EBV-associated Lymphoproliferative Disorders Research Articles

Clinical Features and Risk Factors of Pure Red Cell Aplasia Following Major ABO-Incompatible Allogeneic Hematopoietic Stem Cell Transplantation.

Objective:To study the incidence, risk factors, clinical outcome, management and prevention of pure red cell aplasia (PRCA) following major ABO-incompatible allogeneic hematopoietic stem cell transplantation (allo-HSCT).Method:We retrospectively analyzed 11 cases of PRCA from a series of 42 patients undergoing major ABO-incompatible allo-HSCT from April, 1997 to December, 2005.Results:1. 11 out of the 42 patients developed PRCA (26.1%); 2. All the 11 cases of PRCA were in blood group O recipients of grafts from blood group A donor (n=9) or blood group B donor (n=2). 3. The following factors were associated with an increased risk of PRCA:(1) blood group O recipient;(2) blood group A donor;(3) blood group O/A in recipient/donor pair;4. Only blood group O/A in recipient/donor pair was identified as being significantly associated with the occurrence of PRCA by multivariate analysis (P=0.006); 5. 6 patients who received donor-type plasma exchange did not develop PRCA, and among them, 5 cases were the O blood group recipients. 8 patients obtained spontaneous remission and in the remaining 3 patients, 2 patients with long-lasting PRCA were successfully treated with plasma exchange with donor-type plasma replacement and the other one who was also complicated by EBV-associated lymphoproliferative disorder (EBV-PTLD) responded rapidly to anti-CD20 monoclonal antibody and achieved complete resolution of clinical finding and symptom of both EBV-PTLD and PRCA.Conclusions:The incidence of PRCA in this series of patients was 26.1%. Only blood group A/O in donor/recipient pair is identified as being significantly associated with the occurrence of PRCA by multivariate analysis. Donor-type plasma exchange is an effective approach for the treatment and prophylaxis of PRCA. Anti-CD20 monoclonal antibody is indicated for patients who are not response to conventional therapy.

Successful In Vitro Priming of EBV-Specific CD8+ T Cells Endowed with Strong Cytotoxic Function from T Cells of EBV-Seronegative Children

Epstein-Barr virus (EBV)-seronegative transplant recipients are at high risk of developing EBV-associated post-transplant lymphoproliferative disorder (PTLD), and would maximally benefit from an EBV-directed T-cell therapy for prevention or treatment of PTLD. So far, efforts to activate CD8+ EBV-specific cytotoxic T lymphocytes (CTL) endowed with high specific cytotoxicity from EBV-seronegative children have failed. We compared the CD8+ CTL priming efficiency of three different modified activation protocols, based on lymphoblastoid cell lines (LCL) stimulation potentially enhanced by either LCL presentation through dendritic cells, or selection of IFN-gamma+ cultured cells, or culture in the presence of rhIL-12 and rhIL-7, according to the standard protocol for reactivation of EBV-specific CTL. We found that only specific LCL stimulation in the presence of rhIL-12 and rhIL-7 was able to reproducibly expand EBV-specific CD8+ CTL endowed with strong cytotoxic activity from truly EBV-seronegative children. The lines thus activated, which included specificities toward EBV latent and lytic proteins, showed high percentage CD8+ T cells, with <10% naïve CD8+/CCR7+/CD45RA+ cells. Overall, the total number of CD8+ central memory cells, and of CCR7 T-cell effectors was comparable to that observed in healthy EBV-seropositive controls. In conclusion, it is feasible to activate EBV-specific CD8+ CTL with suitable characteristics for in vivo employment from EBV-seronegative children.

EBV-associated post-transplantation lymphoproliferative disorders; a report of three cases in autologous HSCT patients of T cell lymphoma

EBV-associated post-transplantation lymphoproliferative disorders; a report of three cases in autologous HSCT patients of T cell lymphoma

Senile Epstein-Barr Virus-Associated B-Cell Lymphoproliferative Disorders: a Mini Review

Epstein-Barr virus (EBV) is associated with a number of malignant lymphomas, including Burkitt lymphomas, Hodgkin lymphomas (HLS), immunodeficiency-associated lymphoproliferative disorders (LPDs), and subset of diffuse large B-cell lymphomas. We have recently identified a series of elderly patients afflicted with EBV-associated (EBV-positive) B-cell LPDs in the absence of predisposing immunodeficiencies ; we have named these neoplasms "senile" EBV+ B-cell LPDs. The large series of patients with this disease (n=76) provided additional evidence that this neoplasia, with a median age of onset of 71 years, has the highest incidence in elderly patients aged >50 years, suggesting that this disease may be related to the immunological deterioration that occurs during the aging process. These lesions were pathologically characterized by varying numbers of Hodgkin and Reed-Sternberg (HRS)-like giant cells, often posing a diagnostic problem differentiating this condition from HL. Recent studies, however, have indicated that HL and non-Hodgkin lymphoma (NHL) may be more closely related than previously implied, promoting the general consensus that HRS cells are derived from B cells in most HL cases. The relationship between EBV+ HL and EBV+ B-cell LPDs remains to be clarified. This review provides a unique opportunity to highlight the gray areas between EBV+ HL and EBV+ B-cell LPDs. Further investigations are necessary to clarify the interrelationship, including their overlapping morphological and biological features.

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.

Bortezomib (Velcade™) and the Bcl-2 Inhibitor HA14-1 Synergistically Stimulate Apoptosis in EBV-Transformed Lymphocytes: A Potential Approach to Treatment of EBV-Associated Lymphoproliferative Disorders.

Epstein-Barr virus (EBV) transforms B-cells into immortalized lymphoblastoid cell lines (LCLs) by triggering signaling pathways that lead to the activation of multiple transcription factors, including NF-kappaB. EBV appropriation of the NF-kappaB pathway via EBV-encoded latent membrane protein-1 plays a pivotal role in EBV-mediated up-regulation of cellular growth-promoting and anti-apoptotic genes, including Bcl-2. Proteosome inhibitors provide a possible approach to inhibit constitutive activation of NF-kappaB in EBV-transformed B-cells. To determine whether the proteosome inhibitor bortezomib (PS-341, Velcade™) may have potential as a therapeutic anti-tumor agent in EBV-driven B-cell neoplasms, we evaluated the effect of bortezomib in EBV-immortalized LCLs (Sweig) in the presence and absence of the small molecular inhibitor of Bcl-2, HA14-1. Sweig cells were treated with increasing concentrations of bortezomib (1–1000 nM) for 24 hrs in the absence and presence of HA14-1 (10 uM), and assayed for cell proliferation (by MTT assay), apoptosis (by quantitation of DNA fragmentation in a flow cytometric TUNEL assay), caspase activation (by Western blotting), and levels of Bcl-2 family proteins (by Western blotting). Bortezomib alone inhibited proliferation of LCLs in a dose-dependent manner with an IC50 of 50 nM. At this concentration, bortezomib stimulated apoptosis in only 20% of LCLs, and we observed minimal caspase-3 cleavage. HA14-1 treatment alone had no significant effects on proliferation, apoptosis, or caspase-3 cleavage. When the Bcl-2 inhibitor HA14-1 was added to bortezomib, we observed marked enhancement of anti-proliferative and pro-apoptotic effects in LCLs. This synergistic interaction was observed with sequential exposure of LCLs to bortezomib followed by HA14-1 (8 hrs) or simultaneous exposure to both drugs for 24 hrs, but not when HA14-1 was added 8 hrs prior to bortezomib. In the presence of HA14-1, the IC50 for bortezomib decreased to 10 nM. Bortezomib (25 nM)/HA14-1 stimulated apoptosis in 80% of LCLs compared to bortezomib alone (20%). Moreover, bortezomib/HA14-1 triggered pronounced cleavage of both caspase 9 and 8, as well as caspase 3, suggesting activation of apoptosis through both mitochondrial and extrinsic pathways. Interestingly, Bcl-2 protein levels were increased, with appearance of the pro-apoptotic Bcl-2 cleavage fragment, in LCLs treated with bortezomib/HA14-1. These studies have demonstrated for the first time that bortezomib mediates anti-proliferative and pro-apoptotic effects in EBV-transformed lymphocytes, and that these effects are dramatically enhanced in the presence of a Bcl-2 inhibitor. These findings support further investigation of bortezomib in EBV-associated lymphoproliferative diseases and suggest that combining bortezomib with Bcl-2 antagonists, such as rituximab or Bcl-2 antisense oligonucleotides, may enhance anti-tumor efficacy. Studies are in progress to further delineate the mechanism(s) of interaction between bortezomib and HA14-1 in LCLs, and to evaluate the anti-tumor efficacy of bortezomib in the pre-clinical SCID/human model of EBV-associated lymphoproliferative disease.

Antithymocyte globulin for prevention of graft-versus-host disease

This review aims to discuss current clinical trial using antithymocyte globulin in the context of hematopoietic stem cell transplantation. Published papers, as well as abstracts from European and American meetings, have been used together with original data. The review shows that antithymocyte globulin is used frequently in Europe in the setting of unrelated or family mismatched donor transplants. This may not be the case for American centers, reluctant to introduce antithymocyte globulin possibly due to known side effects such as prolonged immune deficiency and increased incidence of infections, including life threatening Epstein-Barr virus-associated lymphoproliferative disorders. Results from few randomized trials show that antithymocyte globulin reduces acute and chronic graft-versus-host disease, and this is in keeping with results from retrospective analysis on large number of patients. Several issues remain open, such as optimal dose, optimal timing with respect to infusion of stem cells and whether the commercially available agents have comparable effects. Prospective trials are needed to answer these important questions.

Treatment of Epstein–Barr Virus-associated lymphoproliferative disorder (EBV-PTLD) and pure red cell aplasia (PRCA) with Rituximab following unrelated cord blood transplantation: A case report and literature review

Objective: We report the first case of EBV-PTLD and pure red cell aplasia (PRCA) after an unrelated cord blood transplant in China, who was successfully treated with Rituximab.Methods: Case report and literature review.Results: A 5-year-old girl with CML underwent a major ABO-incompatible HLA-identical unrelated cord blood transplantation (U-CBT) in January 2003. The post transplant course was complicated by PRCA. She presented on day + 75 with fever, followed by rapid enlargement of tonsils, and a cluster of lymph nodes in the cervical and submandibular regions. A cervical lymph node biopsy revealed the histopathologic findings consistent with PTLD. The immunoblasts were shown to contain EBV viral genomic DNA by PCR, and immunocytochemistry study for the latent membrane protein 1 (LMP-1) and in situ hybridization for Epstein–Barr encoded RNAs1 (EBER1) were both positive. She responded rapidly to Rituximab and achieved complete resolution of clinical findings and symptoms of both EBV-PTLD and PRCA.Conclusion: EBV-PTLD may occur with increasing frequency due to the increasing numbers of transplant recipients, transplant physician should be aware of this life-threatening complication. Rituximab alone may be an effective therapeutic strategy for patients who develop EBV-PTLD and PRCA after U-CBT.

High Fatality Rate of Epstein-Barr Virus-Associated Lymphoproliferative Disorder Occurring after Bone Marrow Transplantation with Rabbit Antithymocyte Globulin Conditioning Regimens

Epstein-Barr virus (EBV)-associated lymphoproliferative disorder (EBV-LPD) following bone marrow transplantation can be fatal. The major risk factors for the development of EBV-LPD are ex vivo T-cell depletion or in vivo T-cell depletion with either antithymocyte globulin (ATG) or monoclonal anti-T-cell antibodies. Between March 1999 and January 2001, a total of 23 transplants with ATG of equine source (20 transplants) and ATG of rabbit source (3 transplants) used as part of the preparatory regimen were performed at the Barbara Ann Karmanos Cancer Institute in Detroit, Mich. The three patients who received rabbit ATG developed EBV-LPD between 60 and 90 days following bone marrow transplantation. However, there were no cases of EBV-LPD in the equine group. Treatment given in these cases consisted of tapering immunosuppression, antiviral therapy, unprocessed donor lymphocyte infusion, mobilized peripheral blood progenitor cell rescue infusion (one patient), and chemotherapy (one patient). All three patients died of complications from EBV-LPD. The association of rabbit ATG with the development of EBV-LPD suggests that patients receiving rabbit ATG as part of their preparatory regimens require close monitoring of the EBV viral load and possible early intervention with antiviral therapy.

Distribution of Epstein-Barr Virus in Systemic Rheumatic Disease (Rheumatoid Arthritis, Systemic Lupus Erythematosus, Dermatomyositis) With Associated Lymphadenopathy: A Study of 49 Cases

Among systemic rheumatic diseases (SRDs), lymphadenopathy is frequently found in patients with rheumatoid arthritis (RA) and systemic lupus erythematous (SLE). Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) may occur in patients following methotrexate therapy for RA and dermatomyositis (DM). However, little is known about the distribution of EBV in reactive LPDs in patients with SRDs who had no history of methotrexate therapy. We analyzed 49 such patients (SLE=25, RA=23, DM=1) for the presence and distribution of EBV+ cells using Epstein-Barr virus (EBV)-encoded small RNA (EBER) specific in situ hybridization. A positive signal for EBERs was identified in 9 (SLE=5, RA=4) (18%) of 49 cases, and 3 main distribution patterns of EBER+cells could be delineated: pattern A, more than 500 EBER-positive cells were located in the germinal centers as well as interfollicular area (SLE=2); pattern B, EBER + cells were located in a few germinal centers (RA=2); and pattern C, up to 100 EBER+ cells were located in the interfollicular area (SLE=3, RA=2). Recent EBV infection may be a cause of lymph node lesion in only 2 cases of patients with pattern A. However, the pathognomonic significance of pattern B and pattern C EBER + cell distribution patterns still remains unclear. Our study indicates that the underlying immune deficits of patients with SRDs may also play an important role in the development of EBV-associated LPDs in SRDs, as previously suggested by several authors.

Lymphoproliferative disorder of the airway of an adolescent without immunodeficiency

Epstein-Barr virus (EBV) is a ubiquitous viral pathogen in humans that has a unique ability to immortalize B-cells. In immunosuppressed individuals, EBV can produce non-neoplastic lymphoproliferative disorders involving various organs. We describe a case report of EBV-associated lymphoproliferative disorder in an immunocompetent 14-year-old male. The case provides a description of EBV-associated lymphoproliferation affecting the upper and lower respiratory tract. The massive submucosal infiltration of B-cells in the lingual tonsils, trachea, and bronchi produced near-complete airway obstruction resulting in tracheotomy. Neither surgical reduction of lingual tonsils nor treatment with steroids was of benefit. An extensive evaluation for immunodeficiency and neoplasia was normal. Treatment with rituximab, an anti-CD20 antibody, resulted in near-complete resolution of the infiltrative process, sufficient to allow decannulation. Rituximab is a treatment option for the rare occurrence of non-neoplastic, EBV-associated, lymphoproliferative disorders.

Gastrointestinal complications in renal transplant recipients

Gastrointestinal complications are frequent in renal transplant recipients and can include oral lesions, esophagitis, peptic ulcer, diarrhea, colon disorders and malignancy. Oral lesions may be caused by drugs such as cyclosporine and sirolimus, by virus or fungal infections. Leukoplakia may develop in patients with Epstein-Barr virus (EBV) infection. The commonest esophageal disorder is represented by fungal esophagitis usually caused by candida. A number of patients may suffer from nausea, vomiting and gastric discomfort. These disorders are more frequent in patients treated with mycophenolate mofetil (MMF). Peptic ulcer is more rare than in the past. Patients with a history of peptic ulcer are particularly prone to this complication. Other gastroduodenal disorders are caused by cytomegalovirus (CMV) and herpes simplex infection. Diarrhea is a frequent disorder which may be caused by pathogen microorganisms or by immunosuppressive agents. The differential diagnosis may be difficult. Colon disorders mainly consist of hemorrhage, usually sustained by CMV infection, or perforation which may be caused by diverticulitis or intestinal ischemia. Colon cancer, anal carcinoma, and EBV-associated lymphoproliferative disorders are particularly frequent in transplant recipients. A particular gastric lymphoma called mucosa-associated lymphoid tissue (MALT) lymphoma may develop in renal transplant patients. It usually responds to the eradication of Helicobacter pylori.

Analysis of Interleukin-27 (EBI3/p28) Expression in Epstein-Barr Virus- and Human T-Cell Leukemia Virus Type 1-Associated Lymphomas: Heterogeneous Expression of EBI3 Subunit by Tumoral Cells

Interleukin (IL)-27 is a novel heterodimeric cytokine of the IL-12 family that is composed of two subunits, Epstein-Barr virus (EBV)-induced gene 3 (EBI3) and p28. EBI3 is expressed at high levels in EBV-transformed B-cell lines and is induced in vitro by the EBV oncogene LMP1 in a nuclear factor (NF)-kappaB-dependent manner. We show here that EBI3 expression is up-regulated in human T-cell leukemia virus type 1 (HTLV-1)-infected cell lines and IL-2-dependent leukemic cells from adult T-cell leukemia/lymphoma (ATL) patients, compared to normal activated T cells. EBI3 expression was decreased in HTLV-1-transformed cells after treatment with the NF-kappaB inhibitor BAY11-7082 and was induced in Jurkat cells by expression of HTLV-1 wild-type Tax oncoprotein, but not by the Tax mutant M22, which is defective for NF-kappaB activation. In situ analysis of EBI3 and p28 expression in Hodgkin's lymphomas (HLs), in various EBV-associated lymphoproliferative disorders (LPDs) (including post-transplant LPDs and nasal-type NK/T-cell lymphomas), and in ATL showed that EBI3 was expressed by neoplastic cells in all cases of HL and of LMP1-positive EBV-associated LPD, at variable levels in ATL cases, but rarely in control T-cell lymphomas. In contrast, in all lymphomas tested, no or few tumoral cells expressed p28. Consistent with these data, no significant p28 or IL-27 expression was detected in HL-derived cell lines, or in EBV- or HTLV-1-transformed cell lines. This selective overexpression of EBI3 by transformed cells suggests that EBI3 may play a role, independently from its association to p28, in regulating anti-viral or anti-tumoral immune responses.

Follicular lymphoid hyperplasia of the oral cavity representing progressive transformation of germinal center

Follicular lymphoid hyperplasia (FLH) of the oral cavity is a rare and poorly understood lymphoproliferative disorder. We present a case of FLH of the oral cavity presenting with progressive transformation of germinal center (PTGC). The patient was a 49-year-old Japanese woman presenting with a hard mass in the right cheek. The resected specimen contained numerous lymphoid follicles with active germinal centers and a portion of the lymphoid follicles exhibited PTGC. The PTGCs contained a few large lymphoid cells resembling lymphocytic and histiocytic Reed-Sternberg cells of nodular lymphocyte-predominant Hodgkin lymphoma. The PTGC was surrounded by groups of epithelioid cells. In situ hybridization studies demonstrated strong expression of Epstein-Barr virus (EBV)-encoded small RNA in scattered large lymphoid cells in the PTGC. Although the etiology of FLH of the oral cavity remains unclear, the present case suggests that a subset of FLH of the oral cavity appears to be an EBV-associated lymphoproliferative disorder.

Epstein-Barr Virus

1. Anne K. Junker, MD* 1. *Associate Professor, Division of Infectious and Immunological Diseases, Department of Pediatrics, University of British Columbia and Children’s & Women’s Health Centre of British Columbia, Vancouver, BC, Canada Author Disclosure Dr. Junker did not disclose any financial relationships relevant to this article. After completing this article, readers should be able to: 1. Outline the epidemiology of primary Epstein-Barr virus (EBV) infection. 2. Describe and explain the physiologic basis of the clinical features of infectious mononucleosis. 3. Describe and explain the physiologic basis of the common complications of infectious mononucleosis. 4. List the diagnostic tests that can help distinguish acute primary from distant past EBV infection. 5. Review the EBV-associated lymphoproliferative disorders and malignancies. EBV was identified initially in 1964 in tumor tissue from a patient who had African Burkitt lymphoma (BL), a rapidly growing, usually fatal malignancy of the B lymphocyte. When a laboratory technician working with this new virus became ill with mononucleosis and seroconverted to EBV, the link between EBV and mononucleosis became apparent. Soon thereafter, seroepidemiologic studies revealed that EBV infects virtually all of the world’s population, usually as a subclinical or trivial illness in childhood. A decade later, reports of a familial X-linked disorder of fatal infectious mononucleosis highlighted the importance of immunogenetic factors in the management of EBV infection. Now, nearly 40 years after its discovery, EBV continues to captivate clinicians, virologists, oncologists, geneticists, and immunologists attempting to understand this highly successful human pathogen. EBV is a ubiquitous, worldwide pathogen that is harbored persistently by virtually all adults, regardless of geographic location. After primary infection, the virus latently infects circulating B cells and is shed silently into saliva and genital secretions. The colloquial term “kissing disease” acknowledges the oral route by which most people are infected. Spread is associated with close personal contact, so it is not surprising that the age at first infection varies according to living conditions. Infection occurs at an earlier age in the presence of poor hygiene and crowded living conditions; infection rates in …

Active Epstein–Barr virus infection after allogeneic stem cell transplantation: re‐infection or reactivation?

Recipients of allogeneic stem cell transplants (SCT) often show active Epstein-Barr virus (EBV) infection, which may progress to EBV-associated lymphoproliferative disorders. It is not known whether these EBV infections are true reactivations of the endogenous EBV strain or re-infections with an exogenous EBV strain. Fifty-three recipients of matched related or matched unrelated donor grafts were studied. EBV monitoring was based on a realtime TaqMan EBV DNA polymerase chain reaction (PCR) assay in plasma. In 17 patients, EBV DNA PCR monitoring was performed in peripheral blood mononuclear cells (PBMCs) as well. Mouth washings (MWs) were collected pre-transplant from all patients and family donors. Both pre-transplant EBV DNA from MWs and post-transplant EBV DNA from plasma or PBMCs were successfully obtained in 6 patients. A nested PCR targeting the EBV latent membrane protein-1 C-terminus gene was used to determine sequence variations enabling EBV strain typing. In 3 of 6 patients, the post-transplant EBV sequence pattern differed from the pre-transplant pattern, indicating a re-infection post-transplant with an exogenous strain instead of a reactivation of the original endogenous EBV strain. In the other 3 patients, the endogenous strain was identified. Active EBV infection resulting from re-infection was more severe compared with active EBV infection because of reactivation. In conclusion, active EBV infections after allogeneic SCT frequently result from re-infection with an exogenous EBV strain instead of a true reactivation of the endogenous strain and are potentially more severe.

EBV-Associated B-and T-Cell Posttransplant Lymphoproliferative Disorders Following Primary EBV Infection in a Kidney Transplant Recipient

Posttransplant lymphoproliferative disorders (PTLDs) usually are of B-cell lineage and associated with Epstein-Barr virus (EBV). PTLDs of T-cell lineage are much less common and infrequently associated with EBV. We report a rare case of a girl in whom B-cell and T-cell PTLDs developed following 2 EBV-negative kidney transplants. Within 2 years of the second transplantation, the originally EBV-negative patient developed both an EBV-associated clonal B-cell PTLD involving lymph nodes and an EBV-positive T-cell PTLD involving bone marrow and liver. These proliferations occurred concurrently with evidence of primary EBV infection and high plasma viral load. The patient eventually died of multiorgan failure 5 years after the initial transplant (3 years after the second transplant). To our knowledge, only 4 cases of both B-cell and T-cell PTLDs have been reported. Only 2 cases have been proven to be monoclonal and EBV-associated, as in this case, the first following kidney transplantation.

EBV-Associated Tumors: Pathogenetic Insights for Improved Disease Monitoring and Treatment

Epstein-Barr virus (EBV) is a ubiquitous γ-herpes virus that is a well-established risk factor for Hodgkins lymphoma, Burkitts lymphoma, a subset of T cell lymphomas and various tumors of epithelial cell origin with nasopharyngeal carcinoma as the most representative. Furthermore, EBV-associated lymphoproliferative disorders are a well recognized major complication of immune suppression. EBV generally establishes a life-long asymptomatic infection in memory B lymphocytes, by mimicking cellular signaling pathways that regulate antigen-dependent B cell differentiation. In the long-lived memory B lymphocyte pool, the virus is almost completely silent or expresses a very restricted set of latent proteins, evading thus the immune control by EBV-specific effectors. EBV-associated lymphoid and epithelial malignancies are characterized by a peculiar geographic distribution and distinctive epidemiologic and histopathologic and histogenetic features. Moreover, new histogenetic and molecular features have contributed to the recognition and the diagnosis of specific disease categories. The ability of the virus to establish life-long persistent infections in humans and to contribute to cell transformation is related to the biologic properties of a set of EBV-encoded proteins, differently expressed in both normal and transformed cells. In the last decade, our understanding of the latency programs activated by EBV in cellular backgrounds and the function of EBV-encoded proteins has considerably improved. The emerging picture indicates that EBV proteins are able to hijack critical cellular pathways to promote the proliferation and survival of infected cells, while impairing anti-viral immune responses. The recent advances in the elucidation of the mechanisms underlying EBV-induced cell transformation and immune evasion help to design novel treatment approaches for EBV-related malignancies. Moreover, it has been clearly shown that the quantification of circulating EBV DNA is a valuable tool in the diagnosis, clinical monitoring and prognosis of some EBV-associated tumors. Keywords: epstein-barr virus, lymphoma, histogenesis, dna load, immune suppression, aids

The Pathology of NK-Cell Lymphomas and Leukemias

Natural killer (NK) cell lymphomas and leukemias are a rare but clinically important group of neoplasms. Most of these tumors are aggressive, with a high rate of mortality. They include extranodal NK/T-cell lymphomas of nasal type and aggressive NK-cell leukemias. Both are Epstein-Barr virus (EBV) associated and show similar epidemiologic features. A closely related entity seen mainly in children is hydroa vacciniforme-like lymphoma, which also is EBV positive. EBV influences the pathophysiology of these tumors, through the induction of cytokines and chemokines. The differential diagnosis of NK-cell malignancies includes fulminant EBV-associated T-cell lymphoproliferative disorder, a condition referred to in the past as fatal infectious mononucleosis. Benign proliferations of NK cells can be seen in association with viral infection. The disease formerly referred to as blastic NK-cell lymphoma is now considered to be a malignancy derived from a dendritic cell precursor.

Plasmocytome cutané EBV+ isolé chez une malade transplantée rénale : efficacité d’un traitement par rituximab

Postransplant lymphoproliferative disorders are well known complications of solid organ transplant, usually associated with Epstein-Barr virus (EBV). A 25 year old renal transplant patient presented with two subcutaneous nodules on the lower limb that appeared 3 years after a second renal transplantation. Biopsy of one nodule showed an EBV associated plasmocytoma located in the subcutaneous tissue. A complete systemic evaluation showed no evidence of extracutaneous involvement. The patient was treated with anti CD20 therapy (rituximab), and complete remission was achieved. Extranodular localisations of postransplant lymphoproliferative disorders are usually reported, but cutaneous localizations are rarely described. Histological presentation are various, but plasmocytoma-type is infrequent. Initial therapy of cutaneous EBV-associated postransplant lymphoproliferative disorders without extracutaneous involvement consists in reduction of the immunosuppression therapy and/or an antiviral treatment and prolonged surveillance. Treatment with monoclonal anti-CD20 antibodies (rituximab) is proposed.