Clonality of Reed-Sternberg cells in Hodgkin's disease.
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Clone Cells↗
Biomedical subjects
T Marafioti
Publications and source records attributed to T Marafioti.
Common and HIV-related diffuse large B-cell lymphomas differ in their immunoglobulin gene mutation pattern.
HIV-infected patients are at high risk of developing diffuse large B-cell lymphomas (DLBCL). It is currently unclear whether these lymphomas represent Epstein-Barr virus (EBV)-driven lymphoproliferations that develop in the setting of immunodeficiency, or whether these tumours are more closely related to the DLBCL seen in the general population. To clarify this issue, 12 HIV-related DLBCL from 11 patients were analysed for the presence of clonally rearranged and somatically mutated immunoglobulin heavy chain (IgH) genes and their association with EBV was determined. Eleven of the 12 tumour samples displayed monoclonal rearrangements of the IgH genes, with or without a moderate number of somatic mutations in the CDRII and in the FWIII regions (average four mutations). One patient presented two successive lesions; whereas the initial tumour showed an oligoclonal IgH rearrangement, the lymphoma at relapse proved to harbour a monoclonal B-cell population. Ten of 12 tumour samples expressed the EBV encoded small RNAs (EBERs), and six of these EBV-positive cases displayed, in addition, an expression of the EBV encoded nuclear antigen 2 (EBNA-2). The results obtained from HIV-related DLBCL are at variance to those described for DLBCL occurring in the general population, since the latter contain significantly more somatic IgH mutations in the CDRII and in the FWIII regions and are only rarely associated with EBV. It is concluded from these findings that HIV-related DLBCL represent a distinct group of B-cell lymphomas, a significant fraction of which most likely originates from EBV-driven lymphoproliferations, and that half of the cases derive from pre-germinal centre B-cells.
Gene Rearrangement↗
Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease.
PURPOSE: Recent studies have suggested that lymphocyte-predominant Hodgkin's disease (LPHD) is both clinically and pathologically distinct from other forms of Hodgkin's disease, including classical Hodgkin's disease (CHD). However, large-scale clinical studies were lacking. This multicenter, retrospective study investigated the clinical characteristics and course of LPHD patients and lymphocyte-rich classical Hodgkin's disease (LRCHD) patients classified according to morphologic and immunophenotypic criteria. MATERIALS AND METHODS: Clinical data and biopsy material of all available cases initially submitted as LPHD were collected from 17 European and American centers, stained, and reclassified by expert pathologists. RESULTS: The 426 assessable cases were reclassified as LPHD (51%), LRCHD (27%), CHD (5%), non-Hodgkin's lymphoma (3%), and reactive lesion (3%); 11% of cases were not assessable. Patients with LPHD and LRCHD were predominantly male, with early-stage disease and few risk factors. Patients with LRCHD were significantly older. Survival and failure-free survival rates with adequate therapy were similar for patients with LPHD and LRCHD, and were stage-dependent and not significantly better than stage-comparable results for CHD (German trial data). Twenty-seven percent of relapsing LPHD patients had multiple relapses, which is significantly more than the 5% of relapsing LRCHD patients who had multiple relapses. Lymphocyte-predominant Hodgkin's disease patients had significantly superior survival after relapse compared with LRCHD or CHD patients; however, this was partly due to the younger average age of LPHD patients. CONCLUSION: The two subgroups of LPHD and LRCHD bore a close clinical resemblance that was distinct from CHD; the course was similar to that of comparable nodular sclerosis and mixed cellularity patients. Thorough staging is necessary to detect advanced disease in LPHD and LRCHD patients. The question of how to treat such patients, either by reducing treatment intensity or following a "watch and wait" approach, remains unanswered.
Adult↗
Reduced phagocytosis of apoptotic cells in malignant lymphoma.
Efficient removal of lymphocytes undergoing programmed cell death (apoptosis) by macrophages plays an important role for the proper function of normal immune system. Furthermore, in malignant lymphoma, elimination of apoptotic tumor cells by phagocytes contributes to the anti-tumor immune response. It is unknown, however, whether macrophages in normal and malignant lymphoid tissues differ in their ability to recognize and remove apoptotic cells. Our present results demonstrate that normal and malignant lymphoid tissues differ according to the extent of the infiltration by macrophages. The highest densities of macrophages (p < 0.0001) were detected in diffuse large B-cell lymphoma, centroblastic (DLBCL-CB) and immunoblastic variants and Burkitt's lymphoma. The grade of the macrophage infiltration correlated with the proliferation rates of the tumors (p < 0.0001). Compared with normal lymphoid organs, malignant lymphoma contained lower percentages of apoptotic cells phagocytosed by tissue macrophages (p < 0.001). Of all lymphomas tested, mantle cell lymphoma and DLBCL-CB expressed the lowest percentages of phagocytosed apoptotic cells (p < 0.0001).
Apoptosis↗
Origin of nodular lymphocyte-predominant Hodgkin's disease from a clonal expansion of highly mutated germinal-center B cells.
BACKGROUND: The atypical cells of nodular lymphocyte-predominant Hodgkin's disease, designated lymphocytic and histiocytic (L&H) cells, have a B-cell phenotype. To clarify the clonality of these cells, we studied rearranged immunoglobulin genes for the variable region of the heavy chain (V[H] genes) in individual L&H cells from 11 patients with nodular lymphocyte-predominant Hodgkin's disease. We also studied the expression of immunoglobulin light chains by those cells in six of the same patients. METHODS: Single CD20+ L&H cells were isolated from frozen sections by a technique of micromanipulation. The rearranged V(H) genes of these cells were amplified by the polymerase chain reaction (PCR), sequenced, and compared with germ-line V(H) genes. Immunoglobulin light-chain messenger RNA (mRNA) was detected by in situ hybridization. RESULTS: Of 615 L&H cells isolated from all the frozen sections, 160 yielded PCR products. In each of the 11 patients, the L&H cells that could be evaluated had identically rearranged V(H) genes, whether they were isolated from the same nodule, different nodules, or different blocks of tissue. All the V(H) sequences derived from the L&H cells were highly mutated (7.5 to 27.2 percent). In two cases the coding capacity of the V(H) genes was completely or partially disrupted by mutations. Intraclonal diversity was found in six cases, and monotypic immunoglobulin light-chain mRNA was found in six. CONCLUSIONS: The L&H cells of nodular lymphocyte-predominant Hodgkin's disease represent a monoclonal expansion of B cells. The high load of V(H) gene mutations and signs of intraclonal diversity suggest a relation between L&H cells and germinal-center B cells at the centroblastic stage of differentiation.
B-Lymphocytes↗
Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection.
We report here a series of 16 highly malignant diffuse large B-cell lymphomas of the oral cavity with unique immunohistologic features. Fifteen of these developed in human immunodeficiency virus-positive patients. All cases displayed morphologic features of diffuse large-cell lymphomas but strikingly differed from them in that they showed a minimal or absent expression of the leukocyte common antigen as well as of the B-cell antigen CD20. Instead, the tumor cells showed a constant reaction with the plasma cell characteristic antibody VS38c and a frequent reaction with the CD79a antibody. This, in conjunction with a variable expression of cytoplasmic Ig and a monoclonal rearrangement of the Ig heavy chain gene in all of the three tested cases confirmed the B-cell nature, the clonal origin, and the plasmacellular differentiation of these neoplasms. The majority of these tumors were negative for the BCL-6 protein, with the remaining cases showing only a partial and weak expression of this antigen. An association with the Epstein-Barr virus (EBV) was found in 9 of 15 tested cases showing abundant EBV-encoded nuclear RNA transcripts in the absence of EBNA-2. Five of the EBV-positive cases variably expressed LMP-1. We propose to name these tumors plasmablastic lymphomas, in accordance with their morphologic and immunohistologic features. Knowledge of this lymphoma entity is important to avoid confusion with nonlymphoid malignancies due to the lack of commonly used lymphoid markers.
Adult↗
Disappearance of the Epstein-Barr virus in a relapse of Hodgkin's disease.
Hodgkin's disease (HD) is associated with the Epstein-Barr virus (EBV) in approximately half of cases. This is a report of a case of nodular sclerosing HD of the B-cell type that was associated with EBV in the initial manifestation, but was found to be EBV-negative in the relapse of the tumour. Both tumours displayed similar clinical, pathological, and immunohistochemical features. This finding implies that in a given individual EBV can be lost from malignant tumours and therefore shows that the EBV infection is not required to maintain neoplastic growth of HD tumour cells.
Antigens, Viral↗
Differential expression of apoptosis, Bcl-x and c-Myc in normal and malignant lymphoid tissues.
Bcl-x and c-Myc have an important role for the immune response by regulating the programmed cell death (apoptosis) of lymphocytes. Dysfunction of these selection processes can lead to the development of malignant lymphoma. The present study aimed at defining the differential expression of apoptosis, Bcl-x and c-Myc in normal and in malignant lymphoid tissues. Follicular centre lymphoma (FCL-F) and mantle cell lymphoma (MCL) contained the lowest apoptotic indices (AIs), whereas Burkitt's lymphoma (BL) had the highest AIs. The AIs correlated significantly with the growth rates of the tumours and with the extent of Bcl-x expression. Bcl-x was expressed in almost all BL cells, but in few tumour cells in FCL-F and in MCL. c-Myc, in contrast, was found in the majority of the tumour cells in FCL-F and in MCL, but not in BL. Whereas the extent of Bcl-x expression correlated positively with the growth rates, an inverse correlation was observed between the percentages of c-Myc-positive tumour cells and the growth rates of the tumours. We conclude that normal and malignant lymphoid tissues have a distinct pattern of apoptosis and that expression of Bcl-x and c-Myc in B cell lymphoma is differentially regulated.
Apoptosis↗
[Hodgkin's disease: a mystery is being solved].
The cell lineage derivation and type of proliferation (monoclonal versus polyclonal) of the atypical cells in Hodgkin's Disease (HD) has remained in question up until now. Immunophenotypic studies favoured a lymphoid origin. Molecular biological studies using DNA extracted from whole biopsy material provided inconsistent results, probably due to the rarity of the atypical cells in the affected tissue. Hence the molecular biological studies were extended to the analysis of isolated atypical cells. However, even these single cells studies yielded conflicting results. We therefore have improved the technique of single cell isolation from tissue sections and applied it to 25 cases of classical HD and 11 cases of lymphocyte predominant HD (LPHD). We investigated a total of 1,465 single atypical cells for rearranged Ig variable-region chain (V) genes. In all instances in which the single cell DNA lead to a PCR amplification product, these were found to contain identical rearranged V region genes. All of these V region gene sequences proved to be highly mutated. The coding capacity of the rearranged Ig genes was frequently disrupted in classical HD but rarely in LPHD. The V sequences of the latter histotype showed in addition intra-clonal diversity in the majority of patients whereas this was not seen in all but one case of classical HD. Additionally, in 10 to 20% of classical HD cases T-cell antigens and/or cytotoxic molecules could be demonstrated in the atypical cells. These results indicate that, a) the atypical cells of LPHD are a clonal population of neoplastic germinal centre B cells; b) the atypical cells from 80-90% of classical HD cases represent a clonal expansion of B cells which are related to germinal centre B cells or their progeny; and c) the atypical cells of 10-20% of classical HD may originate from T cells.
Antigens, CD↗
Molecular biology of Hodgkin's disease.
The mist surrounding the origin and genesis of HRS cells of classical HD is beginning to dissipate. Molecular biological studies of classical HD at the single cell level strongly suggest that the HRS cells in the majority of cases represent a monoclonal outgrowth of late germinal centre B cells that have lost their capacity to express IG through crippling mutations introduced during the germinal centre reaction. Because of the expression of T cell antigens and/or cytotoxic molecules, the HRS cells of a minority of classical HD cases appear to originate from T cells. Under physiological conditions, B cells that are unable to express IG are eliminated by apoptosis. In most B cell derived classical HD cases, the HRS cells have lost their IG gene coding capacity through mutation and should therefore die of apoptosis. Since this usually does not happen, blockade of the apoptotic pathway may be a major event in the pathogenesis of B cell related classical HD. It is tempting to assume that viruses such as EBV, as well as regulator genes that normally monitor the human genome for damaged DNA, such as TP53, might be involved in the postulated hindrance of the apoptotic pathway, leading to the genesis of classical HRS cells.
Chromosome Aberrations↗
Ig rearrangements in isolated Reed-Sternberg cells: conclusions from four different studies.
The cellular origin and the type of proliferation of the Hodgkin and Reed-Sternberg (HRS) cells, the malignant cells of Hodgkin's disease (HD), is an issue of constant debate. Immunohistochemical and molecularbiological studies of different research groups revealed contradictory results among the different groups ranging from a complete absence to a frequent presence of B-cell or T-cell characteristic features in the HRS cells. The determination of their clonality by cytogenetic means produced no conclusive results. To unequivocally clarify these questions we and others isolated single HRS cells and amplified their immunoglobulin (Ig) rearrangements. Most groups found Ig rearrangements within the HRS cells pointing to a B-cell nature of these HD cases. Individual IgH rearrangements were found in a proportion of the HD cases whereas most cases harbor monoclonal HRS cells with or without additional polyclonal rearranged HRS cells. Further studies are needed to clarify whether the differences among the different groups are caused by the selection of the HD cases used for investigation.
Gene Rearrangement↗
Lymphocyte predominant Hodgkin's disease--a workshop report. European Task Force on Lymphoma.
Since lymphocyte predominant Hodgkin's disease (LPHD) may comprise more than one entity, diagnostic criteria, clinical features, and treatment strategies are still being controversially discussed. Thus, in December 1994 a multinational project on lymphocyte predominant Hodgkin's disease was initiated by the European Task Force on Lymphoma. This project is aimed at clarifying the clinical and histopathological spectrum of LPHD, as well as its relation to T-cell- rich B-cell lymphoma and classical types of HD. 525 paraffin blocks and clinical data of 478 patients from 16 international centres were submitted. At the Third International Symposium on Hodgkin's Lymphoma in Cologne, 232 of these cases were discussed by an expert panel. The preliminary results are presented here. Most cases of LPHD were reclassified into nodular paragranuloma (NP) and lymphocyte rich classical HD. In both groups, a considerable number of cases with atypical features was observed. Few cases of NHL were found among the cohort. LPHD was generally treated according to common standards for HD. The whole group of LPHD did not have a better prognosis than NS; whereas early stage NP did perform better than early stage NS (data from the German Hodgkin's Lymphoma Study Group). There is however a striking discrepancy between good survival and the frequent relapses observed in NP which needs to be elucidated.
Hodgkin Disease↗
Cutaneous aggressive osteoblastoma.
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Adult↗
Burkitt's lymphomas express VH genes with a moderate number of antigen-selected somatic mutations.
The normal counterpart of the neoplastic B cells occurring in Burkitt's lymphomas (BL) is an issue of controversial debate. To clarify this matter, a semi-nested primer polymerase chain reaction was performed to amplify the VDJ rearrangements of the immunoglobulin heavy chain (VH) gene of DNA extracts from 10 (8 sporadic and 2 endemic) BL cases. The resulting amplificates were sequenced for comparison with known germ line VH segments. The control cases comprised six cases of B cell chronic lymphocytic leukemia and six cases of mantle cell lymphoma known to display naive nonmutated, ie, pre-germinal center VH configurations; and eight cases of follicular center lymphoma known to display mutated VH genes with signs of a still-ongoing mutation reaction, characteristic for germinal center cells and lymphomas that derive therefrom. The results of this approach revealed that both sporadic and endemic BL express mutated VH genes with a mutation frequency considerably lower (4.9% and 5.4%, respectively) than that observed in follicular center lymphoma (11.8%). In addition, after subcloning the amplificates, sequence analysis revealed no signs of ongoing mutations. These results led us to conclude that the derivation of neoplastic B cells in BL is definitely not from naive, nonmutated pre-germinal center B cells. Instead, our findings support the view that BL cells stem either from early centroblasts that are arrested after an initial hypermutation reaction, or from germinal center B cells that have differentiated in terms of surface immunoglobulin profile and mutation pattern but not in terms of morphology and proliferation toward SIgM+ IgD- memory B cells because of the deregulated c-myc gene expression.
Burkitt Lymphoma↗
Focal lymphocytic aggregates in chronic hepatitis C: occurrence, immunohistochemical characterization, and relation to markers of autoimmunity.
Intrahepatic lymphocytic aggregates are observed in chronic hepatitis C as well as in autoimmune chronic hepatitis. Autoantibodies and autoimmune manifestations may occur in hepatitis C. It has been suggested that the lymphocytic aggregates play a role in the liver injury of chronic hepatitis C by an immune-mediated mechanism. We studied the occurrence of intrahepatic lymphocytic aggregates and of autoantibodies in a consecutive series of 128 patients with chronic hepatitis C. For the phenotypic characterization of the lymphocytic aggregates cryostat sections and microwaved paraffin embedded sections were immunostained with monoclonal antibodies directed against T cell subsets, B cells, killer/natural killer cells, follicular dendritic cells, and macrophages. Autoantibodies were tested by immunofluorescence (antinuclear, anti-smooth muscle, antimitochondrial) and by enzyme-linked immunosorbent assay (anti-soluble liver antigen, anti-liver/kidney microsome, anti-human receptor for asialoglycoprotein). Focal lymphocytic aggregates in portal tracts were observed in 76 of 128 (59%) patients. The cellular composition of the aggregates was constant: a core of B cells mixed with many T helper/inducer lymphocytes, and an outer ring was prominently formed by T suppressor/cytotoxic lymphocytes. A germinal center was rarely identifiable. The presence of lymphocytic aggregates was inversely correlated with the degree of fibrosis. Lymphocytic aggregates appeared more frequently in chronic persistent and chronic active hepatitis in comparison with cirrhosis and in the presence of bile duct damage. No correlation was found between lymphocytic aggregates and autoantibodies or other markers of autoimmunity. The lymphocytic aggregates are frequent in chronic hepatitis C. Their cellular composition is similar to that of primary lymphoid follicles in lymph nodes. Their presence does not seem to be correlated with features of autoimmunity.
Adult↗
Lectin histochemistry of human meningiomas.
The lectins Peanut agglutinin (PNA), Canavalia ensiformis (Con A), Ulex europaeus-1 (UEA-1), Dolichos biflorus (DBA), Triticum vulgaris (WGA) were studied in a series of 36 meningiomas (16 meningotheliomatous-including 3 recurrences, 7 transitional, 4 angiomatous, 2 "hemangiopericytic", 3 papillary-including 1 recurrence, 4 anaplastic-including 3 recurrences. PNA binds to all cases of meningotheliomatous, transitional, papillary and anaplastic meningiomas (including recurrent cases) but the staining is more intense in tumor cells of anaplastic and papillary type. A semiquantitative study showed differences of PNA-reactivity in the different subtypes of meningiomas. In meningotheliomatous meningiomas PNA-positivity was encountered in numerous neoplastic cells (50%), whereas papillary and anaplastic subtypes expressed strong cytoplasmic staining of few tumor cells (< 5%). Con A shows the same pattern of reactivity described for PNA, but more weakly. Our results suggest that PNA is a marker of differentiation in meningiomas rather than malignant transformation and can have prognostic relevance.
Histocytochemistry↗
Solitary eosinophilic granuloma of cerebral lobes. Value of immunohistochemistry for a diagnostic interpretation.
Primary cerebral eosinophilic granuloma is a very rare lesion. In this study we report a further observation of solitary fronto-parietal eosinophilic granuloma in a child of three years. The immunohistochemical pattern, with the strong positivity of the histiocytic cells for PG-M1, an antibody which does not stain the Langerhans cells, suggests the reactive nature of the granulomatous lesion.
Antigens, CD↗
Amyotrophic choreo-acanthocytosis: a neuropathological and immunocytochemical study.
A 47 year old man, one of a sibship affected by amyotrophic choreo-acanthocytosis was studied neuropathologically after some years of clinical observation. Besides the classic optical findings (neuronal loss, astrocytic gliosis and "status spongiosus" in the basal ganglia, namely in the caudate nucleus) a few MEnk+ and NPY+ neurons were observed immunocytochemically in the striatum. In the spinal cord also, while no neuronal loss was perceivable, both mild demyelination and interfibrillary astrocytic hyperplasia of the long tracts were present. On the other hand, microscopic findings of muscle and peripheral nerve showed no differences from what was previously intra-vitam appreciated in the same patient. The neuropathological and immunocytochemical findings of this case are discussed in relation to the differential diagnosis between amyotrophic choreo-acanthocytosis and Huntington's disease.
Atrophy↗