ALK gene products in anaplastic large cell lymphomas and Hodgkin's disease

The translocation t(2;5)(p23;q35), discovered in CD30+ anaplastic large cell (ALC) lymphomas, creates a potentially oncogenic fusion gene, part of which is contributed by a novel tyrosine kinase, ALK. Absence of ALK expression from normal hematolymphoid cells provides a basis for the morphologic assessment of t(2;5). The distribution of the t(2;5) in ALC lymphomas and Hodgkin's disease (HD), as assayed by nonmorphologic methods, is controversial. We used in situ hybridization and/or immunohistology to show ALK gene products in 85 ALC lymphomas, 82 HD cases, 40 other lymphoproliferations, as well as in 6 HD- and 4 ALC lymphoma-derived cell lines. ALK gene products were restricted to t(2;5)-positive ALC lymphoma cell lines and tumor cells of 16 primary non-B cell, common-type ALC lymphomas. These were mainly from young patients with initial lymphonodal disease. ALK expression was not detectable in any other specimen, including all cases of HD and HD-like type ALC lymphoma as well as secondary ALC lymphomas. Full congruence was noted for labeling results obtained with both methods. In agreement with cytogenetic analyses, but at variance with recently published studies, ALK gene expression distinguishes a subset of ALC lymphomas from other CD30+ lymphomas, including HD. The results do not support concepts attributing a significant role to the t(2;5) in the development of HD.     

Explorers. Christopher Columbus and Leonardo da Vinci

Epstein-Barr virus (EBV) recently has been associated with Hodgkin's disease (HD) and the EBV genome was found in CD30-positive Reed-Sternberg cells. Therefore, tissue sections from 25 cases of HD, 35 cases of CD30-positive non-Hodgkin's lymphoma (NHL) (seven CD30-positive anaplastic large cell lymphomas [ALCLs] and 28 CD30-positive non-ALCLs), and 12 cases of CD30-negative NHL that previously had been screened for the presence of EBV by polymerase chain reaction and DNA in situ hybridization were studied by immunohistochemistry for the expression of the latent EBV proteins, latent membrane protein (LMP), and Epstein-Barr nuclear antigen-2 (EBNA-2). We also analyzed the expression of the B-cell activation molecule CD23 and the adhesion molecules LFA-1/CD11a and ICAM-1/CD54 because the upregulation of these molecules by LMP and/or EBNA-2 in vitro has been related to the EBV-induced lymphocyte growth. Latent membrane protein expression was found in Reed-Sternberg cells in nine of 25 cases (36%) of HD and in large, occasionally Reed-Sternberg-like tumor cells in six of 47 cases (12%) of NHL; these six tumors were CD30-positive, histologically high-grade NHL (one CD30-positive ALCL and five CD30-positive non-ALCLs). All the LMP-positive cases were also polymerase chain reaction EBV positive while LMP expression was not found in polymerase chain reaction EBV-negative HD and NHL. No staining for EBNA-2 was detected in our series. In view of the transforming potential of the LMP, these findings suggest that EBV may be associated with the development of some cases of HD and CD30-positive NHL. These findings also suggest a correlation between the expression of LMP and the detection of CD30 in tumor cells of HD and NHL. In contrast, no correlation was found between the expression of LMP and the detection of CD23, LFA-1/CD11a, and ICAM-1/CD54 in tumor cells of HD and NHL.     

The role of mucosal biopsy in the diagnosis of chronic diarrhea: value of multiple biopsies when colonoscopic finding is normal or nonspecific

The CTLA4 receptor is a CD28 homologue which induces inhibitory effect on activated T-cells. Peripheral T-cells proliferate spontaneously in CTLA4-deficient mice. These results led to an analysis of CTLA4 expression in human lymphomas (n = 82) including Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHLs), using immunohistochemistry. CTLA4 was present in neoplastic cells from most (10/11) T-cell malignancies, except for anaplastic and lymphoblastic subtypes (0/4). Malignant B-cells from rare (3/55) B-NHLs (all of follicular subtype) were also CTLA4-positive. Other B-NHLs (52/55) were negative in malignant B-cells and occasionally positive in T-cells. Reactive small lymphocytes, but not Reed-Sternberg cells, from all (12/12) HD cases were strongly CTLA4-positive. The CTLA4 ligands CD80 and CD86 were simultaneously expressed in most CTLA4-negative lymphoma cases. CTLA4 is thus expressed either in the reactive or in the malignant cell populations, depending on the lymphoma subtype. These results provide new insights leading towards therapeutic strategies based either on enhancement of anti-tumour immunity by CTLA4 blockade in reactive lymphocytes or on triggering of a CTLA4-mediated inhibitory pathway in lymphoma cells.     

Recurrence with histological transformation 40 days after autologous peripheral blood stem cell transplantation (APBSCT) for cutaneous CD30-negative large T cell lymphoma

Localized cutaneous nontender nodules appeared on the back of a 52-year-old Japanese woman. Skin biopsy revealed atypical large T-lymphocytes infiltrating the dermis. CD30 staining was negative in tumor cells. The diagnosis was CD30-negative cutaneous large T cell lymphoma. There was no evidence of peripheral lymphadenopathy or bone marrow involvement. Six cycles of induction chemotherapy were administered and a complete clinical remission (CCR) was attained. Local irradiation was not given. As the clinical course of CD30-negative cutaneous large T cell lymphoma is recurrent and often incurable with conventional chemoradiotherapy, she received high-dose chemotherapy without total body irradiation (TBI) followed by unpurged autologous peripheral blood stem cell transplantation (APBSCT). A relapse in the skin followed 40 days after APBSCT, but tumor cells transformed into a CD30-positive anaplastic large cell lymphoma (ALCL). We question the need for TBI in conditioning and for purged stem cells for APBSCT in patients with high risk cutaneous lymphomas.     

Detection of the t(2;5)-associated NPM/ALK fusion cDNA in peripheral blood cells of healthy individuals

The translocation t(2;5), which leads to the fusion of the nucleophosmin gene (NPM) on chromosome 5q35 to the receptor kinase ALK on chromosome 2p23, is found in CD30+ anaplastic large cell lymphomas and some cases of B-cell lymphoma. Hodgkin's disease (HD) is a malignant lymphoma characterized by large multinucleated tumour cells, Hodgkin and Reed-Sternberg (H&RS) cells, surrounded by a dense lymphohistiocytic infiltrate. Our group recently demonstrated NPM/ALK fusion cDNAs by single-cell RT-PCR in < 3% of CD30+ tumour cells in 2/9 cases of HD. To further delineate the relevance of this finding for HD, we studied the occurrence of NPM/ALK fusion genes in peripheral blood cells of healthy donors by RT-PCR. NPM/ALK fusion cDNAs were found by RT-PCR in 14/29 healthy individuals and confirmed by hybridization with a breakpoint-specific oligonucleotide. Due to the low rate of NPM/ALK-positive cells in the peripheral blood of positive individuals, an assignment to a defined cellular subpopulation was not possible. We conclude that NPM/ALK fusion genes are present in peripheral blood cells of healthy donors. After t(14;18) and t(9;22), t(2;5) represents the third example of tumour-associated translocation products in blood cells of apparently healthy donors. The implications of this finding are discussed.     

ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum

The t(2;5)(p23;q35) translocation associated with CD30-positive anaplastic large cell lymphoma results in the production of a NPM-ALK chimeric protein, consisting of the N-terminal portion of the NPM protein joined to the entire cytoplasmic domain of the neural receptor tyrosine kinase ALK. The ALK gene products were identified in paraffm sections by using a new anti-ALK (cytoplasmic portion) monoclonal antibody (ALKc) that tends to react more strongly than a previously described ALK1 antibody with the nuclei of ALK-expressing tumor cells after microwave heating in 1 mmol/L ethylenediaminetetraacetic acid buffer, pH 8.0. The ALKc monoclonal antibody reacted selectively with 60% of anaplastic large cell lymphoma cases (60 of 100), which occurred mainly in the first three decades of life and consistently displayed a T/null phenotype. This group of ALK-positive tumors showed a wide morphological spectrum including cases with features of anaplastic large cell lymphoma "common" type (75%), "lymphohistiocytic" (10%), "small cell" (8.3%), "giant cell" (3.3%), and "Hodgkin's like" (3.3%). CD30-positive large anaplastic cells expressing the ALK protein both in the cytoplasm and nucleus represented the dominant tumor population in the common, Hodgkin's-like and giant cell types, but they were present at a smaller percentage (often with a perivascular distribution) also in cases with lymphohistiocytic and small cell features. In this study, the ALKc antibody also allowed us to identify small neoplastic cells (usually CD30 negative) with nucleus-restricted ALK positivity that were, by definition, more evident in the small cell variant but were also found in cases with lymphohistiocytic, common, and "Hodgkin's-like" features. These findings, which have not been previously emphasized, strongly suggest that the neoplastic lesion (the NPM-ALK gene) must be present both in the large anaplastic and small tumor cells, and that ALK-positive lymphomas lie on a spectrum, their position being defined by the ratio of small to large neoplastic cells. Notably, about 15% of all ALK-positive lymphomas (usually of the common or giant cell variant) showed a cytoplasm-restricted ALK positivity, which suggests that the ALK gene may have fused with a partner(s) other than NPM. From a diagnostic point of view, detection of the ALK protein was useful in distinguishing anaplastic large cell lymphoma cases of lymphohistiocytic and small cell variants from reactive conditions and other peripheral T-cell lymphoma subtypes, as well as for detecting a small number of tumor cells in lymphohemopoietic tissues. In conclusion, ALK positivity appears to define a clinicopathological entity with a T/null phenotype ("ALK lymphomas"), but one that shows a wider spectrum of morphological patterns than has been appreciated in the past.     

Differential diagnosis between classic Hodgkin's lymphoma, T-cell-rich B-cell lymphoma, and paragranuloma by paraffin immunohistochemistry

There are significant difficulties in the differential diagnosis of lymphomas at the interface between classic Hodgkin's lymphoma and both paragranuloma and T-cell-rich B-cell lymphoma as well as at the interface between T-cell-rich B-cell lymphoma and paragranuloma. We therefore investigated 197 cases (155 classic Hodgkin's lymphomas, 32 T-cell-rich B-cell lymphomas, and 10 paragranulomas) by paraffin immunohistochemistry. Special interest was given to cases with a B-cell phenotype of tumor cells. The reactive inflammatory infiltrate in both classic Hodgkin's lymphoma and T-cell-rich B-cell lymphoma was rich in TIA-1-positive cytolytic lymphocytes, and CD57-positive cells were rarely encountered. In contrast, in paragranuloma CD57-positive cells and small B-lymphocytes predominated the background infiltrate. The tumor cells in cases of classic Hodgkin's lymphoma were positive for CD30 in 95%, for CD15 in 75%, and for CD20 in 22%. Apart from this, vimentin was expressed in >95% of the cases. All cases of T-cell-rich B-cell lymphoma were negative for vimentin, CD30, and CD15. The reactivity of the tumor cells for CD30, CD15, CD20, and vimentin together with the background reactivity for CD57 and TIA-1 seem to reliably discriminate between the entities and should therefore help to increase the interobserver reproducibility of diagnoses in the gray zone around Hodgkin's lymphoma.     

NPM/ALK gene fusion transcripts identify a distinct subgroup of null type Ki-1 positive anaplastic large cell lymphomas

The chromosomal aberration t(2:5) resulting in the juxtaposition of NPM and ALK genes is a well-known feature of several Ki-1+ anaplastic large cell lymphomas (ALCL) of the T-cell type. However, conflicting results have been reported concerning the presence of this gene rearrangement in other ALCL and Hodgkin's disease (HD), respectively. We performed NPM/ALK RT-PCR on 14 cases of ALCL expressing distinct myelomonocytic markers, e.g. CD11c, CD13, CD14 or CD68, but neither T-cell nor B-cell associated antigens (null cell phenotype). The specific translocation was found exclusively in six childhood tumours previously diagnosed as malignant histiocytosis (MH), whereas all adult lymphomas (three ALCL without characteristics of MH, three secondary ALCL following HD) and two paediatric cases of secondary ALCL following HD did not show NPM/ALK gene fusion products. By Southern blotting, the status of T-cell receptor (TCR) and immunoglobulin heavy chain genes (IgH) were investigated; two patients with initially diagnosed MH had the TCRdelta-chain gene rearranged (Ddelta2-Ddelta3 and Vdelta1-Jdelta1, respectively). IgH rearrangements were detected in only one patient with secondary ALCL. Our data indicate a high association of previously diagnosed MH and NPM/ALK gene rearrangements. In one case, this specific translocation was demonstrated at an early stage of development; in another, a mature TCRdelta-chain gene rearrangement was detected. These data support the hypothesis of a lymphoid origin of this subgroup of Ki-1 positive ALCL previously diagnosed as MH.     

CD56-positive cutaneous lymphoma: a poorly recognized entity in the spectrum of primary cutaneous disease

CD56-positive (CD56+) lymphomas, characterized by the expression of the neural cell adhesion molecule on pathological lymphocytes, share a frequent extranodal involvement and a generally aggressive course. Five CD3- CD56+ lymphoma patients presenting with nodular lesions were identified among 180 immunophenotyped cutaneous lymphomas. All the patients were men, with ages ranging from 55 to 78 years. After staging, two patients were diagnosed as having primary cutaneous lymphomas; the remaining three had the secondary cutaneous type. The clinical course was aggressive and four patients died within 8 months from diagnosis. The remaining patient is still alive after a 17-month follow-up. The histological diagnosis was immunoblastic lymphoma in two patients, and medium and large cell pleomorphic lymphoma in three. The angiocentric infiltrate was located mainly in the dermis; azurophilic granules were present in three of the five patients. Immunogenotypic analyses suggested the natural killer cell origin of these neoplasias: all cases exhibited a CD56+ CD3- CD5- T-cell receptor (TCR) silent phenotype, and Southern blot analysis showed a germline configuration of the TCR beta-chain gene.     

Expression of the receptor for urokinase-type plasminogen activator in normal and neoplastic blood cells and hematopoietic tissue

Expression of the receptor for the urokinase type plasminogen activator (uPAR) has been studied by flow cytometry and immunohistology in normal blood and bone marrow cells, in vitro activated lymphoid cells, and tissue samples from reactive lymph nodes (n = 6), thymus (n = 2) and malignant lymphomas (n = 82), or leukemias (n = 32). HL-60 myeloid precursor cells and CD34-positive normal stem cells also were analyzed. In the normal cells, staining was confined to monocytes, macrophages, neutrophils, and myeloid precursors. No labelling was seen of normal or activated lymphoid cells. Purified CD34-positive hematopoietic progenitors were uPAR negative, but expressed uPAR during differentiation in short-term liquid culture stimulated in vitro by recombinant interleukin (IL)-1, IL-3, IL-6, granulocyte-macrophage colony stimulating factor (CSF), granulocyte-CSF, and stem cell factor. Enhanced uPAR expression was also seen in HL-60 cells after induction of differentiation with dimethyl sulfoxide or 1 alpha,25-dihydroxyvitamin D3. In lymphomas and leukemias, the staining pattern was similar to that seen in the normal cells with labelling of monocytic and myeloid that seen in the normal cells with labelling of monocytic and myeloid malignancies, but not of the neoplastic cells in B-cell or T-cell lymphomas or Hodgkin's disease. In conclusion, uPAR is a differentiation marker for myeloid and monocytic cells, and may act to facilitate migration of these cells in normal and pathologic conditions by cell-associated plasminogen activation. Whether expression of uPAR in myeloid and monocytic malignancies relates to their growth and behavior will be an important topic for investigations in the future.     

Relation of follicular dendritic reticulum cells to Reed-Sternberg cells of Hodgkin's disease with emphasis on the expression of CD21 antigen

Based on observations of 66 cases, in which tissues were specially processed to optimize the simultaneous preservation of cell membrane antigens and morphology, we provide evidence in favor of a relationship between follicular dendritic reticulum cells (FDRC) and Reed-Sternberg (RS) cells of Hodgkin's disease (HD) other than the lymphocyte predominance subtype. RS cells were intimately related to the FDRC network (75% of cases), and the expression of CD21 antigen was frequent (41% of cases). Exclusive expression of CD21 antigen was found in 11 cases of HD, while the expression of other B-cell-associated markers (CD19, CD20, CD22) was both variable and inconsistent. The expression of T-cell antigens (CD3, CD4, CD8) was rare. Null phenotype of RS cells was observed in 27 of 66 cases (41%). Epstein-Barr virus (EBV) nucleic acids were found in 34 of 66 (51.5%) cases. Double labeling techniques showed the presence of EBV-positive RS cells within the FDRC network. A non-B-cell origin of RS cells was supported by the differential expression of EBV latent antigens in HD (latent membrane protein+, EB nuclear antigen 2-), which is unusual in EBV-driven lymphoblastoid cell lines and EBV-positive B-cell lymphomas. FDRC and RS cells are known to share morphological traits (binucleated cells), and both cell types possess Fc receptor for IgG. The hypothesis is further backed by the findings of CD15 antigen expression by occasional RS-like dysplastic FDRC in Castleman's disease (five cases), which is characterized by hyperplasia of FDRC. Whether FDRC might be the only cells involved in the conversion to RS cells by the loss or gain of antigens remains to be determined.     

17Beta-hydroxysteroid dehydrogenase types 1 and 2 in human placenta: an immunohistochemical study with correlation to placental development

In estrogen metabolism, the enzymatic properties of the 17beta-hydroxysteroid dehydrogenase (17betaHSD) isozymes play very important roles in steroid hormone metabolism in various tissues, including the placenta. 17betaHSD type 1 catalyzes primarily the reduction of estrone (E1) to estradiol (E2), whereas 17betaHSD type 2 catalyzes primarily the oxidation of E2 to E1. In this study, we examined immunohistochemical localization of 17betaHSD types 1 and 2 in human placenta (31 cases) ranging from 4-40 weeks gestation. The immunoreactivity of 17betaHSD type 1 was exclusively detected in syncytiotrophoblast from 4 weeks gestation to term placenta. Immunoreactivity of 17betaHSD type 2 first appeared in endothelial cells of intravillous vessels at 12 weeks gestation, and the number of 17betaHSD type 2-positive endothelial cells markedly increased up to 19 weeks, then reached a plateau. We quantitatively evaluated the 17betaHSD type 2-positive endothelial cells in chorionic villi and determined the ratio of 17betaHSD type 2-positive endothelial cells using immunohistochemistry of CD34, an endothelial antigen, in serial mirror tissue sections and subsequent image analysis using CAS 200. CD34 was detected from 4 weeks gestation, and its positive areas continued to increase toward term. The 17betaHSD type 2-positive area per CD34-positive area markedly increased from 13 weeks gestation and reached a plateau at 19 weeks gestation, in which almost all endothelial cells were positive for 17betaHSD type 2. 17BetaHSD type 2, therefore, is considered to prevent the passage of excessive estrogens into the fetal circulation at endothelial cells of the intravillous fetal capillaries by catalyzing the inactivation ofE2 to E1.     

The morphologic spectrum of non-Hodgkin's lymphomas with BCL1/cyclin D1 gene rearrangements

BCL1/PRAD1 gene rearrangements involving the cyclin D1 gene are a feature of about 70% of centrocytic/mantle-cell lymphomas (CC/MCL) but are identified in only a small proportion of other B-cell non-Hodgkin's lymphomas. Of 37 lymphomas found to have BCL1/cyclin D1 (PRAD1, CCND1) gene rearrangements, 30 fit the morphologic and immunophenotypic criteria for typical CC/MCL. Seven cases with morphologic features atypical for CC/MCL were identified. CD5+ monoclonal B cells were documented in all these cases. Six cases were subsequently stained for cyclin D1 protein, and all showed nuclear positivity. Five cases had variably sized foci of cells with moderately abundant pale cytoplasm resembling parafollicular/monocytoid B cells, marginal zone cells, hairy cells, or even proliferation centers. Transformed-appearing cells were also present in some lymphomas. In one case, striking follicular colonization created a markedly nodular growth pattern mimicking a follicular lymphoma. A sixth case had a marked predominance of small, round lymphocytes at some sites, mimicking a small lymphocytic lymphoma. Five of these six cases also had areas more typical of CC/MCL. The seventh case was a CD5-positive splenic marginal zone-like lymphoma (SMZL) with plasmacytic differentiation and circulating villous lymphocytes consistent with a splenic lymphoma with villous lymphocytes (SLVL). These cases illustrate the morphologic spectrum of small B-cell lymphoid neoplasms that have BCL1/cyclin D1 gene rearrangements and overexpression of cyclin D1. Despite the BCL1 translocation and cyclin D1 overexpression, the splenic lymphoma with plasmacytic differentiation was definitely not a CC/MCL and fit the clinicopathologic entity of SMZL/SLVL. The other six cases are best considered CC/MCL variants based on a combined morphologic, immunophenotypic, and genotypic evaluation. Genotypic or immunophenotypic studies to identify cyclin D1 rearrangements and overexpression, although not pathognomonic, are useful in recognizing these variant CC/MCL cases, which can mimic almost any of the other well-described but more indolent low-grade B-cell lymphomas and leukemias. Some of the variant CC/MCL cases had features in common with the CD5+ cyclin D1+ SMZL/SLVL, suggesting a possible relationship between these two otherwise distinct entities.     

Epstein-Barr virus-related localized hepatic lymphoproliferative disorders after liver transplantation

BACKGROUND: Localized hepatic post-transplant lymphoproliferative disease is uncommon. In such cases, lymphocyte Epstein-Barr virus (EBV) infection may promote an intrahepatic B-lymphocyte monoclonal expansion. METHODS: From 1990 to 1991, 149 patients underwent liver transplantation for various liver failures. Immunosuppressive therapy was azathioprine, cyclosporine-A, and methylprednisolone. Rejection episodes were treated by methylprednisolone bolus injection with or without OKT3 therapy. Three patients (2%), aged 38, 50, and 47 years, developed lymphoproliferative disease localized in the transplanted livers within 5 months of liver transplantation (a patient had been immunosuppressed for 3 years before the lymphoproliferative disease occurred within the third allografted liver). Diagnoses were obtained by fine needle aspiration. In situ hybridizations were performed with the kappa/lambda mRNA-kit FITC DAKO (DAKO Corporation, Carpenteria, CA) and the early mRNA-EBER oligonucleotide FITC DAKO: RESULTS: Lymphoproliferative diseases were all classified as diffuse polymorphic large cell lymphomas in the working formulation and considered as lymphoproliferative disorders with polymorphic large cells in the Frizzera classification. All large cells were CD20-positive, CD45-positive and CD45RO-negative. In situ mRNA light chain hybridization demonstrated monoclonality in two cases. In all three cases, EBV mRNA was detected in large cells by early mRNA-EBV (EBER) in situ hybridization. Patients were treated with doxorubicin, cyclophosphamide, vincristine, and VM26. Two patients maintained a complete remission 3 years after six cycles of chemotherapy, whereas one died of an early opportunistic infection. CONCLUSION: Epstein-Barr virus may play a special role in the pathogenesis of lymphoproliferative disorders that develop in patients who have undergone liver transplantation.     

CD56+ putative natural killer cell lymphomas: production of cytolytic effectors and related proteins mediating tumor cell apoptosis?

Apoptosis is a regulated form of cell death that may be triggered by natural killer (NK) or cytotoxic T cells, which effect target cell lysis by cytolytic effector and related proteins through complex intracellular signals. This study was aimed to investigate whether there is selective expression of these cytolytic markers in the putative NK-cell lymphomas and whether there is correlation with zonal tumor cell death in these tumors. Expression of the cytolytic effectors perforin, granzyme B9, and the granule membrane protein TIA1 were examined in 24 putative NK-cell lymphomas, 18 postthymic T-cell lymphomas (one case CD8+ CD56+ and three anaplastic large cell lymphomas (ALCL), three T-lymphoblastic lymphomas, and 20 B-cell lymphomas. Nineteen (79%) putative NK-cell lymphomas expressed perforin, and all 24 cases expressed granzyme B9 and TIA1. The only CD8+ CD56+ postthymic T-cell lymphoma also expressed all three cytolytic markers, two CD8- ALCL expressed TIA1; other postthymic T-cell, T-lymphoblastic, and B-cell lymphomas were consistently negative. There was strong correlation between percentage perforin-positive cells and zonal tumor cell death. Angioinvasion, in contrast, was present only in a proportion (37%) of these lymphomas despite the frequent presence of zonal tumor cell death (71%). We propose that cytolytic effector and related proteins produced by putative NK and some CD8+ CD56+ postthymic T-cell lymphomas, probably in conjunction with other mechanisms, may effect massive tumor cell apoptosis. The frequent expression of cytolytic effector markers in the CD2+ surface CD3- CD56+ putative NK-cell lymphomas lends further support to their probable NK cell origin.     

Evaluation of CD23 expression in paraffin-embedded gastric lymphomas of mucosa-associated lymphoid tissue

The CD23 antigen is expressed in a normal subset of B lymphocytes and in some non-Hodgkin's lymphomas. Reactivity for anti-CD23 (BU38) is present in paraffin-embedded tissue in the large majority of nodal small lymphocytic lymphomas, as well as in follicular center cell lymphomas. Most studies of gastric lymphomas of mucosa-associated lymphoid tissue (MALT) reported a lack of CD23, but these studies were performed on frozen tissue. We evaluated CD23 staining in paraffin-embedded tissue in a large series of gastric MALT lymphomas, as well as in cases of chronic gastritis. We assayed 49 well-characterized gastric lymphomas (9 high-grade non-MALT and 40 MALT [20 low grade, 13 mixed low and high grade, and 7 high grade]). High-grade MALT lymphomas without a low-grade component were distinguished from high-grade non-MALT lymphomas by the presence of lymphoepithelial lesions composed of large cells. In addition, we studies nine cases of chronic gastritis containing B-cell aggregates. We used anti-CD23 (BU38) in formalin-fixed, paraffin-embedded tissue. All of our low-grade gastric MALT lymphomas lacked CD23 immunoreactivity. One of the 13 mixed low-grade and high-grade lesions showed CD23 expression in the high-grade component. All of the high-grade MALT and high-grade non-MALT lesions lacked CD23. All of the nine cases of chronic gastritis lacked CD23. CD23 highlighted residual follicular dendritic cells and gastric epithelium. We concluded that gastric MALT lymphomas lacked CD23 (BU38) in paraffin-embedded tissue, with rare exceptions. This lack of CD23 expression might represent a useful feature in small or partially crushed biopsy specimens, particularly in the differential diagnosis with follicular small cleaved cell lymphoma presenting in the gastrointestinal tract.     

Human T-lymphotropic virus type 2 (HTLV-2) provirus in circulating cells of the monocyte/macrophage lineage in patients dually infected with human immunodeficiency virus type 1 and HTLV-2 and having predominantly sensory polyneuropathy

We investigated the presence of human T-lymphotropic virus type 2 (HTLV-2) DNA in the peripheral blood mononuclear cell subsets obtained from 18 patients coinfected with human immunodeficiency virus type 1 and HTLV-2, 6 of whom also had predominantly sensory polyneuropathy (PSP). HTLV-2 DNA and RNA were found in CD8- and CD19-positive cells, and, for patients with PSP, in CD14-positive cells as well. Furthermore, the patients with PSP had higher proviral loads than those without PSP.     

Biased VH family usage in primary gastric B cell lymphoma of mucosa-associated lymphoid tissue-type and the selected V beta expression of T cells infiltrating into the lymphoma cells

Seven cases of primary gastric low-grade B cell lymphoma of mucosa-associated lymphoid tissue (MALT) type, two cases of high-grade B cell lymphoma with a low-grade component and three cases of pure high-grade lymphoma were selected for the current study. The Ig VH gene use of lymphoma cells and the V beta repertoires of infiltrating T cells were investigated. The VH gene analysis showed multiple VH family usage in 12 cases, but the MALT-type lymphoma cell usage was found to be biased for the families that have a low number of VH genes (VHIV and V). Another analysis of lymphoma-infiltrating T cells showed restricted expressions of the V beta repertoire in all seven low-grade cases and three high-grade cases. In those 10 cases, a considerable number of CD4-positive T cells infiltrated into lymphoma cells and RAG-1 was also prominently expressed. Based on these findings, it was thus assumed that the normal counterpart of gastric B cell lymphoma of MALT type is different from the conventional B cell lymphoma, and the restricted expression of V beta repertoires is therefore considered to be a characteristic finding in low-grade B cell lymphomas of MALT type as well as in a proportion of high-grade lymphomas (the so called 'high-grade lymphoma of MALT type').