cells to form Hodgkin and Reed–Sternberg-like giant cells, which correspond with poor prognosis.

Notes: Cell death can be divided into necrosis and apoptosis. In histiocytic necrotizing lymphadenitis (HNL), apoptosis is the main form of cell death. Two molecular mechanisms of T-cell-mediated cytotoxicity, one perforin-based and the other Fas-based, have been demonstrated, and both systems induce apoptosis of the target cells. This study was designed to investigate the Fas and perforin pathways in HNL.〈section xml:id="abs1-2"〉〈title type="main"〉Methods and resultsTwelve cases of HNL were analysed using immunohistochemical staining. The Fas and/or FasL-positive cells, including lymphocytes and histiocytes, were frequently encountered in the necrotizing lesions, however, they were rare in the nonpathological regions. The perforin and/or granzyme-positive cells were also confined in the necrotizing lesions. In double staining, CD8-positive lymphocytes occasionally expressed Fas and/or FasL, and histiocytes also expressed FasL and/or Fas. However, CD4-positive lymphocytes rarely expressed FasL and/or Fas. In a flow cytometric analysis, most of the cytotoxic T-cells, which were recognized by cytolytic granules of TIA-1 and considered to be CD8-positive lymphocytes, expressed FasL and Fas. The perforin-positive lymphocytes also expressed FasL and Fas.〈section xml:id="abs1-3"〉〈title type="main"〉ConclusionIn our previous study, the apoptotic cells were T-cells, especially CD8-positive cells rather than CD4-positive cells. Based on these findings, in Fas and perforin pathways, the CD8-positive cells were considered to be effector and target cells, while histiocytes could possibly be enhancers. As a result, both pathways seemed to induce an abundance of apoptosis and thus induce necrotizing lesions.

Notes: Aims:  Most primary gastrointestinal lymphomas are of B-cell origin and T-cell origin is very rare. Recent studies have suggested that human T-cell lymphotrophic virus type 1 (HTLV-1) may be involved in the development of primary gastric T-cell lymphoma. We analysed 31 patients with primary gastric T-cell lymphoma in south-west Japan, an area endemic for HTLV-1, and determined their phenotypes, genotypes, and HTLV-1 status.Methods and results:  Here we present 31 cases of primary gastric T-cell lymphoma in a HTLV-1-endemic area in Japan and analyse the clinical status, histology, phenotype and virus status. The median age at onset of primary gastric T-cell lymphoma was 57 years with a gender ratio of M:F = 1.58:1. Six of the 31 primary gastric T-cell lymphoma cases had HTLV-1 proviral DNA (five males, one female), nine of the 31 cases were positive for anti-adult T cell leukaemia antibody, without examination of HTLV-1 proviral DNA (five males, four females), eight were non-HTLV-1-associated primary gastric T-cell lymphoma (four males, four females) and the other eight cases were unknown. Primary gastric T-cell lymphoma usually presented as a large ulcerated tumour at the corpus to the antrum and histologically consisted of anaplastic large cell type (n = 2), pleomorphic large cell type (n = 3), pleomorphic medium and large cell type (n = 14), pleomorphic medium cell type (n = 11), and angioimmunoblastic T-cell lymphoma type (n = 1). There were no clear macroscopic and microscopic differences between HTLV-1-associated and non-HTLV-1-associated primary gastric T-cell lymphoma. Most patients died within 2 years of diagnosis, and both types of primary gastric T-cell lymphoma (with and without HTLV-1) were associated with poor prognosis. Cytotoxic marker analysis showed that HTLV-1-associated lymphomas were negative for TIA-1, while non-HTLV-1-associated lymphomas were positive for TIA-1.Conclusions:  Our results suggest that in HTLV-1-endemic areas, patients with HTLV-1-associated primary gastric T-cell lymphoma should be managed carefully and that TIA-1 seems to be useful for identifying the aetiology of this lesion.

Notes: Epstein–Barr virus (EBV) has been demonstrated in about 10% of gastric carcinomas. However, the pathogenetic role of EBV in gastric carcinoma is uncertain. We compared the rate of apoptotic cell death, cell proliferation and the expression of apoptosis-related proteins in gastric carcinomas with or without EBV.〈section xml:id="abs1-2"〉〈title type="main"〉Methods and resultsEpstein–Barr virus was detected in 40 gastric carcinomas by EBV-encoded small RNA-1 in-situ hybridization. Apoptotic cell death, MIB-1, p53, bcl-2 and bcl-x were examined by the terminal deoxynucleotidyl-mediated dUTP-nick end labelling method and immunohistochemistry. We also included 40 age-, sex- and disease stage-matched EBV-negative cases as a control. The number of apoptotic cells was significantly lower in EBV-positive (20 ± 15.1/1000 cells) and bcl-2-positive (17 ± 12.9/1000 cells) tumours than in EBV-negative (43 ± 37.1) and bcl-2-negative tumours (38 ± 32.1, P 〈 0.001, P 〈 0.001, respectively). bcl-2 immunostaining was significantly higher in EBV-positive tumours (24 cases) than in EBV-negative tumours (12 cases, P 〈 0.05). There was no significant difference in bcl-x and p53 expression between EBV-positive and -negative tumours. The number of MIB-1-positive cells in EBV-positive tumours (237 ± 161/1000) was significantly lower than in EBV-negative tumours (480 ± 208/1000 cells, P 〈 0.001).〈section xml:id="abs1-3"〉〈title type="main"〉ConclusionsA low rate of apoptosis and high bcl-2 expression were recognized in EBV-positive gastric carcinomas, suggesting that bcl-2 protein is the main inhibitor of apoptosis in EBV-positive carcinomas. In addition, the low apoptotic and proliferative activities may reflect a low biological activity in EBV-positive gastric carcinomas.