Kuniyoshi Kitoh

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 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.

Inconsistent association of Epstein-Barr virus with CD56 (NCAM)-positive angiocentric lymphoma occuring in sites other than the upper and lower respiratory tract

We previously described nine cases of angiocentric lymphoma of a possible natural killer (NK)‐cell lineage with a surface CD3− CD56+ phenotype occurring in sites other than the upper and lower respiratory tract. This study was performed to investigate the association of Epstein‐Barr virus (EBV) with these lymphomas, using the polymerase chain reaction (PCR) for the presence of EBV‐DNA, in situ hybridization (ISH) for EBV‐encoded small RNAs (EBERs) and immunohistology for EBV‐determined nuclear antigen‐2 (EBNA‐2) and latent membrane protein‐1 (LMP‐1) in paraffin sections. PCR and ISH produced almost identical results, and EBERs were identified in the nuclei of the lymphoma cells of three cases, two of which exhibited LMP‐1 in the cytoplasm of tumour cells without EBNA‐2 expression. Molecular genetic analysis revealed EBV to be incorporated into these three EBER‐positive cases either clonally or biclonally. It was revealed by re‐evaluation of their morphology with the established EBV status on each case that, in contrast to the rather variable and irregular cellular composition of the EBV‐ positive tumours, the EBV‐negative tumours stood out because of their remarkably uniform ‘blastoid’ appearance, and could be grouped as blastic NK‐cell lymphoma. The relationship of the EBV‐positive cases with nasal NK‐cell tumours has yet to be clarified.

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.

Interdigitating cell sarcoma: a morphologic and immunologic study of lymph node lesions in four cases.

lnterdigitating cell sarcoma is an extremely rare tumor. Its presentation and histologic appearance has varied among the reported cases. In this study, the authors investigated four cases of the hematolymphoid malignancy arising within lymph nodes, which were considered to be of interdigitating cell origin. All patients presented in the 6th to 8th decade of life with peripheral lymphadenopathy, and had a relatively indolent clinical course, without bone marrow or skin involvement. Carcinomas were observed as a second neoplasm in two of four patients. Distinctive morphologic features are proliferation of histiocyte‐like cells with nuclear pleomorphism and occasionally multinucleated, paracortical distribution sparing of B‐cell regions, fibrosis, sinus infiltration, and a prominent eosinophi/plasma cell infiltrates. The combination of light microscopic, fine structural, and immu‐nohistochemical features suggested that these tumors derive from interdigitating cells: these tumor cells expressed CD68 (KP1), S‐100 protein and HLA‐DR, but lack CD21 (1F8), desmosomes and Birbeck granules. The diagnosis of interdigitating cell sarcoma should be considered on any pleo‐morphic tumor with the features described in this report.

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.

Ki-1 (CD30) Positive anaplastic large cell lymphoma of T-cell phenotype developing in association with long-standing tuberculous pyothorax: Report of a case with detection of Epstein-Barr virus genome in the tumor cells

We report a case of CD30 positive anaplastic large cell lymphoma of T-cell phenotype developing in association with long-standing tuberculous pyothorax. Phenotypic analysis showed CD1a-, CD2+, CD3+, CD4+, CD5-, CD8-, CD10-, CD19-, CD20 +/-, CD21-, CD25-, CD56-, T-cell receptor (TCR) alpha/beta antigens-, and HLA-DR+ phenotype. Neither rearrangement of TCR beta and gamma chain genes or of immunoglobulin heavy chain gene was detected in DNA extract from fresh material. The lymphoma cells were also shown to express the latent membrane protein-1 and the Epstein-Barr virus (EBV)-encoded nuclear antigen-2 by immunohistochemistry and EBV-encoded small RNAs by in situ hybridization.

Reciprocal control of colon-specific sulfomucin and sialosyl-Tn antigen expression in human colorectal neoplasia

Abstract Histochemical reports claim that sulfomucins decrease and sialylated mucins increase during colon carcinogenesis. We examined the expression of colon-specific sulfomucins and sialosyl Tn antigen (STN) in normal small intestine, normal colorectal mucosa and colorectal tumours at different stages of progression immunohistochemically, using MAb 91.9H specific for colonic sulfomucins and MAb TKH-2 for STN. No expression of sulfomucins recognized by MAb 91.9H was found in normal small intestine, whereas STN staining was pronounced. The converse was the case in normal colorectal mucosa. Sulfomucins were still found in adenomas, but the amounts decreased with depth of invasion in cancers (P<0.001). In contrast, no STN could be detected in benign lesions, but staining became increasingly evident with invasion (P<0.001). This reciprocal control of expression of colon-specific sulfomucins and STN evident in tumour progression indicates that the mucous phenotype shifts from the colonic to the small intestinal type.

Interdigitating cell sarcoma (ICS): evidence of interdigitating cell origin, immunocytochemical studies with monoclonal anti-ICS antibodies

Three independent mouse monoclonal antibodies (mAbs) ID1 (IgG3), ID2 and ID3 (IgM) were raised against whole cells of a surgically resected human interdigitating cell sarcoma (ICS). In immunoperoxidase staining, these mAbs strongly stained the cytoplasm of ICS neoplastic cells as well as interdigitating cells in normal lymphoid tissues. These mAbs also detected monocyte/ macrophages and dendritic cells, although their staining was highly variable depending on tissue distribution of the cells. Additional immuno-histological and enzyme histochemical study revealed that the neoplastic cells of ICS had cytoplasmic acid phosphatase and membranous alkaline phosphatase activity, and also possessed S100fβ protein, Ki-1 antigen, DAKO-macrophage antigen, and weak vimentin activity. Neither rearrangement of immunoglobulin heavy chain gene nor of T-cell receptor genes was detected in the DNA of ICS by Southern hybridization. These observations provide further confirmation of our previous finding (Nakamura et al. 1988, 1989) that the origin of ICS is interdigitating rather than lymphoid cell, and indicate that our mAbs could be useful as a cellular differentiation marker of interdigitating cells and for diagnosis of ICS.