Koichi Koike

Clinicopathologic study of CD56 (NCAM)-positive angiocentric lymphoma occurring in sites other than the upper and lower respiratory tract.

The expression of the neural cell adhesion molecule (NCAM) (CD56, NKH-1) is a rare phenomenon in malignant lymphoma. Recently, several authors, including our group, described the clinicopathologic, phenotypic, and genotypic features of NCAM-positive tumors as a unique subgroup within a larger category of hematolymphoid malignancies. Ten cases of CD56+ angiocentric lymphoma occurring in sites other than the upper aerodigestive tract were studied for evaluating their characteristics. The disease occurred in six men and four women varying from 24 to 85 years (mean age, 53 years) who often exhibited a striking predilection for extranodal sites of involvement, such as the skin, gastrointestinal tract, and muscle, usually in the absence of peripheral lymphadenopathy. Although the cytologic appearances and immunophenotypic profile varied from case to case, these tumors often exhibited azurophilic granules, an angiocentric growth pattern, and surface CD3−, T-cell receptor (TCR) antigens−, and CD56+ phenotype without B-cell phenotype, except for a single case of CD3+, TCRα/β+, and CD56+ phenotype. Genotypic investigation exhibited germline configuration of the TCR β and γ chain genes and the immunoglobulin heavy chain gene in all five cases of surface CD3− phenotype examined, whereas the case of CD3+ phenotype showed rearrangement of TCRβ. They seem to constitute a distinct entity of the lineage spectrum spanning from natural killer (NK) cell to NK-like T cell.

Clinicopathologic study of nasal T/NK‐cell lymphoma among the Japanese

A high prevalence of nasal lymphoma expressing a T‐ or natural killer (NK)‐cell phenotype (NTCL) with frequent association of Epsteln‐Barr virus (EBV) has been indicated in Asians. To Characterize NTCL among the Japanese, the clinlcopathdogic features of 32 cases were evaluated and the casses worn also analyzed for EBV‐RNA using an ISH method. Morphologically, 31 cases were Identified by atypical pleomorphic lymphoid infiltrates with polymorphous, anglcentric, and necrotic features. Their lymphoma cells ranged in size from small to large and were mixed in varying proportion from case to case. The other one case showed a monomorphic ‘blastic’ appearance. EBV‐encoded small RNA (EBER) was detected in the neoplastic cells of 27 of the 32 cases examined. In the five EBV‐negative cases, one was the ‘blastic’ type. Clonal T‐cell receptor gene rearrangement was detected in none of seven cases examined. The patients had a median follow‐up of 9 months (range, 1 month to 14 years and 11 months). The Kaplan‐Meler estimate of overall survival was 49% at 5 years, correlating with clinical stage. These data support the concept that most cases of NTCL are identified as tumors with T/NK‐cell characteristics and EBV association, distincity different from other peripheral T‐cell lymphomas. Furthermore, the one case of an EBV‐negative ‘blastic’ variant appears not to fit well Into the pleomorphic category but more closely resembles the pathologic features of extranasal angiocentric lymphoma with lymphoblastold appearance. This study also showed no clear difference in clinical aspects other than the original site or in prognosis, between NTCL and extranasal angiocentric lymphomas despite the higher incidence of EBV association and the tendency for that peculiar anatomical site to be restricted to the former group.

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.

Alterations of Integrin Expression in Human Lung Cancer

Integrins are cell‐surface receptors which are involved in cell‐matrix and/or cell‐cell adhesion. They have been suggested to play a role in tumor invasion and metastasis. We examined the expression of various integrin subunits in normal and cancer cells of the lung using 33 human lung cancer cell lines as well as 6 lung cancer samples from which tumor cell lines could be established. This study clearly demonstrated that changes in the expression of certain integrins occur frequently in lung cancer, especially in small cell lung cancer. Loss of the α1 subunit of the β1 integrin family appears to be the most prominent change, although loss of other integrin subunits such as α2 or emergence of some integrin subunits such as αv can also be observed. These results suggest that changes in integrin expression may contribute to the invasive and/or metastatic behavior of lung cancer.

Phenotypic analysis of peripheral T/NK cell lymphoma: Study of 408 Japanese cases with special reference to their anatomical sites

The World Health Organization (WHO) classification of malignant lymphoma presented a list of disease entities well defined by clinical, immunological and genetic features. Therefore, the current diagnosis of peripheral T/NK‐cell lymphomas (PTNKLs) essentially requires the inclusion of anatomical sites of disease and phenotypical features. We analyzed 408 Japanese cases of PTNKLs in order to clarify the relationship between anatomical sites of disease and phenotypical features and to translate the functional subsets of T and NK cells into their diagnoses for further understanding lymphomatic biology. The T/NK‐cell lymphoma entities were allocated into three categories: (i) cytotoxic memory T‐cell and/or NK‐cell lymphoma (n = 151) consisting of extranodal NK/T‐cell tumors other than mycosis fungoides (MF); (ii) non‐cytotoxic memory T‐cell lymphoma (n = 142) consisting of nodal and cutaneous tumors such as angioimmunoblastic T‐cell lymphoma, adult T‐cell lymphoma/leukemia and MF; and (iii) anaplastic lymphoma kinase positive anaplastic large cell lymphoma (n = 110) that has unique features and might be regarded as cytotoxic ‘naive’ T‐cell lymphoma. Overall, these three categories were significantly correlated with age of onset, anatomical sites, the level of expression of cytotoxic molecules and CD45RO, and association with Epstein–Barr virus. This concept might provide a new insight enabling further understanding of the interrelationships among WHO T/NK‐cell disease entities.

Phenotypic and genotypic characterization of 14 leukemia and lymphoma cell lines with 11q23 translocations.

11q23 translocation is the most popular chromosomal abnormality in infant leukemia. In adults, it is often encountered in non-Hodgkins lymphoma (NHL). In this study, we analyzed the phenotypic and genotypic characteristics of 9 acute leukemic cell lines with 11q23 translocations and one with deletion of the 11q23 locus, nine of which were established by researchers in this group, together with 4 NHL cell lines with 11q23 translocations. All lines were considered to belong to the B-cell lineage at different stages. All 10 leukemic lines showed clonal rearrangement of the immunoglobulin heavy chain (IgH) gene: two corresponded to the B-precursor stage (CD19+, cytoplasmic mu-), while the other 8 corresponded to the pre-B stage (cytoplasmic mu+). All 4 NHL lines showed rearrangements of both the IgH and Ig kappa genes with three expressing surface Ig; specifically, mature B-cell phenotype. As for myelocytic-monocytic markers, at least one out of 4 antigens examined were positive in 8 of the 10 leukemic cell lines, while only one of the 4 NHL lines was reactive. There were essentially no clear phenotypic or genotypic differences between t(4;11) and t(11;19) cell lines, supporting the view that both diseases have similar clinicopathological characteristics. These cell lines are also valuable for cloning genes at the chromosomal breakpoints.

Increased Risk of Colorectal Cancer Due to Interactions Between Meat Consumption and the CD36 Gene A52C Polymorphism Among Japanese

Abstract: A previous study showed expression of CD36, recently reported to play important roles in metabolism of oxidized low-density lipoprotein and long-chain fatty acids and to be positively correlated with colon cancer prognosis. To examine relationships between colorectal cancer and the CD36 gene A52C polymorphism according to meat consumption as a surrogate for saturated fatty acid intake, we conducted the present hospital-based, case-control study of 128 cases and 238 non-cancer controls. Consumption of meat and vegetables/fruit was divided into three (low, moderate, and high) and two (low and high) groups, respectively. Regarding the risk of colorectal cancer on cross-classifying subjects for the CD36 genotype and meat consumption, the odds ratio (OR) for the C/C genotype with moderate meat consumption relative to the A/A genotype with low meat consumption was 8.30 (95% confidence interval, CI = 2.15–32.00). None of individuals with the C/C genotype was in the high meat consumption group. In the low vegetables/fruit consumption group, the OR for the C/C genotype relative to the A/A genotype was 3.03 (95% CI = 1.12–7.90). Our findings suggest that interactions between moderate-high meat consumption and the CD36 gene A52C polymorphism may increase the risk of colorectal cancer.

Genuine cd7 expression in acute leukemia and lymphoblastic lymphoma

CD7 has been used as a valuable marker for normal and malignant T cells and also for a proportion of acute nonlymphocytic leukemia (ANLL) cells. Difference in reactivity was noticed among CD7 antibodies, however, when tested against ANLL cells and myeloid/monocytoid cell lines; Tp40 antibody produced in our laboratories was not reactive with the HL-60 promyelocytic line, whereas 4A antibody was reactive, even though both detected a quite similar or an identical epitope on CD7 molecule. Preincubation of HL-60 cells with human immunoglobulin preparation clearly negated the reactivity by 4A, suggesting that 4A antibody is not reactive to CD7 itself, but it probably binds with immunoglobulin G Fc receptors expressed on HL-60 cells. Five cases of ANLL which were positive with 4A antibody were selected and tested with Tp40 antibody, and only two were found to be positive. Expression of CD7 mRNA in these two cases (but not in other cases) was also demonstrated by Northern blotting with a cDNA probe for CD7 recently cloned in our laboratories, indicating that CD7 is expressed on a certain fraction of ANLL, although the positive cases may be smaller than the reports so far appeared. A Northern blot study was also conducted with two acute lymphocytic leukemia cases and one lymphoblastic lymphoma case with CD7+, CD2-/+/-, CD5-/+/- phenotype and germline T cell receptor beta genes. CD7 mRNA is expressed in all three cases and CD3 mRNA is also observed in two cases, suggesting that these tumor cells are of T precursor origin.

Serological analysis of cell surface antigens of HL-60 cells before and after treatment with a phorbol ester tumor promoter

The human HL-60 cell line derived from acute promyelocytic leukemia, consisting of promyelocytic type of cells, was able to differentiate into adherent cells with monocytemacrophage features by the treatment with 12-0-tetradecanoyl phorbol-13-acetate (TPA). Cell surface antigens of HL-60 cells before and after TPA treatment were studied with monoclonal antibodies and four hybridoma clones producing IgM antibodies were established. Two antibodies (HL-21 and HL-47) reacted only with the immunizing TPA-treated HL-60 cells, and HL-1 antibody produced against untreated cells was reactive with both TPA-treated and untreated cells, but HL-5 antibody reacted predominantly with the immunizing untreated cells. Serological reactivity against various types of normal hematopoietic cells and acute leukemias (diagnosed by the French-American-British classification) was studied by immune adherence assay and immuno-electron microscopy. HL-21 antibody was reactive with monocytes and most cases of M4 and M5 types of acute non-lymphocytic leukemia cells. HL-47 antibody did not react with the cells of myelocyte-monocyte lineage or mature lymphocytes, but it did react with one-third of acute lymphocytic leukemia (L1 and L2) cases. Since all HL-47+ cases were included in the group of common ALL antigen positive cases, it was estimated that HL-47 is a differentiation antigen present on lymphocyte precursors, from which null-cell type acute lymphocytic leukemia cells generally originate. HL-1 antibody reacted with the cells of myelocyte-monocyte lineage as well as those of most acute non-lymphocytic leukemias. HL-5 antibody reacted with granulocytes and M2 type of acute myelocytic leukemia cases, and also with M5 type of acute monocytic leukemia cases. Serological studies of these antibodies revealed that TPA can induce to differentiate HL-60 cells not only into HL-21+ macrophage-like cells, but also into HL-47+ lymphoid stem cells. In addition, these antibodies were demonstrated to be very valuable for differential diagnosis of acute leukemias.

Angioimmunoblastic T-cell lymphoma (angioimmunoblastic lymphadenopathy with dysproteinemia [AILD]-type T-cell lymphoma) followed by Hodgkin's disease associated with Epstein-Barr virus.

A patient is described with angioimmunoblastic T‐cell lymphoma (AIL] (angidmmunoblastic lymphadenopathy with dysprotelrrrpmia [AILD]‐type T‐cell lymphoma), which was later followed by Hodgkins disease. At the time of the initial diagnasis, histological examination of a cervical lymph node showed a typical picture of AIL with abundant clear calls which were CD45RO+, CD43+, and CD20‐‐, and there was no evidence of a monoclonal B‐cell proliferation by Immunohistochemical analysis. In situ hybridization for Epstein‐Barr virus (EBV) was negative. Interposed by a bout of recurrence, the patient developed, 16 years later, a left subparotid mass which showed histologic features of Hodgkins disease, mixed cellularity type. Diagnostic Reed‐Sternberg cells and their variants were CD30+, CD15‐‐ and CD20+. Neither rearrangement of TCR beta and gamma chain genes nor of immunoglobulin heavy chain and kappa light chain genes was detected in DNA extract from fresh material. In situ hybridization showed the presence of EBV within the Reed‐Sternberg cells. The data show that EBV was not etiologically related to AIL in this case. Further, the deficit in cellular immunity that accompanied AIL conceivably permit primary EBV infection or reactivation of latent infection, which eventuated in development of Hodgkins disease, but the exact pathogenesis remains uncertain.