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PubMed1994

Epstein-Barr virus-associated lymphoproliferative disorder of granular lymphocytes presenting initially as cutaneous vasculitis.

Lymphoproliferative disorders of granular lymphocytes (LDGL) represent a family of diseases characterized by persistent granular lymphocytosis with variable prognosis. The Epstein-Barr virus (EBV) has been occasionally linked with the development of LDGL. However, cutaneous manifestations of LDGL have rarely been reported. One patient had cutaneous vasculitis for 10 years before a definite diagnosis of LDGL was made. Chronic EBV infection was documented serologically and EBV DNA was detected in the peripheral blood lymphocytes. EBV RNA was detected in the nuclei of infiltrating lymphoid cells expressing CD43 in a skin biopsy specimen. A cytogenetic study showed clonal chromosomal abnormalities. This is the first report of EBV-associated LDGL of natural killer cells with cutaneous manifestations.

Child↗

PubMed2006

Molecular immunoglobulin/T-cell receptor clonality diagnosis by gene scan in lymphoproliferative disorders.

There remains significant controversy over the techniques used for clonal diagnosis of lymphoproliferative disorders because of questions regarding the sensitivity, specificity and throughput. This has stimulated us to explore the use of gene scan to determine clonality of Immunoglobulin (Ig)/T-cell receptor (TCR) (gamma gene rearrangement in a variety of morphologically, cytochemically, pathologically and immunophenotypically defined precursor B/T-ALL (12 patients), 5 patients with NHL, 10 patients with CLL and a group of reactive lymphocytosis as a reference group (10 subjects). Polymerase chain reaction (PCR) was done for IgH gene (FR3a, FR2b, LJH and JH primers) and for TCR gamma gene and the malignant clone was identified using gene scan (GS) analysis. In the ALL group, monoclonality was detected using GS and using IgH (FR2b) 75% had a clonal band, 63% with IgH (FR3a) and 88% with a combination of FR3a/FR2b. The results of TCR gamma monoclonality were 50% using primer mix I, 25% using primer mix II and 75% using a combination. In the CLL group, clonal IgH gene rearrangement was detected by FR2b in 80% of cases, while by FR3a clonal rearrangement was detected in 60%, the combination of FR2b and FR3a increased the detection rate to 90%. In B-cell NHL, the FR2b was clonally rearranged in 50% while FR3 was positive in 25%. In reactive lymphocytosis, all cases revealed polyclonal rearrangement with TCR gamma primers. The sensitivity and positive predictive value of GS was 100% and the specificity and negative predictive value was 86.6%. In conclusion, gene scanning provides a sensitive and specific method for detection of the malignant clone in PCR product in patients with lymphoproliferative disorders.

Electrophoresis, Capillary↗

PubMed2006

CD30+ lymphoproliferative disorders: histopathology, differential diagnosis, new variants, and simulators.

CD30+ lymphoproliferative disorders of the skin (CD30+ LPD) represent a well-defined spectrum of primary cutaneous T-cell lymphomas which have been recognized as distinct entities in recent lymphoma classifications. Lymphomatoid papulosis and anaplastic large-cell lymphoma share the expression of CD30 antigen as a common phenotypic hallmark but differ in regard to their clinical and histologic features as well as their biologic behavior. This article summarizes the histologic features of CD30+ LPD and presents recently identified new clinicopathologic variants of CD30+ LPD. There is an increasing number of reactive inflammatory disorders and neoplastic diseases which are composed of or contain a significant number of CD30+ cells and mimic LyP or anaplastic large cell lymphoma clinically or histologically. Differential diagnostic considerations focus on other lymphoproliferative processes with CD30+ tumor cells as well as non-lymphoid neoplasms and inflammatory simulators. The term CD30+ pseudolymphoma is proposed to designate inflammatory processes with CD30+ T cells. The final diagnosis of CD30+ LPD is based on a synthesis of clinical, histologic, phenotypic, and molecular genetic findings.

Biomarkers, Tumor↗

PubMed2001

Chorioretinal post-transplant lymphoproliferative disorder induced by the Epstein-Barr virus.

BACKGROUND: The Epstein-Barr virus (EBV) is responsible for the lymphoproliferative disorders observed in transplanted patients. METHODS: The case history is described of a 59 year old man with a chorioretinal lesion who had received a single lung transplant and was on immunosuppressive treatment. Immunoglobulin gene rearrangement and EBV detection by polymerase chain reaction (PCR) with semiquantification were used on the vitreous material. RESULTS: A proliferation of B lymphocytes with a monoclonal subpopulation was found by PCR on the vitreous sample. The large amounts of EBV genomes found in the vitreous suggest that EBV was the cause of the lymphoproliferation. Healing of the lesion was achieved by a decrease in immunosuppressive treatment and the use of nucleotide analogues. CONCLUSION: The diagnosis of ocular post-transplant lymphoproliferative disorder (PTLD) can be made by PCR on vitreous material. Early diagnosis and treatment can lead to regression of limited monoclonal lesions.

Choroid Diseases↗

PubMed2004

T-bet, a T-cell-associated transcription factor, is expressed in a subset of B-cell lymphoproliferative disorders.

T-bet, a T-box transcription factor, is expressed in CD4+ T lymphocytes committed to Th1 T-cell development and in a subset of T-cell non-Hodgkin lymphomas. Recent evidence indicates that T-bet also is expressed in B lymphocytes and might participate in immunoglobulin class switching. We examined T-bet expression in 116 cases of B-cell lymphoproliferative disorders by immunostaining and found that T-bet was expressed consistently in precursor B-cell lymphoblastic leukemia/lymphoblastic lymphoma (14/14 cases) in contrast with precursor T-cell lymphoblastic leukemia/lymphoblastic lymphoma, which is consistently T-bet- (13 cases), as previously reported. T-bet is expressed in memory B cell-derived neoplasms (chronic lymphocytic leukemia, marginal zone lymphoma, hairy cell leukemia; 35/42 cases) but not in cases of mantle cell, follicular, and large cell lymphoma (43 cases). Expression of T-bet in precursor B-cell lymphoblastic leukemia/lymphoblastic lymphoma was confirmed by Western blot analysis. The expression of T-bet in a significant subset of B-cell lymphoproliferative disorders but not in the vast majority of reactive B cells suggests it might have a role in the oncogenesis of T-bet+ B-cell neoplasms. In addition, T-bet should serve as a useful new marker for the diagnosis and subtyping of B-cell lymphoproliferative disorders.

Animals↗

PubMed2005

The CD45 isoform B220 identifies select subsets of human B cells and B-cell lymphoproliferative disorders.

The B220 isoform of CD45, a pan B-cell marker in mice, is expressed by only a subset of human B cells that do not express the memory B-cell marker CD27, suggesting that it is a differentiation-specific isoform of CD45. We examined normal human peripheral blood B cells, secondary lymphoid tissue, and a range of human B-cell lymphoproliferative disorders for the expression of B220 by flow cytometric immunophenotyping and immunohistochemical staining. We found that a subset of human B cells in peripheral blood is positive for B220 by flow cytometric immunophenotypic analysis. In reactive lymphoid tissues, B220 is expressed by B cells occupying the mantle zones and by a subpopulation of germinal center cells, but, in contrast, marginal zone B cells in the spleen do not express B220. Of 94 cases of B-cell lymphoproliferative disorders, 33 (35%) were positive for B220 by flow cytometric immunophenotypic analysis, including most cases of marginal zone lymphoma, follicular lymphoma, and lymphoplasmacytic lymphoma. In contrast, all cases of precursor B lymphoblastic leukemia/lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma were negative for B220. Immunohistochemical staining for B220 correlated with flow cytometric analysis for all cases studied by both methods. Our data demonstrate that B220 is expressed in a select subset of normal, reactive B cells in a pattern that is consistent with a marker of naive B cells. However, this restricted expression pattern is not seen in B-cell lymphoproliferative disorders. Discordance between the B220 expression patterns of normal mantle and marginal zone B cells and their respective neoplastic counterparts may aid in the distinction between normal and neoplastic proliferations at these anatomical sites.

B-Lymphocytes↗

PubMed1998

Cutaneous CD30+ lymphoproliferative disorders: expression of bcl-2 and proteins of the tumor necrosis factor receptor superfamily.

The spectrum of CD30+ cutaneous lymphoproliferative disorders is characterized by the histology of a high-grade lymphoma but frequent clinical regression of skin lesions in lymphomatoid papulosis (LyP) and occasional regression in CD30+ large cell lymphomas (LCLs). A recent study shows that apoptosis may be a significant mechanism of regression of LyP (Arch Dermatol 133:828-833, 1997). Therefore, we studied expression of proteins that induce apoptosis, including CD27, CD40, CD95, and nerve growth factor receptor (NGF-R), as well as anti-apoptotic protein bcl-2 in skin lesions from 25 patients within the spectrum of CD30+ cutaneous lymphoma. Our results show consistent expression of CD95 (APO-1/Fas), but rare or absent expression of CD27, CD40, and NGF-R on tumor cells from both regressing LyP lesions and nonregressing CD30+ lymphomas. Bcl-2 was expressed at low levels in LyP and at high levels in pleomorphic CD30+ lymphomas. These results indicate that, in addition to CD30, CD95 expression is preferentially expressed at high levels in all cutaneous CD30+ lymphomas and suggest that CD95 may play a role in the regression of CD30+ skin lesions. Expression of bcl-2 appears to protect tumor cells from apoptosis in CD30+ lymphoproliferative disorders.

Adult↗

PubMed2002

Infusion of autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication.

Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorders (PTLDs) are a well-recognized complication of immunosuppression in solid organ transplant recipients. The reported therapeutic approaches are frequently complicated by rejection, toxicity, and other infectious pathologies, and overall mortality in patients with unresponsive PTLD remains high. Thus, low-toxicity treatment options or, preferably, some form of prophylactic/preemptive intervention are warranted to improve PTLD outcome in this setting. We assessed whether transfer of EBV-specific cytotoxic T lymphocytes (CTLs) generated in vitro from the peripheral blood of allograft recipients receiving immunosuppression could increase EBV-specific killing in vivo without augmenting the probability of graft rejection. Autologous EBV-specific CTLs were generated for 23 patients who were identified as being at risk of developing PTLD through the finding of elevated EBV DNA load. Of the 23 patients, 7 received 1 to 5 infusions of EBV-specific CTLs. CTL transfer was well tolerated, and none of the patients showed any evidence of rejection. An increase of the EBV-specific cytotoxicity was observed after infusion, notwithstanding continuation of immunosuppressive therapy. EBV DNA levels had a 1.5- to 3-log decrease in 5 patients, whereas in the other 2 graft recipients CTL transfer had no apparent stable effect on EBV load. Our data suggest that the infusion of autologous EBV-specific CTLs obtained from peripheral blood mononuclear cells recovered at the time of viral reactivation is able to augment virus-specific immune response and to reduce viral load in organ transplant recipients. This approach may, therefore, be safely used as prophylaxis of EBV-related lymphoproliferative disorders in these patients, following a strategy of preemptive therapy guided by EBV DNA levels.

CD3 Complex↗

PubMed1994

S-100-positive T-cell lymphoproliferative disorder. A case report and review of the literature.

The authors describe a patient with a S-100-positive T-cell lymphoproliferative disorder, characterized by clinically aggressive behavior, with leukemic dissemination and death within 1 year of the onset of symptoms. The neoplastic cells had abundant amphophilic cytoplasm, suggestive of plasmacytoid differentiation, but demonstrated a mature T-cell immunophenotype characteristic of the suppressor-cytotoxic subset. In addition, the cells expressed the S-100 protein within the cytoplasm. Genotypic studies were performed by Southern blot analysis, which demonstrated beta-chain T-cell receptor gene rearrangement, further confirming the T-cell nature of this disorder. This case had features very similar to those of the seven cases previously reported. It has been proposed that the S-100-positive T-cell lymphoproliferative disorder is a distinctive clinicopathologic entity.

Adult↗

PubMed2004

Post-transplant lymphoproliferative disorder limited to the skin.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a condition affecting immunosuppressed transplant patients and has a variety of clinical presentations. It is rarely found in the skin, and cases of PTLD in the skin are usually linked with lymph node or other organ involvement. METHODS: We report a case of plasmacytoid PTLD that is limited to the skin. A 63-year-old man with a history of cardiac transplant presented with exophytic tumors involving the lower extremity. The diagnosis and classification of the various forms of PTLD are discussed. RESULTS: Histology, immunohistochemical stains, and in situ hybridization revealed an aggressive plasmacytoid tumor that was Epstein-Barr virus positive. The patient's tumors resolved with decreased immunosuppression and localized radiation. CONCLUSION: This case is unusual for several reasons including involvement limited to the skin, presentation 15 years following transplant, and plasmacytoid phenotype of the tumor. This disorder will likely be seen by dermatologists and dermatopathologists with the increasing use of immunosuppressive medications in the dermatologist's patient population.

Epstein-Barr Virus Infections↗

PubMed1999

Low-grade monoclonal Epstein-Barr virus-associated lymphoproliferative disorder of the brain presenting as human immunodeficiency virus-associated encephalopathy in a child with acquired immunodeficiency syndrome.

The association of the Epstein-Barr virus with human immunodeficiency virus-associated primary central nervous system lymphomas is well known. We describe a pediatric patient infected with human immunodeficiency virus who developed a lesion in the central nervous system that appeared to be histologically reactive and that proved to be an Epstein-Barr virus-associated monoclonal B-cell lymphoproliferative disorder by molecular analysis. An 8-year-old girl was diagnosed with vertically transmitted human immunodeficiency virus infection at age 5, for which she was treated empirically with a combination of zidovudine and didanosine. At the age of 7 years, during evaluation for entry into an antiretroviral protocol, a single hypodense frontal lobe lesion was identified by computed tomography. After unsuccessful treatment for presumed toxoplasmosis and progressive neurologic deterioration, a stereotactic brain biopsy was performed. Although the biopsy contained a polymorphic lymphoid infiltrate that appeared to be cytologically reactive, polymerase chain reaction and in situ hybridization studies revealed a monoclonal Epstein-Barr virus-associated B-cell lymphoproliferative disorder, which was reminiscent of polymorphic B-cell hyperplasia observed in the setting of immunosuppression following organ transplantation. Postoperative therapy included steroids and antiretroviral therapy. The lesion decreased slightly in size, and the child's neurologic status was relatively unremarkable for 5 months. Subsequently, she developed cytomegalovirus retinitis, progressive encephalopathy, and died with pancytopenia. This case represents a newly described manifestation of Epstein-Barr virus-associated lymphoproliferative disorder, a diagnosis that should be considered in patients with neurologic symptoms and immunodeficiency. In addition, this case exhibited histologic features reminiscent of posttransplant lymphoproliferative disease, a histologic pattern that to our knowledge has not previously been reported in the setting of acquired immunodeficiency syndrome.

AIDS Dementia Complex↗

PubMed1997

Lymphoproliferative disorders associated with congenital immunodeficiencies.

This report reviews the clinicopathologic, immunologic, and molecular biological features of the congenital immunodeficiencies and their associated lymphoproliferative disorders (LPD) including cases presented at the Third Slide Workshop of the Society of Hematopathology, held in Duarte California, in October 1995. The congenital immunodeficiencies most commonly associated with LPD include Wiskott-Aldrich syndrome (WAS), common variable immunodeficiency (CVID), ataxia telangiectasia (AT), severe combined immunodeficiency (SCID), X-linked lymphoproliferative disorder (XLP), and hyper-IgM syndrome. Each form of immunodeficiency disorder is associated with its own risk factors, which affect the pattern of LPD encountered. AT is characterized by a defect in DNA repair. The lymphomas and leukemias in this syndrome resemble those seen in sporadic LPD, but tend to occur at an earlier age. Epstein-Barr virus (EBV) plays an important role in the LPD associated with many immunodeficiency disorders including WAS, CVID, SCID, and XLP. One should use a combination of clinical, histopathologic and molecular data in the evaluation of lymphoproliferative lesions in this group of patients. Immunophenotypic and molecular evidence of clonality does not necessarily imply an aggressive clinical course, an exemplified by some LPD in WAS, which may show evidence of monoclonality in serum and lymph nodes, and yet still behave in a benign or indolent fashion.

Humans↗

PubMed1993

Detection of Epstein-Barr virus DNA in sequential renal transplant biopsy specimens using the polymerase chain reaction. Report of a patient with a posttransplant lymphoproliferative disorder.

The polymerase chain reaction was used to retrospectively examine frozen and paraffin-embedded tissue from four sequential renal biopsy specimens, a pretransplant skin biopsy specimen, a postauricular lymph node, and an allograft nephrectomy specimen for the presence of Epstein-Barr virus (EBV) DNA in a 29-year-old man who developed diffuse lymphadenopathy 2 months after a cadaveric renal transplant. The EBV primers used amplify a 245-base pair fragment of the EBV IR3 sequence and were run in parallel with a pair of human beta-globin gene primers as positive DNA integrity controls. Epstein-Barr virus DNA was detected in three of the four renal allograft biopsy specimens, the post-auricular lymph node, and the renal allograft nephrectomy specimen. Initial detection occurred 34 days posttransplant and 23 days prior to the diagnosis of posttransplant lymphoproliferative disorder. Examination of a skin biopsy specimen obtained prior to transplantation and of the initial posttransplant renal allograft biopsy specimen 15 days posttransplant did not demonstrate EBV DNA. The findings of serologic studies performed at the time of diagnosis of the posttransplant lymphoproliferative disorder suggested a remote EBV infection. These results further demonstrate the association of EBV with posttransplant lymphoproliferative disorder and suggest a possible role for polymerase chain reaction in the early detection of EBV in transplant patients. Larger retrospective studies are needed to determine the prognostic significance of EBV DNA found in routine renal allograft biopsy specimens.

Adult↗

PubMed1992

B-cell lymphoproliferative disorders in solid-organ transplant patients: detection of Epstein-Barr virus by in situ hybridization.

B-cell lymphoproliferative disorders (BLPDs) occur in approximately 2% of transplant recipients and are frequently fatal. Indirect serologic evidence has implicated Epstein-Barr virus (EBV) as an etiologic factor in these lesions. Direct evidence of the presence of EBV in these lesions has been obtained in relatively few cases. We used in situ hybridization (ISH) with a probe for the BamHI-W region of the EBV genome to study 52 tissue specimens from 28 solid-organ transplant patients who had BLPD. Epstein-Barr virus-infected lymphoid cells were identified in 26 of these 28 patients. The two patients without ISH evidence of EBV infection showed no distinctive clinical, morphologic, or serologic features. Previous filter-hybridization studies of these two patients had demonstrated evidence of EBV infection. Seven additional transplant patients without evidence of BLPD were studied as controls and showed no evidence of EBV in their lymphoid cells by ISH. These data provide further support for the etiologic role of EBV in the pathogenesis of posttransplantation lymphoproliferative disorders.

Adolescent↗

PubMed2002

Post-transplant lymphoproliferative disorders: improved outcome after clinico-pathologically tailored treatment.

BACKGROUND AND OBJECTIVES: Clinical and pathologic variability of post-transplant lymphoproliferative disorders (PTLDs), their aggressive behavior and the recognized therapy-related toxicity make management of patients with these disorders difficult. Assessment of first-line treatment and identification of prognostic factors need to be better defined. DESIGN AND METHODS: Data on 40 PTLDs which developed in adult solid organ recipients were analyzed in order to evaluate clinical and pathologic features, response to treatment and prognostic factors. Data were collected retrospectively between 1989 and 1996; since 1997 a prospective study has been activated. RESULTS: The median time from transplant to PTLD was 56 months. Regarding histologic features, plasmacytic hyperplasia was diagnosed in 5 patients (12.5%), polymorphic lymphoproliferative disorders in 3 (7.5%), malignant lymphoma in 32 (80%). The diagnosis was made at autopsy in eight patients (20%). Late-onset PTLDs (>12 months from transplant) occurred in 33 patients (83%), EBV-negative forms in 12 (31%). Relevant differences have been observed between EBV-positive and EBV-negative forms. Twenty-nine patients completed their scheduled treatment and are evaluable for outcome. The cumulative probability of survival at 1 year is 57% (CI 37.6-73.4) and the median survival time of the entire group has not been reached at 54 months. Clinical stage, performance status, lactate dehydrogenase and number of sites are predictive factors for survival. The International Prognostic Index and the PTLD index are able to identify different risk groups. INTERPRETATION AND CONCLUSIONS: Although rare, PTLDs are a significant cause of mortality in allograft recipients. Therapy tailored on histologic and clinical features of PTLD is feasible and is able to give long-lasting complete responses.

Adult↗

PubMed2005

Fulminant Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disorder with hemophagocytosis following autologous peripheral blood stem cell transplantation for relapsed angioimmunoblastic T-cell lymphoma.

Post-transplant lymphoproliferative disorder (PTLD) is a complication that can develop after either solid-organ or hematopoietic stem cell transplantation (HSCT). T-cell PTLD is a rare disorder, especially following autologous HSCT. Here we report a case of T-cell PTLD which occurred after autologous peripheral blood stem cell transplantation (PBSCT) for relapsed angioimmunoblastic T-cell lymphoma (AILT). Three months after the transplant, the patient developed fever with elevated plasma Epstein-Barr virus (EBV)-PCR values. The patient subsequently developed pneumonitis, hepatomegaly and marked pancytopenia due to hemophagocytosis. The patient died of multi-organ failure, despite antiviral and steroid pulse therapy. Our post-mortem study confirmed the marked proliferation of EBV-infected T-cells that differed from the original AILT clone and macrophages/histiocytes were observed in the marrow, liver, lymph nodes and lungs. Phagocytosis was most evident in the bone marrow. The patient's AILT remained in complete remission. To the best of our knowledge, this is the first case of fulminant EBV-associated T-cell lymphoproliferative disorder (LPD) following autologous HSCT.

Antigens, CD↗

PubMed2005

Post-transplantation lymphoproliferative disorder: the spectrum of imaging appearances.

Post-transplantation lymphoproliferative disorder (PTLD) is a serious complication of chronic immunosuppression following solid organ transplantation. Clinical presentation is non-specific and almost any organ can be affected. Early diagnosis is associated with a better prognosis but requires tissue sampling to ascertain the histopathological subtype of disease which cannot be predicted on imaging features alone. The radiologist has a key role in detecting the disorder, guiding biopsy and monitoring response to treatment which often only involves a reduction in immunosuppressive therapy. The aim of this paper is to illustrate the wide spectrum of imaging features in PTLD and emphasize the more specific findings which allow the diagnosis to be suggested at an early stage.

Humans↗

PubMed1998

Lymphoproliferative disorders in rheumatoid arthritis patients on low-dose methotrexate.

Methotrexate is the most widely used second-line treatment in rheumatoid arthritis because of its excellent efficacy and safety profile. However, since 1991, about 100 cases of lymphoproliferative disorders have been reported in rheumatoid arthritis patients under methotrexate therapy. Four characteristics similar to those in lymphomas associated with immunodeficiency were identified during a review of the 48 cases for which detailed information is available. (1) Most cases were non-Hodgkin's B-cell lymphomas of the large cell or diffuse mixed type. (2) Extranodal involvement (55% of cases) was unusually common. (3) Evidence of Epstein-Barr infection was found in 46% of tested patients. (4) Of the 14 patients treated by methotrexate withdrawal alone, eight achieved a full remission, with follow-ups ranging from one to five years. These characteristics suggest a role for two factors: (1) the abnormalities in cell-mediated immunity seen in rheumatoid arthritis may promote latent Epstein-Barr virus infection, which may in turn lead to proliferation of malignant lymphoid cells; (2) the immunomodulatory effects of methotrexate may promote the development not only of opportunistic infections but also of Epstein-Barr virus-related lymphoproliferative disorders. There is no firm evidence to date that methotrexate has a direct oncogenic effect and no excess in malignant diseases has been reported with this drug. In conclusion, the rate of occurrence of lymphoproliferative disorders induced by low-dose methotrexate therapy remains controversial, although the characteristics of the malignancies and the possibility of a complete remission after methotrexate withdrawal militate against a chance association. Epidemiologic and other studies are needed to clarify this issue.

Adolescent↗