Tadashi Motoori

Clinicopathologic study of large cell anaplastic lymphoma (ki‐1‐positive large cell lymphoma) among the japanese

The clinical, prognostic, phenotypic, and genotypic findings of 30 patients with large cell anaplastic lymphoma (Ki‐1‐positive large cell lymphoma) were analyzed. There were 13 male and 17 female patients (male‐female ratio, 0.8) whose ages ranged from 3 to 81 years of age (mean, 28 years of age; 67% of the patients younger than 30 years of age). The 5‐year survival rate was 52%; this was better than that of other types of high‐grade peripheral T‐cell lymphoma. Histologic examination showed distinctive morphologic features such as tumor cell pleomorphism, sinus infiltration, fibrosis, partial lymph node involvement, sparing of B‐cell regions, and occasional plasma cell infiltrates. Eighty percent of the cases were of T‐cell phenotype, and others expressed neither B‐cell nor T‐cell markers. The tumors were frequently positive for a histocompatibility antigen (HLA‐DR), CD25 (the interleukin‐2 receptor), and epithelial membrane antigen. Rearrangements of the T‐cell receptor beta gene were observed in nine of 13 cases (69%). These findings indicated that many of the tumors had the phenotype and genotype of activated T‐cells. This study also showed that large cell anaplastic lymphoma has a survival figure intermediate between Hodgkins disease and low‐grade peripheral T‐cell lymphoma.

Nodal cytotoxic lymphoma spectrum: a clinicopathologic study of 66 patients.

The expression of cytotoxic granule-associated proteins has been reported in some T-cell or natural killer (NK)-cell lymphomas of mostly extranodal origin, but rarely of nodal origin except for anaplastic large cell lymphoma (ALCL) and Hodgkins disease (HD). This study analyzed 66 nodal lymphomas expressing T-cell intracellular antigen-1 (TIA-1) and/or granzyme B to characterize the clinicopathologic spectrum of these neoplasms. Four main groups could be delineated. The first group consisted of p80/anaplastic lymphoma kinase (ALK)-positive ALCL (n = 35). The patients were 2 to 62 years of age (median age, 16 years), and the lymphomas pursued a relatively indolent clinical course. The tumors were phenotypically of either T- or null-cell type with constant expression of CD30, epithelial membrane antigen (EMA), and p80/ALK, but not CD15 or BCL2. None harbored Epstein-Barr virus (EBV). The second group consisted of peripheral T/NK-cell lymphoma, the nodal high-grade cytotoxic type (n = 13). The patients were 29 to 72 years in age (median age, 55 years), and the tumors pursued an aggressive clinical course. The tumors often showed pleomorphic, anaplastic, or centroblastoid morphology, and were featured by either EBV association or CD56 expression. The third group consisted of peripheral T-cell lymphoma, of the nodal low-grade cytotoxic type (n = 8). The patients, three men and five women, were 31 to 75 years old (median age, 61 years). Notably, six of them exhibited lymphoepithelioid (Lennerts) lymphoma. The fourth group consisted of cytotoxic Hodgkins-like ALCL/HD (n = 10), included seven cases of Hodgkins-like ALCL and three cases of HD, and was characterized by the presence of Reed-Sternberg cells and often the CD15+ phenotype. The patients were all men except for one woman, and they ranged in age from 24 to 84 years (median age, 62 years). The link among these four groups was reinforced by the presence of a highly characteristic large cell with horseshoelike or reniform nuclei-the frequent expression of CD30 and EMA-and the often lack of T-cell receptor-alphabeta. In this series, the expression of p80/ALK and CD56 was also associated with favorable and poor prognoses respectively (p<0.001, log-rank test).

Immunohistochemical Analysis of Cyclin D1 Protein in Hematopoietic Neoplasms with Special Reference to Mantle Cell Lymphoma

Immunohistochemical expression of PRAD1/cyclin D1 protein has been investigated in 106 tissue specimens of 104 cases of lymphoma, non‐neoplastic lymphoid disorders and other hematologic malignancies by employing the monoclonal antibody 5D4 with formalin‐fixed paraffin‐embedded sections, using the microwave oven heating method. Positive neoplastic cells were found in 60 (74%) of 81 cases of non‐Hodgkins lymphoma. The positivity pattern was nuclear in 17 (85%) of 20 cases of mantle cell lymphoma in which cytoplasmic staining was also seen. This pattern of cyclin D1 positivity was in contrast to the negative staining of normal reactive mantle zones. In the other cases, positivity appeared to lie within the cell cytoplasm without nuclear staining, and most of the nodal follicular and diffuse B‐cell lymphomas variously expressed PRAD1/cyclin D1. In contrast, the reaction was absent in a significant number of T‐cell and extranodal B‐cell lymphomas. Immunolocalization of PRAD1/cyclin D1 expression appears to be a useful diagnostic adjunct to discriminate mantle cell lymphoma from other non‐Hodgkins lymphomas.

Phenotypic analysis of peripheral T cell lymphoma among the Japanese

From 1980 to 1990, 174 peripheral T cell lymphomas were studied morphologically and immunophenotypically with a panel of monoclonal antibodies which were reactive with T cell differentiation antigens in cryostat sections and/or cell suspensions. Histologically, 57% of the lymphomas were categorized into low‐grade tumors according to the updated Kiel classification, while 41% were high‐grade tumors. By immunologic studies, 50% of the lymphomas were of helper/inducer (CD4) phenotype, 6% were of cytotoxic/suppressor (CD8) phenotype, 3% expressed both CD4 and CD8, 3% lacked both CD4 and CD8, and 36% were phenotypically undetermined because of an admixture of a fairly even number of CD4 and CD8‐positive cells. The phenotypically undetermined cases were more frequently noted in the low‐grade groups than in the high‐grade group, and the latter often showed a loss of pan‐T antigens, although there was no definite correlation between the histologic category and the immunophenotype. CD25, which is strongly manifested in anti‐HTLV‐1 antibody‐positive cases, was negative or only weakly expressed in anti‐HTLV‐1 antibody‐negative cases. Anaplastic large cell lymphomas (LC‐Ana) strongly expressed CD30, which was also detectable in only large blast‐like cells in the low‐grade tumors. Seventy‐one per cent of the lymphomas expressed la antigens. In this series, the clinical data were available on 154 patients. For individual markers, the expression of CD30 and HLA‐DR were associated with a longer actuarial survival (P< 0.01 and P < 0.05 by the generalized Wilcoxon test). The absence of CD25 or the presence of CD3 on tumor cells correlated with a relatively favorable prognosis, but not significantly. The detection of CD4 and CD8 had relatively little prognostic value. In the cases excluding LC‐Ana, a significant difference was also recognized between the groups with and without CD25, CD30 and HLA‐DR (P < 0.05 by the generalized Wilcoxon test). These results suggest that the immunophenotypic analysis of peripheral T cell lymphoma provided its use as an adjunct to a histopathologic diagnosis and was related to prognostic prediction.

Clinicopathologic study of 212 cases of peripheral T-cell lymphoma among the Japanese

Background. Postthymic/peripheral T‐cell malignancy shows significant histopathologic and clinical diversity, even in its prognosis, and the correlations remain to be debated.

Hodgkin's disease expressing follicular dendritic cell marker CD21 without any other B-cell marker: a clinicopathologic study of nine cases.

Reed-Sternberg (RS) and Hodgkins (H) cells are considered to be the neoplastic cells in Hodgkins disease (HD). Although most data suggest their lymphoid origin, the nature of these cells still remains a subject of controversy. Recently, a number of RS cells have been found to express an antigen that is also present on follicular dendritic cells (FDCs), asserting FDCs as the possible progenitor cells of H-RS cells. This prompted us to investigate whether these CD21-positive cases had distinct clinicopathologic characteristics. In a series of 94 examined cases of HD, we identified 9 CD21-positive ones (4 of 37 cases of nodular sclerosis, 1 of 41 mixed cellularity, and 4 of 12 lymphocyte depletion HD) without any other B-cell marker on paraffin sections. The patients varied in age from 16 to 82 years (median, 50 years) and included six men and three women. They had superficial or mesenteric lymphadenopathy without hepatosplenomegaly. Peripheral blood leukocytosis was seen in three patients. The clinical course was indolent, and all patients but one achieved an initial complete response with HD-based treatment regimens, although three of them relapsed. Morphologically, two subgroups could be delineated. Six of the cases were characterized, besides by the classic RS cells, by a varying number of the cells with the distinctive walnutlike or cerebrumlike nuclei and cytologically with cytoplasmic processes. Their fine structural examination also revealed villous processes, but no desmosomes. The other three cases had multinucleated RS cells often with triangular nuclei, but not cytoplasmic processes. The percentage of CD21-positive tumor cells ranged from less than 10% to 60% among the H-RS cells. These RS cells were positive for CD30 (9 of 9), CD15 (7 of 9), CD68 (1 of 8), fascin (8 of 8), S-100 protein (1 of 7), and epithelial membrane antigen (2 of 8) on paraffin sections. Notably, of eight cases examined on frozen sections, two showed immunostaining for DRC1, CD35, R4/23, and Ki-M4p. Only CD35 was also detected in the other two cases. Genotypic investigation showed germline configuration of the T-cell receptor beta and gamma chain genes and the immunoglobulin heavy chain gene in all eight cases examined. In situ hybridization showed Epstein-Barr virus sequences in four cases, three of which were examined by the terminal region analysis and showed the Epstein-Barr virus to be monoclonal. We concluded that in a small proportion (9.6%) of HD, H-RS cells might be derived from FDCs and that they appear to represent a distinct pathologic variant based on morphologic and phenotypic traits within the framework of HD.

Angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: a clinicopathological and immunohistochemical study of 10 cases.

An absence of germinal centers is one of the histological characteristics of angioimmunoblastic T‐cell lymphoma (AITL). We report here 10 unusual cases of AITL with hyperplastic germinal centers. The clinical presentation of each patient was characterized by generalized lymphadenopathy, constitutional symptoms and polyclonal hypergammaglobulinemia. The initial biopsy findings of each patient were similar and were characterized by hyperplastic germinal centers with ill‐defined borders and a proliferation of high endothelial venules (HEV). In the paracortical area there was a mixed infiltrate including irregularly shaped clusters or small nests of clear cells in all cases. Moreover, the clear cells invaded the lymphoid follicles, resulting in expansion of the germinal centers, except for one case. Immunohistochemistry revealed that the tumor cells, including clear cells, were CD4‐expressing T cells. Some of the atypical lymphocytes were also Bcl‐6‐positive. A majority of the follicular dendritic cell networks showed a normal/reactive or an expanded/disrupted pattern in all cases. Moreover, three lesions possessed a few large irregularly shaped proliferations of follicular dendritic cells around the HEV. Four cases progressed to AITL within a few years. The present 10 cases probably represent an early stage of AITL preceding follicular dendritic cell hyperplasia. Detection of clear cells, Bcl‐6‐positive atypical T lymphocytes, and foci of irregularly shaped proliferation of follicular dendritic cells appears to be critical for early diagnosis and treatment of AITL with hyperplastic follicles.

Clinical implications of nodal marginal zone B-cell lymphoma among Japanese: study of 65 cases

To clarify the clinical presentation and outcome of nodal marginal zone B‐cell lymphoma (NMZBL), 65 Japanese patients with this disease were studied and compared with the published literature from western countries. The clinical findings of our 65 cases were similar to those of their cases in some aspects: (1) 58% of the patients were >60 years old (median age, 64 years); (2) there was a slight female predominance; (3) 90% of the patients exhibited asymptomatic lymphadenopathy in the head and neck area; (4) only a minority of patients had B symptoms (6%) and poor performance status (8%); and (5) only 5% of patients were positive for M‐protein. However, the 65 patients in this series exhibited relatively longer 5‐year overall survival (85%) and failure‐free survival (60%) than the NMZBL series published in western literature, suggesting that NMZBL should be classified as indolent lymphoma. Moreover, based on the histological findings, we further classified four histological subtypes as follows: (1) splenic type (n = 7); (2) floral type (n = 9); (3) mucosa‐associated lymphoid tissue (MALT) type (n = 29); and (4) diffuse large B‐cell lymphoma (DLBCL) + MALT type (n = 20). DLBCL + MALT type exhibited significantly poorer 5‐year overall survival than the splenic variant. The recognition of DLBCL + MALT type appears important. No API2–MALT1 fusion transcript was detected in any of the 14 cases examined. (Cancer Sci 2007; 98: 44–49)

Clinicopathologic study of primary gastric lymphoma of B cell phenotype with special reference to low‐grade B cell lymphoma of mucosa‐associated lymphoid tissue among the Japanese

Resection specimens from 83 patients with primary gastric lymphoma (PGL) of B cell phenotype at stage IE and at stage IIE, according to the Ann Arbor classification were investigated. Histologically, these lymphomas could be divided into four types: Type I lesions (n=24) were entirely made up of MALT lymphoma; Type II lesions (n=13) were predominantly MALT lymphoma containing one to a few foci of high‐grade B cell lymphoma; Type III lesions (n=22) consisted largely of high‐grade lymphoma with small areas of low‐grade MALT lymphoma; and Type IV lesions (n=24) were pure high‐grade B cell lymphoma, mostly of the large cefi type. All patients had undergone primary gastric resection, and 14 received additional chemotherapy (n=12), or both chemotherapy and radiotherapy (n=2). The survival probability was significantly higher for Types I and II lymphomas than for Types III and IV tumors (P < 0.05 by the generalized Wilcoxon test). According to The General Rules for the Gastric Cancer Study by the Japanese Research Society for Gastric Cancer, the stage of disease showed a clear distinction between each of them (P < 0.01 by the generalized Wilcoxon test). This staging method seemed to serve well as a prognostic indicator. The histological typing of the PGL of the present series also seemed to correlate with the gross appearance, pathologic stage and prognosis. Furthermore, the expression of cyclin D1, bcl‐2 and p53 protein, and PCNA was immunohistochemically investigated in 42 cases of the present series. Most of the low‐grade PGL (Types I and II) had less than 60% PCNA‐positive cells, whereas the high‐grade PGL (Types III and IV) had more than 60% positive cells. In a study for cyclin D1 protein, no cases showed the nuclear staining pattern characteristic for mantle cell lymphoma, and the cytoplasmic staining frequently observed in the node‐based large B cell lymphoma was seldom identified in the PGL. This discrepancy might suggest a lineage difference among the morphologically similar, but site‐dierent, lymphomas. On the other hand, bcl‐2 protein overexpression was almost equal in frequency between the gastric and node‐based high‐grade B cell lymphomas. This is in contrast to the reports from Western countries, in which the majority of high‐grade gastric tumors were bcl‐2 negative.

Progressive Transformation of Germinal Centers: A Clinicopathological Study of 42 Japanese Patients:

To clarify the clinicopathological features of progressive transformation of germinal center (PTGC) unrelated to nodular lymphocyte predominant Hodgkins lymphoma in Japanese patients, we reviewed 42 cases and compared the results with those of the United States and Germany. Our results were similar to theirs, with male predominance (M/F ratio, 3:1) and the presentation of a solitary asymptomatic enlarged lymph node in the head and neck area as the common features. However, in Japan, PTGC occurs more frequently in elderly patients. In this study, 12 (29%) of the patients with PTGC were aged 60 years or more. Thirteen patients (31%) with lymphadenopathy in the neck and head area had developed localized chronic inflammation (chronic sialoadenitis=4, chronic tonsillitis=3, infectious epidermal cyst=2) or an autoimmune disorder (hyperthyroidism=2 and bronchial asthma=2). None of the patients developed a malignant lymphoma during the follow-up period of 5 to 238 months (median 27 months). Histologically, in a single longitudinal section of the lymph node, the PTGC occupied up to 5% of the total follicles in 22 patients, 5-10% in 10, 10-20% in 7, and more than 20% in 3. In 5 (12%) patients, an association with prominent marginal zone hyperplasia was also noted. This study also indicates that nodal involvement by various low-grade B-cell lymphomas exhibiting marginal zone distribution patterns should be considered as a differential diagnosis of PTGC. Moreover, in Japan, PTGC is thought to be involved in the etiology of florid reactive follicular hyperplasia in elderly patients.