Hiroaki Suefuji

Clinicopathological features of cutaneous lesions of adult T-cell leukaemia/ lymphoma.

Background  Adult T‐cell leukaemia/lymphoma (ATLL) is a human malignancy associated with human T‐cell leukaemia virus type I (HTLV‐I). ATLL frequently involves the skin.

Non-b, Non-t Neoplasms With Lymphoblast Morphology: Further Clarification and Classification

We studied the morphologic, immunohistochemical, and clinical characteristics of 158 cases of lymphoblastic lymphoma. Based on immunophenotyping and cell lineage, cases were classified into B-cell type (CD20,CD19 or CD79a+, n = 53), T-cell type (surface CD3+, n = 84), and non-B, non-T type (B cell marker− and surface CD3−, n = 21). The latter group was further divided based on immunohistochemistry into: 1) CD7+ stem cell lymphoma (CD7+SCL) [CD4−, CD7+, CD33+/−, CD56−], 2) blastic natural killer cell lymphoma (B-NKL) [CD4−, CD7+/−, CD33−, CD56+, CD123−], 3) myeloid/NK precursor cell leukemia (M/NKL) [CD4−, CD7+, CD33+, CD56+], and 4) CD4+CD56+ hematodermic malignancy (CD4+CD56+) type [CD4+, CD7+/−, CD33−, CD56+, CD123+]. The CD7+SCL and M/NKL types frequently exhibited bone marrow invasion and mediastinal masses. All CD4+CD56+ types were associated with skin lesions. B-NKL type is included into Blastic NK lymphoma in new World Health Organization classification with CD4+CD56+ type. But the cases of B-NKL were more reminiscent of CD7+SCL or M/NKL type than the CD4+CD56+ type, both clinically and histologically. We propose that blastic NK lymphoma, a disease entity in the new WHO classification, should be divided into two types based on phenotypes and clinical features. The non-B, non-T lymphomas exhibited poorer prognoses, similar to that of B-cell lymphomas, than T-cell type tumors (P = 0.009). Among the 21 tumors, the prognosis of the four subtypes did not differ significantly; however, cases receiving aggressive chemotherapy and stem cell transplantation had a more favorable prognosis than those receiving only traditional chemotherapy and radiation therapy (P = 0.0089).

Expression of Chemokine Receptor CXCR3 and its Ligand, Mig, in Gastric and Thyroid Marginal Zone Lymphomas. Possible Migration and Autocrine Mechanism

Chemokine receptors mediate the migration of lymphocytes through the binding of ligands, and the expression is differentially regulated in lymphocyte subsets. CXCR3 is usually expressed in Th1 T cells, however, recently is reported to be expressed in B cell chronic lymphocytic leukemia, mucosa-associated lymphoid tissue type lymphoma (MALT) (extranodal marginal zone lymphoma), and other B cell non-Hodgkin lymphomas. Our study was designed to investigate the expression of CXCR3 and its ligand Mig, and their relationships in MALT using immunohistochemistry. In addition, CCR4, which is characteristic Th2 helper phenotype, and its ligand thymus and activation-regulated chemokine (TARC), were compared with CXCR3, as Th1 phenotype. We studied 14 cases of gastric B cell lymphoma [low-grade MALT, 5 cases; high-grade MALT, 5 cases; and diffuse large (DL), 4 cases] and 16 cases of thyroid B cell lymphoma [low-grade MALT, 4 cases; high-grade MALT, 5 cases; and DL, 7 cases]. CXCR3-expressing lymphoid cells were detected in all cases. In double immunostaining (CXCR3-CD20), gastric and thyroid low/high MALT showed CXCR3-positive neoplastic B cells, but DL, except two cases, did not. In DL, CXCR3-positive lymphoid cells were mainly reactive T-cells (CD3-positive cells). Mig was expressed mainly in stromal cells (histiocytes, macrophages, fibroblasts, and endothelial cells). In gastric lymphoma, low-grade MALT contained abundant Mig-strongly expressing cells, while staining in high-grade MALT and DL was mild. In thyroid lymphoma, staining was strong in low- and high-grade MALT, but moderate in DL. In double-staining, CXCR3-Mig-coexpressing lymphoma cells were abundant in high MALT of the stomach and thyroid, but rare in other subtypes. TARC-positive cells and CCR4-positive cells were rarely encountered in all cases. Our results indicate a tendency for low-grade MALT to contain CXCR3 + Mig m lymphoma cells, high-grade to contain CXCR3 + Mig + and DL to contain CRCR3 m Mig m lymphoma cells. We speculate that CXCR3 is associated with migration of lymphoma cells in low-grade MALT, and autocrine function in high-grade MALT, and not associated with any function in DL.

CXCR3-positive B cells found at elevated frequency in the peripheral blood of patients with MALT lymphoma are attracted by MIG and belong to the lymphoma clone

Chemokine receptors mediate the migration of lymphocytes through binding of their ligands. CXCR3 is expressed in Th1 T cells; however, CXCR3 was recently reported in B‐cell mucosa‐associated lymphoid tissue (MALT)‐type lymphoma and splenic marginal zone lymphoma. To investigate whether CXCR3‐positive B lymphocytes in peripheral blood (PB) migrate to MALT and spleen, and whether the lymphoma clone is present in PB, we studied 16 cases of MALT lymphoma. In MALT cases, CXCR3‐positive B lymphocytes in PB could migrate to MIG, the CXCR3 ligand. Immunohistochemical analysis showed that MALT lymphoma cells expressed CXCR3, whereas epithelial glands and/or stromal cells expressed MIG. In the PCR analysis for VH gene rearrangements, MALT lymphoma showed monoclonal or oligoclonal bands. In addition, in 8 of 16 MALT cases, the VH gene rearrangement of MALT lymphoma had the same bands as the CXCR3‐positive B lymphocytes in PB. In 4 cases, the same clones of DNA sequences were confirmed in MALT lymphoma and CXCR3‐positive B lymphocytes of PB. The findings support the theory that CXCR3‐positive B lymphocytes in PB of MALT patients belong to the lymphoma clone and migrate to MIG‐expressing mucosa‐associated lymphoid tissue. It seemed to be associated with the dissemination of MALT lymphoma.

Imbalances of chemokines, chemokine receptors and cytokines in Hodgkin lymphoma: classical Hodgkin lymphoma vs. Hodgkin-like ATLL.

Classical Hodgkin lymphoma (HL) is characterized by the presence of Hodgkin and Reed‐Sternberg cells (H&RS) and a prominent lymphocytic infiltration. We previously reported Hodgkin‐like adult T‐cell leukemia/lymphoma (HL‐like ATLL) (new WHO classification). Various CXC and CC chemokines are expressed on H&RS cells and the relationships between chemokines and the chemokine receptor (R) are thought to be important for selectivity of local immunity of Th1 and Th2 T cells. To clarify the role of T‐cell immunity in classical HL and Hodgkin‐like ATLL, we performed gene expression profiling (chemokine, chemokine R and cytokine DNA chips) in 12 cases {classical HL, 8 cases [mixed cellularity (MC) type, 4; nodular sclerosis (NS) type, 4]; Hodgkin‐like ATLL, 4 cases} and immunohistochemical staining in 29 cases (MC, 10; NS, 10; Hodgkin‐like ATLL, 9). EBV‐infected H&RS cells were detected in 9 of 10 cases of HL MC, 5 of 9 of HL‐like ATLL and 2 of 10 HL NS. T‐cell‐directed chemokine thymus‐ and activation‐regulated chemokine (TARC)‐ and/or macrophage‐derived chemokine (MDC)‐positive H&RS cells were detected in all 20 cases of HL MC and HL NS but only in 5 of 9 cases of HL‐like ATLL. Interferon‐γ‐inducible protein‐10 (IP10)‐ and monokine induced by interferon‐γ (MIG)‐positive H&RS cells were detected in all 10 HL MC but only in 5 of 10 cases of HL NS and 2 of 9 cases of HL‐like ATLL. However, 2 of 5 cases of HL‐like ATLL with EBV infection and 2 of 2 HL NS with EBV had IP10/MIG‐positive H&RS cells. The chemokine expressions in H&RS cells seemed to be associated with EBV infection rather than histologic subtypes. In the DNA chip expression analysis, classical HL and HL‐like ATLL had a mixed Th1/Th2‐type profile, and HL MC (EBV‐positive) and HL NS (EBV‐negative) were differentially clustered. However, 2 cases of HL‐like ATLL clustered with HL MS and the other 2 cases of HL‐like ATLL clustered with HL NS. The former HL‐like ATLL had EBV infection in H&RS cells, whereas the latter did not have EBV infection. This finding also suggests that EBV might influence local expression of chemokines rather than HL subtypes. Our results indicate that local immunologic disorder or imbalance appears to influence the formation of H&RS cells and that in HL‐like ATLL, HTLV‐1 infection might not be necessary for H&RS cell formation.

Variation of Clinical Target Volume Definition among Japanese Radiation Oncologists in External Beam Radiotherapy for Prostate Cancer

BACKGROUND We investigated the interobserver variation in the prostate target volume and the trend toward the use of diagnostic computed tomography (CT) or magnetic resonance (MR) images for treatment planning. METHODS Twenty-five radiation oncologists were asked to draw the external contour of the prostate on CT images (0.3 cm spacing) of a patient with localized prostate cancer. They also answered a questionnaire regarding the use of diagnostic CT or MR images for the contouring. RESULTS Of the 25 physicians, 28% rarely or never referred to the diagnostic CT images. In contrast, the physicians tended to refer to the MR images more frequently. Approximately 50% of the physicians believed in the usefulness of contrast-enhanced images for the delineation of the prostate. As for the variation of the prostate contouring, the median craniocaudal prostate length was 36 mm (range, 21-54 mm), and the median prostate volume was 43.5 cm(3) (range, 23.8-98.3 cm(3)). The interobserver variability was not significant in the duration as a radiation oncologist, the board certification status as radiation oncologists, and the number of treatment plans developed for prostate cancer during the last 1 year. CONCLUSION A wide variety of the definitions of the prostate was found among Japanese radiation oncologists.

The clinical characteristics and non-steroidal treatment for radiation-induced bronchiolitis obliterans organizing pneumonia syndrome after breast-conserving therapy

PURPOSE A rare and unique occurrence of radiation-induced pulmonary injury was observed outside the tangential field for early breast cancer treatment. The findings appeared to be idiopathic and were termed radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome. The goal of this study was to report and determine the incidence, analyze the characteristics of the pulmonary lesions on the images and also investigate the treatment methods. MATERIALS AND METHODS A retrospective analysis was conducted of 616 consecutive patients that underwent breast-conserving therapy (BCT) from January 1992 to December 2008. The patients were observed at least one year after radiotherapy for BCT. Radiotherapy was administered by 4 MV photons in all patients. The patients underwent chest X-rays periodically. If the BOOP syndrome was found, chest computed tomography (CT) were conducted to identify the characteristics of the pulmonary lesion outside the radiation field. RESULTS The incidence of the radiation-induced BOOP syndrome was 12 patients (1.9%). Six of them had fever and cough, 6 had no symptoms. The pulmonary lesions were classified into four patterns on chest CT. Progression of the pulmonary lesions observed on chest X-ray were classified into three patterns. BOOP syndrome appeared within 5.6 months after radiotherapy and completely disappeared within 12 months after its onset. Their clinical conditions were not severe and these pulmonary lesions disappeared gradually without use of steroids in our institution. There was no death caused by BOOP syndrome. CONCLUSIONS Although the incidence of BOOP syndrome and its associated prognosis are not significant, this clinical condition must be carefully followed using diagnositic imaging in order to not over administer steroids.

HTLV-1 carriers with B-cell lymphoma of localized stage head and neck: prognosis, clinical and immunopathological features

Summary.  Human T‐lymphotropic virus type I (HTLV‐I) is closely associated with T‐cell lymphoma/leukaemia, which always shows monoclonal HTLV‐1 provirus DNA integration. HTLV‐1 is not associated with B‐cell lymphoma. The relationship between B‐cell lymphoma and HTLV‐1 was analysed retrospectively in early stage B‐cell non‐Hodgkins lymphoma (NHL) according to HTLV‐1 infection and pathological features. We analysed 198 cases of head and neck B‐cell NHL treated with radiotherapy and/or chemotherapy; 21 were seropositive and 177 were seronegative for HTLV‐1. We also immunostained 26 cases of diffuse large B‐cell lymphoma (DLBL), including 12 seropositive and 14 seronegative for HTLV‐1 respectively, for CD20, CD3, CD4, CD8, CD56, MIB‐1 and T‐cell‐restricted intracellular antigen (TIA‐1) to examine the phenotype, immunity and proliferation activity. The 5‐year overall survival rates were 78% and 49% (P = 0·007, log rank test) for HTLV‐1 seronegative and seropositive cases respectively. Infection with HTLV‐1 was significantly associated with poor survival in patients with B‐cell lymphoma by multivariate analysis. For DLBL, HTLV‐1 infection was not a significant factor, but the overall survival curve was similar to that of the 21 seropositive B‐cell lymphoma cases. Lymphoma cells were negative for TIA‐1, but the background lymphocytes were positive for this marker. The number of TIA‐1‐positive cells was higher in HTLV‐1‐negative cases than in‐positive cases. In conclusion, patients with B‐cell‐NHL (B‐NHL) who are also HTLV‐1 carriers have a poorer prognosis than non‐carriers. HTLV‐1 does not seem to be associated with lymphomagenesis of the B phenotype itself, but correlates with host immunity by reducing the number of cytotoxic T‐cells.

Relationship between 2-deoxy-2-[18F]-fluoro-d-glucose uptake and clinicopathological factors in patients with diffuse large B-cell lymphoma

Abstract The aim of this study was to investigate correlations between the standardized uptake value of the biopsy site (BSUVmax) and levels of glucose transporter (GLUT)-1, GLUT-3 and hexokinase-II (HK-II), between BSUVmax and the Ki-67 proliferation index (MIB-1), and between BSUVmax and clinicopathological factors. Sixty-eight patients with diffuse large B-cell lymphoma (DLBCL) were included in this study. BSUVmax was significantly correlated with GLUT-1, GLUT-3 and the International Prognostic Index (IPI) (GLUT-1: r = 0.584, IPI: r = 0.363, p < 0.001; GLUT-3: r = 0.369, p = 0.009; IPI: r = 0.363, p = 0.004), but not with MIB-1 and HK-II. A statistically significant correlation was observed between GLUT-3 expression and each of IPI and gene expression profiling (GEP) (IPI: p = 0.0186; GEP: p = 0.0179). 2-Deoxy-2-[18F]-fluoro-d-glucose (FDG) uptake was significantly correlated with the levels of GLUT-1 and GLUT-3 and with IPI. The results indicated that GLUT-3 expression is related to GEP and IPI, and that BSUVmax and GLUT-3 may have a relationship with the prognosis of DLBCL.

Automated estimation of number of implanted iodine-125 seeds for prostate brachytherapy based on two-view analysis of pelvic radiographs

Digital pelvic radiographs are used to identify the locations of implanted iodine-125 seeds and their numbers after insertion. However, it is difficult and laborious to visually identify and count all implanted seeds on the pelvic radiographs within a short time. Therefore, our purpose in this research was to develop an automated method for estimation of the number of implanted seeds based on two-view analysis of pelvic radiographs. First, the images of the seed candidates on the pelvic image were enhanced using a difference of Gaussian filter, and were identified by binarizing the enhanced image with a threshold value determined by multiple-gray level thresholding. Second, a simple rule-base method using ten image features was applied for false positive removal. Third, the candidates for the likely number of a multiply overlapping seed region, which may include one or more seeds, were estimated by a seed area histogram analysis and calculation of the probability of the likely number of overlapping seeds. As a result, the proposed method detected 99.9% of implanted seeds with 0.71 false positives per image on average in a test for training cases, and 99.2% with 0.32 false positives in a validation test. Moreover, the number of implanted seeds was estimated correctly at an overall recognition rate of 100% in the validation test using the proposed method. Therefore, the verification time for the number of implanted seeds could be reduced by the provision of several candidates for the likely number of seeds.