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As part of an investigation of mononuclear phagocytes in malignant lymphoma, measurement of immune-mediated erythrophagocytosis and rosette formation was carried out on cells grown in suspension culture at the monocyte (Day 0) and macrophage (Day 6) stages; the culture medium contained autologous serum. Cells were derived from 10 patients with untreated non-Hodgkin's lymphoma (NHL) and from 12 normal individuals. The results were subjected to Analysis of Variance and demonstrated a significant difference between the two groups with respect to erythrophagocytosis but not to rosette formation. In the NHL group, the proportion of erythrophagocytic cells showed no significant increase between the monocyte and macrophage stages (0.07 to 0.09), in contrast to the marked increase seen in the normal group (0.09 to 0.24). In a pilot investigation to examine the possible role of factors in the serum, cells derived from the NHL patients were cultured with serum from healthy donors; they showed no significant difference in the immune-mediated functions from those grown in autologous serum. Overall, the results provide further quantitative evidence of defective macrophage maturation in NHL, presumably reflecting the compromise of host defence mechanisms.
Virchows Arch B Cell Pathol Incl Mol Pathol 1992
PMID:Immune-mediated interactions during macrophage development in non-Hodgkin's lymphoma. 135 20

We have studied four cases of fatal B-cell lymphoproliferative syndrome (LPS) developing among 333 patients (incidence 1.2%) treated with allogeneic bone marrow transplantation (BMT). All four patients had received a T-cell depleted graft. Onset of the first clinical symptoms (palpable lymph node enlargement in three and IgA-lambda paraproteinemia in two patients) occurred between 41 and 188 days post-BMT (median 76 days). The course of the LPS was rapidly progressive in all cases, leading to death in 2-5 weeks. The peripheral blood showed progressive pancytopenia with disproportionally high numbers of activated NK cells, apparently compensating for the T-cell deficiency. Post-mortem histological studies disclosed polymorphic B-cell proliferations, most pronounced in the lymph nodes, spleen, liver, lungs and kidneys. Lymphohemopoietic cells were of donor origin in three patients. In the fourth patient, graft failure suggested a host origin for the proliferating cells. Immunophenotyping and gene rearrangement analysis revealed polyclonal proliferation in one patient, monoclonal proliferation in another patient, and an oligoclonal pattern in the other two patients. The clinical behavior of the LPS was independent of clonality. Immunohistologically, the proliferating cells showed characteristics of relatively mature B-cells in three cases, and pre-B-cell features in one case. Epstein Barr virus (EBV) serology indicated seroconversion (primary infection) in one child, and chronic active EBV infection in both adults. EBV DNA as well as EBV nuclear antigen (EBNA) were detected in infiltrated tissues of all four patients. The labeling pattern on in situ hybridization suggested a replicative EBV infection comparable to that in lymphoblastoid cell lines. We conclude that EBV-associated LPS developing as a result of post-transplant immunodeficiency is a distinct clinicopathologic entity, differing from non-Hodgkin's lymphoma (including Burkitt's lymphoma) and infectious mononucleosis of the immunocompetent host.
Virchows Arch B Cell Pathol Incl Mol Pathol 1991
PMID:Fatal B-cell lymphoproliferative syndrome in allogeneic marrow graft recipients. A clinical, immunobiological and pathological study. 168 38

Discriminant analysis of morphometric data on the ultrastructure of developing macrophages has been used to classify 62 individual subjects into one of the 3 groups of origin, namely normal, Hodgkin's disease and non-Hodgkin's lymphoma, each finding being compared with the known diagnosis. The data had been obtained from blood monocytes grown in suspension culture over a period of 6 days, and related to whole cell, nucleus, nucleoli and mitochondria. Over 80% of subjects were correctly classified as between the 3 groups and over 90% as to their normality or otherwise. Although the non-specific nature of changes in defence cells makes it unlikely that morphometric studies of macrophages will find a place in the diagnosis of specific malignancies, the present work indicates it could be useful in assessing host response and hence prognosis and response to treatment. Discriminant analysis of quantitative differences in cell structure could have wide clinico-pathological application.
Virchows Arch B Cell Pathol Incl Mol Pathol 1990
PMID:Morphometry of macrophage development in malignant lymphoma. Predictive value of discriminant analysis. 197 Jun 79

Fourteen examples of non-Hodgkin's lymphoma (NHL) and four of Hodgkin's disease in patients with AIDS as well as lymph nodes exhibiting changes related to the lymphadenopathy syndrome (LAS) from 11 HIV-positive individuals were studied for the presence of Epstein-Barr virus (EBV) genome both by in situ DNA hybridization and blotting techniques. Both methods were performed using formalin-fixed paraffin-embedded material. All the NHLs were of high malignancy and all but one were of the B-cell type. Of the four examples of Hodgkin's disease, two were lymphocytic predominant, one of mixed cellularity and one of the nodular sclerosing variety. The lymph nodes of patients with LAS were mostly stage I with marked follicular hyperplasia. In 7 of the 14 NHLs the presence of EBV-DNA was clearly demonstrated by dot-blotting and by in situ hybridization. All lymph nodes from the patients with LAS and AIDS-related Hodgkin's disease were negative for EBV by dot-blot and in situ hybridization assays. We conclude that EBV plays a role in the development of AIDS-related lymphomas, but the fact that half these lymphomas are EBV-negative suggests that other mechanisms such as polyclonal stimulation of B-cells by HIV products may also be important.
Virchows Arch B Cell Pathol Incl Mol Pathol 1990
PMID:Identification of EBV-DNA in lymph nodes from patients with lymphadenopathy and lymphomas associated with AIDS. 197 Jun 81

Macrophage development in 20 untreated patients with non-Hodgkin's lymphoma (NHL) has been studied and compared with that in 20 normal subjects. Morphometric measurements were carried out on ultrastructural features of cell, nucleus and mitochondria during 6 days suspension culture of blood monocytes in the presence of autologous serum and lymphocytes. The results were subjected to multivariate and univariate analysis of variance. Statistically significant differences were found between the subject groups with respect to the volumes and surface areas of cell, nucleus and mitochondria, to the excess surface membrane of cell and nucleus (as compared with equivalent spheres) and to the number of mitochondrial profiles per section. It would appear that the patients' cell grew less, showed less elaboration of surface features and had reduced nuclear and mitochondrial development, the latter affecting mitochondrial numbers rather than individual size. The findings provide further evidence that mononuclear phagocytes are deranged in NHL.
Virchows Arch B Cell Pathol Incl Mol Pathol 1988
PMID:Disordered development of macrophages in non-Hodgkin's lymphoma. 290 92

Body cavity effusions in malignant non-Hodgkin's lymphomas, particularly in the early stages of those neoplasms, are rare in comparison to the far more common effusions in other malignant diseases and in inflammatory processes. Therefore, the cytological differential diagnosis is of great importance. Of 7,000 pleural and 1,700 ascitic effusions, only 42 cases were malignant non-Hodgkin's lymphoma and in 30 lymphoma was suspected. When lymphoma is suspected, particularly low-grade lymphoma, there are great difficulties in making a differential diagnosis. Using the more or less typical cellular and nuclear criteria of the various lymphoma types, an attempt was made to classify the unequivocal lymphomas according to the Kiel classification of malignant non-Hodgkin's lymphomas. In principle these criteria are the same in cytological and histological examinations. In 31 cases the lymphoma subtype could be specified and confirmed in part by subsequent histological examination. Apart from the suspect lymphoma cases (40%), cases of a low grade of malignancy were predominantly observed (28%). Lymphomas with a high grade of malignancy were less frequently encountered (15%), a proportion similar to that of unclassifiable lymphomas (16%). Apparently the cytological and karyological criteria are not yet adequate to classify lymphomas from conventionally prepared cytological specimens with a higher degree of accuracy.
Virchows Arch B Cell Pathol Incl Mol Pathol 1981
PMID:[Cytodiagnosis of malignant non-Hodgkin's lymphomas in effusions (author's transl)]. 611 40

In crucial cases the diagnosis of non-Hodgkin's lymphoma (NHL) still represents a challenge to the pathologist since morphological criteria do not always help to distinguish between reactive and malignant lymphoproliferations. Clonality assays are a useful supplement since monoclonal cell proliferation is strong evidence for malignancy. The polymerase chain reaction (PCR) can be utilized to establish the clonal origin of B- or T-cell lymphocyte populations by amplification of rearranged immunoglobulin and T-cell receptor (TCR) genes. In the present study DNA was isolated from a variety of neoplastic and nonneoplastic formalin-fixed, paraffin-embedded lymph nodes (n = 62), cutaneous tissue (n = 9), samples of miscellaneous origin (n = 11), and reported here for the first time, decalcified bone marrow samples (n = 35). These samples were submitted to PCR-based assays directed against the immunoglobulin heavy-chain (IgH), immunoglobulin kappa light-chain (IgL kappa), and TCR gamma chain genes. The impact of various decalcifying agents on the ability to amplify DNA was investigated by PCR-based amplification of a single copy gene. Buffered and nonbuffered EDTA was found not to impede amplification of DNA fragments up to 300 bp in length. In lymph node and cutaneous specimens monoclonality was detected in 83% of B-NHL cases using a seminested PCR approach for the amplification of IgH, whereas the same approach gave rise to monoclonal bands in 80% of bone marrow samples. The subsequent amplification of IgL kappa helped to raise the sensitivity of detection to 94%. Monoclonality was detected in seven of nine T-cell NHLs by amplification of TCR gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Med (Berl) 1995 May
PMID:PCR-based assays for the detection of monoclonality in non-Hodgkin's lymphoma: application to formalin-fixed, paraffin-embedded tissue and decalcified bone marrow samples. 767 Sep 27

The polymerase chain reaction (PCR) is a highly sensitive technique for the detection of lymphoma cells presenting specific rearrangements or translocations, like the t(14;18). However, few methods are available for the quantitative evaluation of clinical samples, especially using nested PCR. In this study, we describe a method for the semiquantitative estimation of low numbers of lymphoma cells using the nested PCR methodology. Samples evaluated consisted of RL cells, a non-Hodgkin's lymphoma cell line harbouring a bcl-2 translocation, mixed with normal mononuclear cells (MC) obtained from bone marrow or peripheral blood. DNA was extracted from samples with RL:MC ratios ranging from 5 x 10(-2) to 5 x 10(-7), and amplified for detection of this translocation. The product of this first amplification reaction was serially diluted 10-fold from 10(0) to 10(-7). Then each fraction was PCR-amplified with nested oligonucleotide primers. Aliquots of the second amplification were electrophoresed on a 2% agarose gel and stained with ethidium bromide. Within the range tested, there was a log-linear relationship between the number of PCR positive bands and the number of translocated cells in each sample. This procedure was highly reproducible in experiments evaluating the interrun and intrarun variability. In addition, there was no interaction with normal cells obtained from peripheral blood or bone marrow, or from different individuals. Furthermore, results were identical with two different cell lines and consistent with patient lymphoma cells obtained from a lymph node biopsy.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Probes 1994 Dec
PMID:A non-isotopic nested polymerase chain reaction method to quantitate minimal residual disease in patients with non-Hodgkin's lymphoma. 770 Feb 65

Large-cell anaplastic lymphomas (LCAL) are characterized by their distinctive morphology together with expression of the CD30 antigen. In addition, a chromosomal translocation, t(2;5) (p23; q35), can be detected in most cases. A significant proportion of LCALs carry rearrangements of the T-cell receptor-gamma (TCR-gamma) locus and display a T-cell phenotype. In about a third of the cases, another type of non-Hodgkin-lymphoma precedes LCAL. Early transformations of non-Hodgkin's lymphoma into LCAL might escape clinical detection in a significant number of cases. The existence of clonally related lymphoid cells within the lymph node infiltrates must be claimed in these cases. Recently, a small-cell-predominant variant of LCAL was described in which only few large tumor cells expressing the CD30 antigen are found together with numerous small lymphocytes, which are frequently CD30-. This observation in particular prompted us to investigate the clonal relationship of the tumor cell compartment and admixed small lymphocytes in one case of common LCAL with T-cell genotype. For this purpose, we chose to amplify rearranged TCR-gamma sequences from single cells isolated from immunostained frozen sections by using a micromanipulator. A total of 119 cells were investigated. Amplification products were obtained in 17 of 79 CD3+ cells, 12 of 30 CD30+ cells, and three of 10 CD20+ cells. The nucleotide sequences were determined in 28 cells by nonradioactive sequencing. In 11 CD30+ cells, the predominant rearrangement of TCR-gamma was identified. No clonal diversity was observed. The small CD3+ lymphocytes were unrelated to the anaplastic CD30+ tumor cells. This report describes a method to analyze rearrangements of the TCR-gamma in single cells isolated from immunostained frozen sections. Application of this technique revealed an absence of clonal diversity in a case of LCAL and documented the polyclonal nature of admixed small CD3+ lymphocytes.
Diagn Mol Pathol 1996 Mar
PMID:Single-cell analysis of T-cell receptor-gamma rearrangements in large-cell anaplastic lymphoma. 891 40

The NPM-ALK fusion gene, formed by the t(2;5)(p23;q35) translocation in non-Hodgkin's lymphoma, encodes a 75-kDa hybrid protein that contains the amino-terminal 117 amino acid residues of the nucleolar phosphoprotein nucleophosmin (NPM) joined to the entire cytoplasmic portion of the receptor tyrosine kinase ALK (anaplastic lymphoma kinase). Here, we demonstrate the transforming ability of NPM-ALK and show that oncogenesis by the chimeric protein requires the activation of its kinase function as a result of oligomerization mediated by the NPM segment. Sedimentation gradient experiments revealed that NPM-ALK forms in vivo multimeric complexes of approximately 200 kDa or greater that also contain normal NPM. Cell fractionation studies of the t(2;5) translocation-containing lymphoma cell line SUP-M2 showed NPM-ALK to be localized within both the cytoplasmic and nuclear compartments. Immunostaining performed with both polyclonal and monoclonal anti-ALK antibodies confirmed the dual location of the oncoprotein and also indicated that NPM-ALK is abundant within both the nucleoplasm and the nucleolus. An intact NPM segment is absolutely required for NPM-ALK-mediated oncogenesis, as indicated by our observation that three different NPM-ALK mutant proteins lacking nonoverlapping portions of the NPM segment were each unable to form complexes, lacked kinase activity in vivo, and failed to transform cells. However, NPM could be functionally replaced in the fusion protein with the portion of the unrelated translocated promoter region (TPR) protein that activates the TPR-MET fusion kinase by mediating dimerization through its leucine zipper motif. This engineered TPR-ALK hybrid protein, which transformed cells almost as efficiently as NPM-ALK, was localized solely within the cytoplasm of cells. These data indicate that the nuclear and nucleolar localization of NPM-ALK, which probably occur because of transport via the shuttling activity of NPM, is not required for oncogenesis. Further, the activation of the truncated ALK protein by a completely heterologous oligomerization domain suggests that the functionally important role of the NPM segment of NPM-ALK in transformation is restricted to the formation of kinase-active oligomers and does not involve the alteration of normal NPM functions.
Mol Cell Biol 1997 Apr
PMID:Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis. 912 81


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