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PubMed2006

Impact of Epstein-Barr virus in monomorphic B-cell posttransplant lymphoproliferative disorders: a histogenetic study.

The heterogeneity of the posttransplant lymphoproliferative disorders (PTLDs) is well recognized. However, in contrast to other immunodeficiency-associated lymphomas or diffuse large B-cell lymphomas in general, studies of the histogenetic spectrum of the large category of monomorphic B-cell cases have been more limited, produced conflicting results, and have paid little attention to the impact of Epstein-Barr virus (EBV). Therefore, 30 monomorphic B-cell PTLD from 27 patients were analyzed using EBER in situ hybridization for EBV and a panel of antibodies directed against CD20, CD3/bcl-6, CD10, MUM-1/IRF4, CD138, and bcl-2. The results were correlated with the histopathologic features and clinical outcome. All PTLD were CD20 with 23% CD10, 53% bcl-6, 67% MUM-1/IRF4, 13% CD138, 83% bcl-2 and 67% EBV. 30% of the PTLD had a germinal center (GC) profile (CD10, bcl-6, MUM-1/IRF4, CD138), 53% a "late GC/early post-GC" profile (CD10, bcl-6, MUM-1/IRF4, CD138), 13% a post-GC profile (CD10, bcl-6, MUM-1/IRF4, CD138) and 3% an indeterminate profile (all markers negative). EBV positivity was associated with MUM-1/IRF4 expression (P=0.005) and with a non-GC phenotype (P=0.01). All CD138 cases were EBV. The cases with a GC phenotype were the most likely to resemble transformed GC cells (P=0.023). No statistically significant survival differences could be documented between those with a GC versus non-GC phenotype. These results highlight the broad histogenetic spectrum of monomorphic B-cell PTLD. They demonstrate the association of EBV positivity with a non-GC phenotype and suggest that EBV PTLD are more like lymphomas that arise in immunocompetent individuals. The lack of a demonstrable correlation with survival may relate to the relatively small number of cases studied.

Adult↗

PubMed1988

The interleukin-2 receptor and its expression in the acute leukaemias and lymphoproliferative disorders.

The expression of the interleukin-2 receptor (IL-2R) was investigated in a total of 117 cases of acute leukaemia and lymphoproliferative disorder. The results confirm reports that the interleukin-2 receptor can be expressed on cells of myeloid lineage and in cases of Hairy Cell Leukaemia. They extend knowledge of the expression of the IL-2R in cases of lymphoproliferative disorders.

Acute Disease↗

PubMed1999

Posttransplantation lymphoproliferative disorder in liver recipients: characteristics, management, and outcome.

Posttransplantation lymphoproliferative disorder (PTLD) is a well-recognized complication of organ transplantation. The aim of this study, performed over 9 years, was to examine the histopathological findings, clinical course, and outcome of patients who, having undergone orthotopic liver transplantation (OLT), developed PTLD. The sample included 7 adult liver allograft recipients (1.7%), 4 men and 3 women, with a mean age of 53 years (range, 40 to 61 years) who developed PTLD 1 to 36 months post-OLT (mean, 6 months). Four patients received either antithymocyte globulin as primary immunosuppression or OKT3 for steroid-resistant cellular rejection. Four patients had localized hepatic tumor with or without regional lymph node involvement, 2 patients had extralymphoreticular disease (head of pancreas and chest wall), and 1 patient had spleen and lymph node involvement. All tumors were B-cell lymphomas; three polymorphic and four monomorphic. Clonality was assessed by immunostaining for kappa and lambda and gene rearrangement. Monoclonality was found in 4 patients and polyclonality in 2 (1 of whom progressed to monoclonality); in 2 patients, clonality could not be determined. Immunohistochemistry findings for the presence of the Epstein-Barr virus (EBV)-determined nuclear antigen and the latent membrane protein 1 were noted in lymphoma tissue in 6 patients. Immunosuppressive therapy was decreased in all patients. Polyclonal tumors were treated with acyclovir (1 patient is in complete remission and 1 patient died), and monoclonal tumors with systemic chemotherapy (2 patients are in complete remission and 2 patients died). One patient was treated with monoclonal antibodies (CD20) but failed to respond, and 1 patient was treated with excision and is in complete remission. The mortality rate was 43%; for the remainder, median survival is 21 months (range, 10 to 42 months). We conclude that PTLD may re-present early after OLT. EBV has a special role in the pathogenesis, combined with immunosuppressive therapy. The outcome is poor, and new therapeutic approaches are needed.

Adult↗

PubMed1981

Increased bone marrow mast cells in preleukemic syndromes, acute leukemia, and lymphoproliferative disorders.

Increased numbers of bone marrow mast cells were found in 45 (2.2%) of 2,000 bone marrow specimens obtained from patients who had hematologic disorders. Mast cells were most frequently seen in the marrows of patients who had preleukemic syndromes, lymphoproliferative disorders, and acute leukemia. The 16 patients who had preleukemic syndromes included those with refractory sideroblastic and megaloblastic anemia (with or without an excess of blasts), idiopathic pancytopenia or pure erythrocytic aplasia, paroxysmal nocturnal hemoglobinuria, idiopathic refractory neutropenia, agranulocytosis or thrombocytopenia, and persistent eosinophilia. Five of the seven patients who had acute leukemia had nonlymphoblastic leukemia; two had blastic crisis of chronic granulocytic leukemia. Of the 13 patients who had lymphoproliferative disorders, eight had chronic lymphocytic leukemia, three had macroglobulinemia, and two had non-Hodgkin's lymphoma. Three patients who had chronic renal failure associated with severe anemia and two who had chronic liver disease, splenomegaly, or hypersplenism were also encountered. In this study there appeared to be a consistent relationship between the presence of increased numbers of mast cells and the lymphocyte and plasma cell counts in the bone marrow. The significance of the presence of secondary mastocytosis in premalignant lesions, neoplasia, and, in particular, lympho- and myeloproliferative disorders, is still unclear.

Acute Disease↗

PubMed1981

Clinical spectrum of lymphoproliferative disorders in renal transplant recipients and evidence for the role of Epstein-Barr virus.

Six renal transplant recipients with abnormal lymphoproliferative disorders were studied in an attempt to define their clinical features and the role of Epstein-Barr virus (EBV) in their pathogenesis. Patients were either teenage (three) or in the sixth decade (three). The younger patients presented an average of 3 months after transplantation with fever, sore throat, and lymphadenopathy; had been markedly immunosuppressed; frequently had preceding or concomitant cytomegalovirus infections; and two of three had a rapidly fatal course. The older patients presented an average of 5 years after transplantation while on maintenance immunosuppressive drugs; in two of three cases with an oropharyngeal tumor; and had a more indolent, but frequently fatal, clinical course. The most frequent sites of biopsy-proven involvement in these patients were lymph nodes (three), the oropharynx (three), liver (three), bone marrow (three), transplanted kidney (three), colon (two), and central nervous system (two). EBV-specific antibody titers including anti-viral capsid antigen IgG, anti-viral capsid antigen IgM, anti-early antigen, and anti-Epstein-Barr nuclear antigen were serially measured in all patients. Four patients demonstrated serological evidence of a primary (one) or reactivation (three) EBV infection. No patient had significant changes in anti-early antigen or anti-Epstein-Barr nuclear antigen titers. All three patients tested for oropharyngeal shedding of EBV were positive. A touch imprint of one tumor was stained for the presence of Epstein-Barr nuclear antigen, and a majority of cells were positive. EBV complementary RNA/DNA filter hybridization and/or viral DNA/DNA reassociation analysis performed on tumor biopsy specimens in five patients demonstrated multiple EBV genome equivalents per cell in all eight specimens tested. Clinical, pathological, serological, and molecular hybridization studies provide substantial evidence that EBV was the cause of these lymphoproliferative disorders occurring after renal transplantation. Impaired host defenses allow the EBV-transformed B-lymphocytes to escape normal control mechanisms. This impairment is invariable and influenced by many factors resulting in the observed spectrum of disease. Cytogenetic changes, however, may also be important.

Adolescent↗

PubMed1996

Detection of clonal immunoglobulin heavy-chain gene rearrangements in cases of suspected lymphoproliferative disorders: comparison of polymerase chain reaction and Southern blot analysis.

Demonstration of clonality is supportive of a diagnosis of malignancy in cases of lymphoproliferative disorders. Determination of clonality at the molecular level is currently accomplished by Southern analysis; however, the polymerase chain reaction offers a potential alternative that is rapid, simple, and less expensive. To test its feasibility as a diagnostic test, we amplified the DNA from 121 suspected lymphoproliferative disorders submitted for gene rearrangement studies. In comparison to Southern analyses, a sensitivity of 70% and specificity of 96% were obtained. To test the effect of primer variability in the joining region of the heavy-chain gene, we substituted a more degenerate primer but found no changes in sensitivity or specificity. We conclude that the polymerase chain reaction has current application with minute or fixed specimens and may generally serve as a rapid, initial evaluation for B-cell clonality, followed by Southern analysis in negative cases. However, higher overall sensitivity must be achieved before this technique can replace Southern analysis as the method of choice in determining clonal gene rearrangements.

Base Sequence↗

PubMed1984

Systemic lymphoproliferative disorder with morphologic features of Castleman's disease. Immunoperoxidase study of cytoplasmic immunoglobulins.

Lymph node biopsy specimens from nine patients with a systemic lymphoproliferative disorder morphologically resembling Castleman's disease were studied for the presence of cytoplasmic immunoglobulins. After trypsinization of tissue sections, the avidin-biotin-peroxidase method was used to stain for IgG, IgA, and IgM heavy chains and kappa and lambda light chains. All cases showed polyclonal proliferation of plasma cells. The predominant immunoglobulin class observed was IgG. The IgM-containing cells tended to be localized concentrically around germinal centers. No notable changes were seen in multiple biopsy specimens from five patients. Polyclonal staining was also observed in lymph nodes obtained at autopsy from a patient who died of a disseminated atypical immunoproliferative process. The polyclonal staining pattern in these cases confirms the reactive nature of this systemic lymphoproliferative disorder.

Adult↗

PubMed2005

Immunophenotyping of lymphoproliferative disorders: state of the art.

Immunophenotyping was introduced into diagnostic pathology over 30 years ago to assist in the diagnosis and classification of lymphoproliferative disorders. Today the role of immunophenotyping has been expanded beyond this to include the detection of markers of prognosis, determination of disease phenotypes associated with specific chromosomal abnormalities, detection of targets for immunotherapy and to monitor residual disease. Immunoperoxidase detection methods remain the most popular in histopathology, whilst flow cytometry is most commonly applied for haematological samples. The range of monoclonal antibodies available, including those which work in routinely performed tissue specimens, continues to increase. This is in part a result of gene expression studies identifying precise genetic signatures for certain lymphoproliferative disorders and the generation of new protein markers to gene products of upregulated genes. This review summarises the current status and applications of immunophenotyping in the assessment of many of the lymphoid malignancies.

Flow Cytometry↗

PubMed1999

Epstein Barr virus-associated lymphoproliferative-disorders primarily involving the skin.

In cases of solid organ or bone marrow transplantation, up to 2 to 10% of patients may develop lymphoproliferative disorders (LPD), often induced by Epstein-Barr virus (EBV). Despite a morphology mimicking malignant lymphoma, in some cases the lesions will disappear completely after the degree of immunosuppression is lowered. Lately, similar processes have been described in non-transplant, immunosuppressed patients. A SNOMED search was performed on the database of three hospitals between 1990 and 1997, to identify patients with immunosuppression-related lymphoproliferative disorders (IR-LPD) involving primarily the skin. Two patients were identified. One was 2 years after kidney transplantation, and the other was being treated with methotrexate for dermatomyositis. In both biopsies, there was a diffuse perivascular proliferation of large lymphocytes with ample cytoplasm and pleomorphic nuclei, associated with extensive dermal and subcutaneous necrosis. Immunohistochemical studies revealed expression of CD20, CD45RO, CD43, CD30, EBV-LMP1, and EBV-NA2 by the atypical lymphocytes in both cases and, in one case, of the EBV-transcriptional replication activation protein. In both cases the lesions completely disappeared and have not recurred. Primary involvement of the skin by IR-LPD is very rare. Based on our results, it is possible that some of these cases in the skin contain EBV and co-express CD30 and T- and B-cell markers. The diagnosis of IR-LPD should be considered in cutaneous lymphoid proliferations in immunosuppressed patients. Before rendering an unequivocal diagnosis of malignant lymphoma, reduction of immunosuppression and follow-up of 4-8 weeks should be considered.

Adult↗

PubMed1994

Epstein-Barr virus-associated lymphoproliferative disorders in oral cavity after heart transplantation: report of a case.

Clinical manifestations of Epstein-Barr virus associated with post-heart transplant lymphoproliferative disorders (PTLD) are variable. Over one-half of the PTLD express extranodal presentations, of which gastrointestinal symptoms are the most common. Development of oral ulcers is an extremely rare initial manifestation with only three such cases having been reported. A case of oropharyngeal presentation of PTLD is described here. The clinical presentations and pathologic spectrums of PTLD are discussed. Posttransplant lymphoproliferative disorders are considered to be iatrogenic and life-threatening and are associated with immunosuppressive agents and Epstein-Barr virus infection. Early diagnosis and appropriate management could prevent the fatal progression of such disorders. The need to analyse tumor clonality along with observation of clinical presentations and microscopic pathology in order to diagnose PTLD is discussed.

Adolescent↗

PubMed1998

Simian-virus-40 footprints in human lymphoproliferative disorders of HIV- and HIV+ patients.

SV40 sequences were investigated by PCR DNA amplification followed by filter hybridization in a series of human lymphoproliferative disorders obtained from human-immunodeficiency-virus (HIV)-seronegative and HIV-infected patients. Our PCR and filter-hybridization conditions enabled us to detect SV40 sequences in the range of 10(-4) to 10(-2) genome equivalents per cell. In non-Hodgkin's lymphomas (NHL) from HIV- patients, SV40 footprints were found in 11 out of 79 (13.9%) samples, while in NHL from HIV+ patients SV40 DNA sequences were detected in 2/16 (12.5%). In Hodgkin's disease (HD), SV40 sequences were found in 7/43 (16.3%) and 1/12 (8.3%) in HIV- and HIV+ patients respectively. A slightly higher prevalence of SV40 footprints was observed in reactive lympho-adenopathies both in HIV- (3/9, 33.3%) and in HIV+ (6/17, 35.3%) patients. Sequence analysis of 2 NHL and 2 HD DNA samples established that the amplified PCR products belong to the SV40 sequences. SV40 prevalence and load were similar in samples from HIV-seronegative and HIV-infected individuals, suggesting that SV40 probably does not undergo strong reactivation phenomena in the context of HIV-related immunosuppression. Moreover, the large T-antigen(Tag) expression was detected by immunohistochemistry in 5/18 SV40-DNA-positive samples analyzed; however, few tumor cells (<1%) in 3/5 samples displayed positivity for SV40 Tag, while this viral oncoprotein was revealed in several reactive histiocytes present in all 5 SV40-positive tissues. These results suggest that the lymphoid tissue could represent a reservoir for SV40 and may constitute the first step in understanding whether this DNA tumor polyomavirus has a role in the pathogenesis of human lymphoproliferative disorders.

Antigens, Polyomavirus Transforming↗

PubMed1989

Lymphoproliferative disorders and hematologic malignancies following organ transplantation.

Eleven allograft recipients (one cardiac, one hepatic, nine renal) at the Massachusetts General Hospital developed a lymphoproliferative disorder or leukemia. Six (all renal) patients received conventional immunosuppressive therapy (CIT), four received cyclosporin A (CsA) (one cardiac, one hepatic, two renal), and one received CIT for his first transplant and CsA for his second transplant (both renal). The interval from transplant to onset of the hematologic disorder ranged from 2 mo to 3 yr in the CsA group and from 6 mo to 9 yr in the CIT group and was 16 yr in the patient with two allografts. There were eight malignant lymphomas, seven of which were extranodal, (four immunoblastic, one large noncleaved cell, one small noncleaved cell, one plasmacytoma, one unclassifiable), one case of polymorphic diffuse B cell hyperplasia and two cases of acute myeloid leukemia. Frozen section immunohistochemistry in six cases showed monotypic immunoglobulin in four lymphomas, (including the plasmacytoma), an immunoglobulin-negative B cell phenotype in one lymphoma, and polytypic immunoglobulin in the case of polymorphic hyperplasia. One lymphoma showed a monotypic immunoglobulin-producing B cell population in one site and an immunoglobulin-negative B cell population in another site. With an immunoglobulin heavy chain gene-specific probe, Southern blot analysis of tissue from these two sites revealed two distinct rearrangements. When tissue from a second case of lymphoma was analyzed by Southern blot, identical rearrangements of the heavy chain gene were found in tumor from two separate sites. Similar to the experience of others, we find an increased incidence of lymphoma and a slightly increased incidence of acute myeloid leukemia in allograft recipients. In contrast to other reports, we found a predominance of monoclonal B cell malignancies, a more polymorphous histologic appearance of the lymphoproliferative disorders in CsA patients, and one case each of "multiclonal" and "monoclonal" lymphomas when tumor from separate sites was tested for gene rearrangement.

Adolescent↗

PubMedDate not supplied

Lack of Fas and Fas-L mutations in patients with lymphoproliferative disorders associated with Sjögren's syndrome and type II mixed cryoglobulinemia.

OBJECTIVE: Murine models (MRL/gld/gld mice) and recent evidence in humans suggest a possible role of Fas and Fas ligand (Fas-L) germline mutations in the pathogenesis of autoimmune-related lymphoproliferation, including adult cases. In this study, the presence of Fas and Fas-L germline mutations was investigated in a consecutive series of adult patients with lymphoproliferative disorders occurring in the context of Sjögren's syndrome (SS) and type II mixed cryoglobulinemia (MC). METHODS: 11 patients (8 primary SS and 3 type II MC; F/M: 10/1; mean age 64 yrs.) were investigated. All patients were suffering from atypical lymphoproliferative disorders or MALT lymphoproliferative lesions (mean duration 3.5 yrs.). Four patients later developed a malignant lymphoma. DNA from peripheral blood mononuclear cells from 11 patients and 10 controls was tested for germline mutations in the Fas gene (exons 4, 8 and 9) and Fas-L gene (exon 4) by the polymerase chain reaction-single strand conformation polymorphism (SSCP) method. RESULTS: All DNA samples from both patients and controls showed amplification of Fas and Fas-L specific fragments. Identical SSCP migration patterns were observed in all the cases, indicating the lack of mutations in the whole series. CONCLUSION: Although it cannot be excluded that Fas and Fas-L mutations might be present in exons different from those analyzed, our data do not support the hypothesis that germline mutations in these genes are responsible for a major subset of lymphoproliferative syndromes in adult patients with SS and type II MC. Additional studies would be worthwhile in SLE-related lymphoproliferation, which is, however, a subset of limited clinical relevance when considering all cases with autoimmune-related lymphoproliferation.

Aged↗

PubMed1986

Uracil-DNA glycosylase activity in chronic lymphoproliferative disorders.

The activity of uracil-DNA glycosylase, a repair enzyme for the excision of uracil from DNA, was studied in patients with chronic lymphoproliferative disorders and with malignant plasma cell dyscrasias. The biochemical assay was performed on mononuclear cells, isolated by density gradient centrifugation from peripheral blood, from bone marrow or from both. The activity of the uracil-DNA glycosylase of peripheral blood cells in 8/8 cases of myeloma and in 3/3 cases of Waldenström's macroglobulinemia was in the same range as in 22 non-hematological control patients, i.e. 2.4-25.1 U/mg of protein. Higher activities were found in 9/12 cases of chronic lymphocytic leukemia (CLL), in 2/4 cases of hairy cell leukemia (HCL), in 2/2 cases of chronic T-cell lymphocytosis and in the only case of small cell lymphocytic lymphoma. Follow-up of some CLL and HCL patients revealed that uracil-DNA glycosylase activity was fairly stable during the course of the disease. We conclude that malignant cells in chronic lymphoproliferative disorders are characterized by a normal or even increased capability to repair DNA, as exemplified by uracil-DNA glycosylase in this study.

Adult↗

PubMed1992

Primary immunodeficiency diseases and Epstein-Barr virus-induced lymphoproliferative disorders.

Increased incidence of malignant disorders is noted in patients with both primary and acquired immunodeficiency diseases. The pathogenetic mechanism(s) for these disorders remain unclear. Defective immunosurveillance of these patients, however, is mainly postulated to be responsible for the increased risk of these malignant disorders. Of the malignant disorders, Epstein-Barr virus (EBV)-induced lymphoproliferative disorders (LPD) have been increasingly reported, possibly due to improved therapeutic management techniques such as bone marrow transplantation, which results in prolonged survival periods for the primary immunodeficiency; the dramatic development of immunosuppressive treatments for transplant recipients; and the growing numbers of acquired immunodeficiency syndrome (AIDS) patients. This review focuses on the primary immunodeficiency diseases and EBV-induced LPD, and discusses pathogenetic mechanism(s) for the increased incidence of these malignant disorders.

Adolescent↗

PubMed2000

Longitudinal dynamics of Epstein-Barr virus-specific cytotoxic T lymphocytes during posttransplant lymphoproliferative disorder.

Epstein-Barr virus (EBV)-associated lymphoproliferative disorder (LPD) is a serious complication after allogeneic bone marrow transplantation (BMT). Dynamics of EBV-specific cytotoxic T lymphocytes (CTL), which are important in controlling EBV during the LPD, have not been fully elucidated. A patient with Wiskot-Aldrich's syndrome was diagnosed as suffering from LPD on day 47 after BMT. Fluorescence-activated cell sorter (FACS) analysis for interferon-gamma production revealed that >70% of the patient's CD8(+) T cells were EBV specific. The patient's lymphocytes were directly cytotoxic to donor-derived EBV-positive lymphoblastoid cells, which was blocked by an anti-class I antibody. EBV-specific CD8(+) T cell counts declined in parallel with EBV genome load, and full recovery of LPD was obtained with relaxation of immunosuppressive drugs. The results illustrate longitudinal dynamics of EBV-specific CTL during the posttransplant LPD; they also illustrate the advantages of using FACS analysis for EBV-specific CTL to make decisions about treatment.

Antigens, Surface↗

PubMed2002

Mismatch repair gene expression in malignant lymphoproliferative disorders of B-cell origin.

We investigated mismatch repair (MMR) gene expression in 31 lymphoid tissue specimens and bone marrow aspirates with malignant lymphoproliferative disorders of B-cell origin (25 cases of lymphoma and six cases of plasma cell myeloma). A multiplex RT-PCR assay was employed to assess the relative expression of the hMSH2, hMLH1 and hPMS1 genes, as compared to beta-actin, which was used as an internal control of gene expression. MSH2 was further evaluated at the protein level by immunohistochemistry. The findings were compared to those of a control group of lymphoid tissue specimens without evidence of malignancy (n = 6). Changes in MMR gene expression were observed in 10 out of 31 cases of the study group (32%). All three MMR gene transcripts were low in two out of six plasma cell myelomas, which had extensive bone marrow infiltration by neoplastic cells. The hMSH2 transcript was present in all cases of lymphoma, while the expression of hMLH1 and hPMS1 was significantly low in some large B-cell lymphomas (four and five out of 14 cases, respectively) and in mantle cell lymphomas of the blastoid type (two out of two cases). No MMR gene aberrations were found in seven cases of B-cell lymphocytic leukemia and two cases of mantle cell lymphoma of centrocyte-like type. These findings demonstrate that the expression rates of the hMSH2, hMLH1 and hPMS1 genes differ among various types of B-cell lymphoproliferative disorders, and suggest that MMR gene expression may be related to the natural history of these neoplasms. This study identified a higher incidence of MMR gene aberrations in lymphoma types characterized by aggressive biologic behavior, as compared to neoplasms with a more indolent course.

Adaptor Proteins, Signal Transducing↗

PubMed1984

Lymphoproliferative disorders in cardiac transplant recipients are multiclonal lymphomas.

Tissue specimens from 5 immunosuppressed cardiac transplant recipients with lymphoproliferative disorders were examined for rearrangements in immunoglobulin DNA. In each case DNA analysis of tissues obtained from several sites or at various times showed different clonal immunoglobulin gene rearrangements for each of the three immunoglobulin gene loci. These findings indicate that lymphoproliferative disorders in immunosuppressed cardiac transplant recipients represent multiclonal or oligoclonal B cell lymphomas.

Biopsy↗