Hepatosplenic gammadelta-T-cell lymphoma with leukemic course after renal transplantation

Hepatosplenic gammadelta-T-cell lymphoma (HSTCL) is a rare extranodal T-cell non-Hodgkin's lymphoma (T-NHL) with only 46 well-documented cases in medical literature. Notably, a relatively high number of these case reports (15%) describe the occurrence of HSTCL after solid organ transplantation. We describe the case of a 45-year-old man who developed a leukemic HSTCL 5 years after renal transplantation and continous immunosuppression with cyclosporine A and prednisolone. After a rapid clinical course, the patient died and autopsy was performed. The malignant lymphocytes showed a natural killer-like gammadelta-T-cell phenotype (CD2(+), CD3(+), CD7(+), TCR gammadelta(+), CD56(+), TIA-1(+), CD4(-), CD8(-), and TCR alphabeta(-)) and infiltrated the sinusoids of liver and the red pulp of the spleen. Cytogenetically, an isochromosome 7q, trisomy 8, Y-loss, and a translocation t(1;4) was detectable. This case shows the difficulties of recognizing HSTCL early in the clinical course and underlines that all types of T-NHL, nodal as well as extranodal, have to be considered in the differential diagnosis of posttransplantation lymphoproliferative disorders. Moreover, HSTCL seems to occur as a specific late complication of solid organ transplantation.     

Pediatric oral Epstein-Barr virus associated self-remitting CD30+ lymphoproliferative disorder: A distinct entity

Epstein-Barr virus (EBV) has a well-known association with lymphoproliferative disorders of B and T cell origin. EBV-related B cell lymphoproliferative disorders include Hodgkin and Burkitt lymphomas, lymphomatoid granulomatosis, EBV positive diffuse large cell B cell lymphoma of the elderly, as well as B cell lymphomas associated with solid organ transplantation and methotrexate use. EBV-related T cell disorders are primarily represented by NK/T- cell lymphoma. In a subset of patients, EBV has been implicated in CD30 positive B cell lymphoproliferative disorders of the oral mucosa falling under the rubric of the mucocutaneous ulcer of the oral cavity. We previously reported on an index series of endogenous CD30 positive T cell lymphoproliferative disorder of the oral cavity resembling borderline type C lymphomatoid papulosis. The clinical manifestation of type C oral lymphomatoid papulosis is that of a recurrent self-remitting ulcer of the oral mucosa, which histologically resembles anaplastic large cell lymphoma. Such cases can be misdiagnosed as aggressive lymphoma leading to unnecessary treatment with aggressive chemotherapeutic regimens. Whereas none of the patients in our index series exhibited EBV positivity, here we discuss a very unique example of a 14-year-old girl diagnosed with EBV positive CD30 positive lymphoproliferative disorder strongly resembling the cases of intra-oral type C lymphomatoid papulosis. The patient was initially diagnosed by a senior hematopathology consultant as having EBV positive aggressive NK/T-cell lymphoma. The significance of raising physician awareness regarding pediatric oral EBV associated CD30 positive lymphoproliferative disease of the oral cavity lies in preventing inadvertent exposure to toxic chemotherapeutic agents intended for treatment of aggressive look-alikes, namely anaplastic large cell lymphoma. Additionally, we include a literature review of similar reports of pediatric intra-oral EBV positive CD30 positive T cell lymphoproliferative disease.     

Clinical characteristics,outcome and the role of viral load in nontransplant patients with Epstein--Barr viraemia

Epstein--Barr virus (EBV) is important in the development of post-transplant lymphoproliferative disease in allogeneic stem cell and solid organ transplant recipients. We have studied the clinical significance of EBV DNAaemia among nontransplant patients in a tertiary referral hospital. We retrospectively reviewed the medical records for main diagnosis, outcome, immunosuppressive/cytotoxic chemotherapy and other opportunistic infections of the patients who were found -positive in quantitative real-time PCR assay for EBV (EBV-qPCR) between the years 2000 and 2007. Allogeneic stem cell and solid organ transplant recipients were excluded, and all patients in nonsurgical adult wards were included. Altogether, 62 patients had at least one plasma sample -positive with an EBV-qPCR. Fifteen were immunocompetent, most had primary EBV infection, and the outcome was good. On the other hand, 36 had malignant disease, seven had HIV infection and seven had immunosuppressive conditions of an other aetiology. All but one of the malignancies were of lymphoid origin, and most of these patients had a history of multiple cytotoxic treatments. Immunosuppressed patients had higher viral loads. EBV viraemia is associated with severe immunosuppression and lymphoid malignancies.     

T-cell large granular lymphocytic leukemia of donor origin occurring after allogeneic bone marrow transplantation for B-cell lymphoproliferative disorders

T-cell lymphoproliferative disorders are uncommon occurrences after bone marrow transplantation (BMT). We describe 2 patients in whom a monoclonal T-cell large granular lymphocytosis (T-LGL) developed after allogeneic BMT for B-cell lymphoproliferative disorders. Both patients showed a persistent expansion of CD3+, CD8+, and CD57+ large granular lymphocytes of donor origin with clonally rearranged T-cell receptor gamma genes and no evidence of Epstein-Barr virus-related infection. The manifestations were consistent with T-LGL leukemia as defined by the World Health Organization criteria. In both patients, graft-vs-host disease developed, and 1 had recurrent episodes of cytomegalovirus viremia. The other patient had received a graft from a hepatitis C antibody-positive donor without developing any signs of hepatitis C infection. Both patients remain in complete remission from their B-cell lymphoproliferative disorders and do not have symptoms related to T-LGL leukemia. These data show that T-LGL leukemia should be included as one of the types of posttransplantation lymphoproliferative disorders that can occur after allogeneic BMT for B-cell neoplasms.     

ALK-positive anaplastic large cell lymphoma with leukemic peripheral blood involvement is a clinicopathologic entity with an unfavorable prognosis. Report of three cases and review of the literature

Leukemic peripheral blood involvement in anaplastic large cell lymphoma (ALCL) is uncommon. We describe 3 children with such manifestations and review the features of 9 pediatric and adult patients previously described in the literature. Leukemic involvement in ALCL may occur at the time of initial diagnosis or develop during the course of disease. It most often is associated with the small cell histologic features and the t(2;5)(p23;q35). Clinical features commonly include significant respiratory distress, diffuse lung infiltrates or pleural effusions, and hepatosplenomegaly. Most cases have an aberrant T-cell immunophenotype with frequent expression of myeloid antigens, most often CD11b or CD13. Ten of the 12 cases reviewed had a poor response to therapy or early relapse. Thus, while anaplastic lymphoma kinase-positive ALCL and young patient age generally are associated with a favorable prognosis, leukemic involvement seems to identify a high-risk malignant neoplasm that requires more aggressive therapy, including hematopoietic stem cell transplantation.     

EBV-associated, extranodal NK-cell lymphoma, nasal type of the breast, after heart transplantation.

Post-transplantation lymphoproliferative disorders (PTLDs) are predominantly Epstein-Barr virus (EBV)-associated B-cell lymphoproliferations. PTLDs of T-cell lineage are rare, mostly reported after renal transplantation and show less frequent association with EBV. NK-cell lymphomas after transplantation (NK-cell PTLDs) are very rare; only five cases are reported so far in the English literature, all developed after renal transplantation. We describe a case of EBV-associated, extranodal NK-cell lymphoma of nasal type, involving the breast in a cardiac allograft recipient 5 years after transplantation. The neoplastic cells are positive for CD2, cytoplasmic CD3, CD7, CD43, CD56, TIA-1 and p53; and negative for surface CD3 and CD57. Analysis of T-cell receptor beta and gamma genes fails to show clonal rearrangement. EBV studies show clonal episomal integration of EBV and latency II pattern (EBER-1+, LMP-1+, EBNA-1+, EBNA-2-). In conclusion, NK-cell PTLDs are rare complications that arise relatively late after solid organ transplantation, show strong association with EBV, and can follow an aggressive clinical course. To the best of our knowledge, we present the first reported case of NK-cell PTLD after cardiac transplantation and the unifying clinical and diagnostic features of NK-cell PTLDs occurring after solid organ transplantation.     

Lymphoproliferative disorders in Oxford renal transplant recipients

BACKGROUND: Increased cancer incidence, particularly lymphoproliferative disease, is a complication of immunosuppression in organ transplantation. Non-Hodgkin's lymphomas (NHLs) occur frequently during the first year after transplantation, more so in North America than in Europe. METHODS: This study audited and correlated the demographic, clinical, pathological, and outcome features of post-transplant lymphoproliferative disorders (PTLDs) in a large centre in Oxford, and assessed whether the time of onset fitted more with the European or North American pattern. RESULTS: There were 1383 renal transplants in the study period and 27 patients developed lymphoma: 26 NHLs and one Hodgkin's disease (1.95%). Four of the patients never received cyclosporin. The mean time of diagnosis after transplant was 46 months. Most tumours (21/27) presented extranodally. Management included reduction of immunosuppression, surgical excision, antiviral treatment, radiotherapy, and chemotherapy. Three patients presented in the first post-transplant year-0.34% of cyclosporin managed patients-similar to the North American incidence, although the incidence of extranodal late PTLDs was also high (mean onset, 36 months v 15 months international mean). Post-transplant lymphomas were the most common malignancy associated with death in transplant patients. CONCLUSIONS: PTLDs occurred in 2% of renal transplant patients, presenting both in the first year in association with cyclosporin use, as in North America, but also in subsequent years, giving an overall presentation time later than the international mean. The disease usually presented extranodally, accounting for the wide range of symptoms and signs. Despite awareness and active management, the disease contributed to death in more that 50% of patients with PTLDs.     

Anti-B-cell monoclonal antibodies in the treatment of severe B-cell lymphoproliferative syndrome following bone marrow and organ transplantation

BACKGROUND. The B-cell lymphoproliferative syndrome is an infrequent life-threatening complication of marrow or organ transplantation that is the consequence of profound immunosuppression. The results of treatment have been disappointing, although a small number of patients have been cured by chemoradiotherapy or antiviral agents after a reduction in the dosage of immunosuppressive therapy. We report here the results of treating this disorder with anti-B-cell antibodies. METHODS. Twenty-six patients in whom aggressive B-cell lymphoproliferative syndrome developed after bone marrow (n = 14) or organ (n = 12) transplantation received 0.2 mg of CD21-specific and of CD24-specific antibodies per kilogram of body weight for 10 consecutive days in an open, prospective, multicenter trial. RESULTS. The treatment was well tolerated. All patients had transient neutropenia, apparently because the CD24 molecule is also expressed on granulocytes. The treatment was ineffective in seven patients with monoclonal B-cell proliferation. In contrast, 16 patients with oligoclonal B-cell proliferation had complete remission. Systemic remission also occurred in two other patients with oligoclonal proliferation who had central nervous system involvement, although they subsequently died because of progression of the central nervous system disease. In one patient who died early, clonality was not determined. Of the 16 patients who had complete remission, 2 with persistent immunodeficiency due to graft (marrow) rejection or acute graft-versus-host disease had a relapse, and the 1 with graft-versus-host disease subsequently died. Eleven patients were alive and disease-free after a median follow-up of 35 months (5 of 14 marrow recipients and 6 of 12 organ recipients). Four other patients in complete remission died of unrelated causes 4 to 12 months after treatment. CONCLUSIONS. Intravenous administration of anti-B-cell antibodies may be effective in controlling diffuse, severe, oligoclonal B-cell proliferation not involving the central nervous system.     

Clinical Characteristics of Monomorphic Post-transplant Lymphoproliferative Disorders

Post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous group of lymphoproliferative disorders associated with immunosuppression and Epstein-Barr virus infection. PTLD is classified into three major categories: early lesions, polymorphic PTLD, and monomorphic PTLD. The majority of monomorphic PTLD cases are non-Hodgkin''s lymphoma of B-cell origin. This retrospective study was conducted to investigate the incidence, clinical manifestation, treatment, and outcomes of monomorphic PTLD among 5,817 recipients of solid organ or allogeneic hematopoietic stem cell transplantation from five institutions. Fourteen patients with monomorphic PTLD were identified (male:female 11:3; median age 42.6 yr, range 24-60). The overall incidence rate was 0.24%. The most common disease type was diffuse large B cell lymphoma (n=7). The median time between the transplant and diagnosis of PTLD was 85.8 months. However, all cases of PTLD after allogeneic hematopoietic stem cell transplantation occurred within 1 yr after transplantation. Ten of the 14 patients had EBV-positive tumor. Fourteen patients received combination systemic chemotherapy and four patients were treated with radiation therapy. Ten patients achieved a complete response (CR) and two patients a partial response (PR). The median follow-up period for surviving patients was 36.6 months. Nine patients remain alive (eight CR, one PR). Nine of 11 solid organ transplantations preserved graft function. The present study indicates a lower incidence rate and a longer median time before the development of PTLD than those of previous reports. Careful monitoring was needed after allogeneic hematopoietic stem cell transplantation for PTLD.     

Anaplastic T large cell lymphoma diagnosed by exfoliative cytology in a post renal transplant patient

In the last two decades posttransplant lymphoproliferative disorders (PTLDs) have been recognized as a complication of organ transplantation with immunosuppression. The reported incidence of PTLDs in renal transplant patients ranges between 0.3-3% (Birkeland et al., Transplantation 1999;67:876-881). In contrast to the reported incidence of PTLDs in post bone marrow transplant, it is 1% in HLA-matched recipients and up to 20% in HLA mismatched T-cell depleted bone marrow recipients (Curtis et al., Blood 1996;94:2208-2216). In cardiac transplant recipients the reported incidence of PTLDs is between 1.8-9.8 (Mihalov et al., Clin Transplant 1996;10:248-255). PTLDs are predominately extranodal. They have varied morphologic patterns and clonality, but almost all are associated with Epstein-Barr virus (EBV). The vast majority are of B cell lineage; only about 10% are of T-cell origin. We report a T-cell anaplastic large cell lymphoma (ALCL) presenting with bilateral pleural effusion and liver involvement in a renal transplant recipient.     

Complete resolution of posttransplant lymphoproliferative disorder (diffuse large B-cell lymphoma) with reduction of immunosuppressive therapy

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation. PTLD is the disorder arising from the combined effects of Epstein-Barr virus associated lymphoid proliferation with the disruption of the normal immune control by the cytotoxic T cells. The treatment for PTLD is one of the most controversial topics in solid organ transplantation. It is well known that the initial management of PTLD is a reduction of immunosuppression. Early diagnosis and the early reduction in immunosuppression are essential even for monomorphic lymphoma. We report here on a case of the complete resolution of PTLD (diffuse large B cell lymphoma) which occurred after a drastic reduction of immunosuppression in a renal transplant recipient.     

Post-transplantation Lymphoproliferative Disease

Post-transplant lymphoproliferative disorders are a varied group of disease processes that follow both solid organ and bone marrow transplantation. The disorders are typically associated with the Epstein-Barr virus and, as a consequence, have contributed greatly to our understanding of the role of human viruses in the pathogenesis of malignant disease. They have also expanded our understanding of the role of immunosurveillance in the prevention and control of malignancies which has, in turn, led to exciting developments in the use of transferred or adoptive immunotherapy for the treatment of cancer. This technology holds great potential for the treatment of these and other diseases associated with immunodeficiency states. When recognized early in their natural history, the post-transplant lymphoproliferative disorders appear to be curable; later detection frequently leads to a fatal outcome. Prompt diagnosis of these disorders by the clinician caring for the transplant patient is therefore critical.     

Epithelioid granulomas of the bone marrow in non-Hodgkin's lymphoproliferative malignancies

Ten cases of epithelioid granulomas in the bone marrow of patients with various non-Hodgkin's lymphoproliferative malignancies have been encountered. These included six with non-Hodgkin's lymphoma (three histiocytic and three poorly differentiated lymphocytic types), three with multiple myeloma, and one with acute lymphoblastic leukemia. The bone marrow was not involved by the primary disease in two of the six patients with lymphoma, whereas three with lymphoma showed both granulomatous and lymphomatous lesions in the same marrow specimens, and in one, these lesions were seen in the marrow at different times. The three myeloma patients showed evidence of both myeloma and granulomas in their marrow. In the case of acute lymphoblastic leukemia, the bone marrow showed only granulomas, the leukemic process being in complete remission. Although small numbers of similar cases have been reported before, the authors were unable to find a previous report of acute lymphoblastic leukemia associated with bone marrow granulomas. Although the pathogenesis and the clinical significance of the granulomatous lesion of the bone marrow in non-Hodgkin's lymphoproliferative malignancies are unknown, this lesion should be differentiated from infectious or lipid granulomas as well as from involvement by the primary disease.     

Post-immunosuppressive and immunomodulatory therapy lymphoproliferative disorders of the gastrointestinal tract

Post-immunosuppressive and immunomodulatory therapy lymphoproliferative disorders occur during immunosuppressive treatment following allogeneic solid organ or stem cell transplant (post-transplant lymphoproliferative disorder, PTLD) or for autoimmune disorders. These disorders commonly initially present in the gastrointestinal tract, and up to 30% of patients have been shown to have GI involvement. Post-immunosuppressive therapy lymphoproliferative disorders are frequently associated with Epstein–Barr virus (EBV) and encompass a wide spectrum of morphologic and clinical presentation. EBV-negative and T-cell lymphoproliferations occur to be increasing, and a high index of suspicion is required on the part of the pathologist for timely diagnosis and treatment.     

Diagnostic approach to T- and NK-cell lymphoproliferative disorders in the gastrointestinal tract

Most gastrointestinal NK and T cell lymphomas are aggressive in behavior, although in recent years a subset of indolent lymphoproliferative disorders have been described, which must be distinguished from their more malignant mimics. Intestinal T-cell lymphomas may arise from intra-epithelial lymphocytes and display epitheliotropism, such as enteropathy-associated T-cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma. They are both aggressive in behavior but differ in their clinic-pathological features. On the other hand, intra-epithelial lymphocytes are not prominent in intestinal T-cell lymphoma, NOS, which is a diagnosis of exclusion and probably represents a heterogeneous group of entities. Indolent lymphoproliferative disorders of NK- and T-cells of both CD8 and CD4 subsets share a chronic, recurring clinical course but display differences from each other. CD8+ T-cell lymphoproliferative disorder of GI tract has a low proliferative fraction and does not progress nor undergo large cell transformation. Whilst NK-cell enteropathy runs an indolent clinical course, it may display a high proliferation fraction. On the other hand, CD4+ indolent T-cell lymphoproliferative disorder displays variable proliferation rates and may progress or transform after a number of years. In Asia and South America, it is not uncommon to see involvement of the gastrointestinal tract by EBV-associated extranodal NK/T cell lymphoma, nasal type, which must be distinguished from NK cell enteropathy and EBV-associated mucocutaneous ulcers.     

Generation of EBV-specific CTLs suitable for adoptive immunotherapy of EBV-associated lymphoproliferative disease following allogeneic transplantation

Lymphoproliferative disease induced by EBV (EBV-LPD) is a complication of allogeneic transplantation caused by T-cell immunodeficiency. EBV-LPD responds poorly to conventional treatment modalities. Recently, adoptive transfer of EBV-specific, HLA-class I-restricted CTL lines was shown to be effective both as prophylaxis and as treatment of EBV-LPD. The CTL lines are produced by in vitro selection of EBV-specific memory T cells contained in MNC of EBV-seropositive individuals by repeated stimulation with irradiated EBV-transformed cells. The non-EBV-reactive and potentially alloreactive cells remain unactivated. Twenty-one CTL lines were initiated. All were successfully generated and shown to be HLA-restricted and EBV-specific as well as CD8/CD4 and CD45RO positive T cells. The majority of the CTL lines were generated from BMT donors, but two CTL lines were obtained from solid organ transplant recipients receiving immunosuppression. Evidence of probable in vivo efficacy is presented. Development of efficient adoptive T-cell strategies for EBV-positive malignancies could serve as a model for treatment of other viral or malignant disorders.     

The therapy of virus-associated epithelial tumors of the face and the lips in organ transplant recipients

The risk of developing malignant cutaneous neoplasms is increased after organ transplantation. We report three patients with malignant tumors of the epithelium of the facial skin and the lips after kidney and heart transplantation, respectively. They showed an aggressive course of the disease with more than five synchronous or metachronous basal cell and squamous cell carcinomas. Tissue samples were Epstein-Barr virus (EBV) positive by PCR. Using an in situ hybridization technique EBV-encoded RNA (EBER) was detected in tumor-infiltrating lymphocytes. The aggressive course was not alone controllable by surgical or radiological therapy. The systemic and topical application of cidofovir (Vistide) led to remarkable remissions, to a better confinement and operability of the tumors, and to a cessation of tumor pain. The photodynamic therapy represents another opportunity for managing superficial local recurrences and multiple tumors. In conclusion, the results of these case reports demonstrate that combined antiviral, photodynamic and surgical therapy may be used successfully to treat aggressive cutaneous malignancies in patients after organ transplantation.     

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.     

De novo cancers and post-transplant lymphoproliferative disorder in adult liver transplantation

De novo cancer is one of the most serious complications after organ transplantation. Chronic immunosuppression, viral agents, pretransplant chronic alcohol-induced and other addictive behavior-induced injury are important conditions associated with the development of de novo cancers in solid organ transplants. The aim of the study was to evaluate types and clinical course of de novo cancers in adult liver transplant recipients. Data regarding 502 adult patients who underwent to 554 liver transplantations have been collected. Sex, age at transplantation, immunosuppressive regimen, time from transplantation to diagnosis of cancer, cancer type, surgical and non-surgical treatments and follow-up time have been analyzed as well as acute rejection episodes and viral status. Thirty patients developed 31 de novo cancers. The predominant tumors were carcinoma of the skin, lymphomas and Kaposi's sarcoma. Kaposi's sarcoma and lung cancer were associated with greater mortality. In lymphomas and Kaposi's sarcoma, a high rate of graft involvement was observed. In liver transplant recipients, de novo cancers demand strategies focusing on prophylactic and careful long-term screening protocols. Lymphomas and Kaposi's sarcoma should be ruled out in all patients with clinical manifestations of chronic biliary obstruction.     

Treatment options for post-transplant lymphoproliferative disorder and other Epstein-Barr virus-associated malignancies

Epstein-Barr virus (EBV) is associated with a range of malignancies that largely arise from a defect in EBV-specific cytotoxic T lymphocyte (CTL) immunity and function. Much work has focused on the reconstitution of CTL immunity to EBV in transplant patients, in whom immunosuppression modalities render them susceptible to post-transplant lymphoproliferative disease (PTLD). Adoptive transfer of autologous CTLs is effective at both preventing and curing PTLD in solid organ transplant recipients and can produce a long-term memory response and protection against recurring disease. In this review, the benefits and restrictions of administering EBV-specific CTLs for the treatment of PTLD are discussed and compared with emerging therapies including the generation of allogeneic human leukocyte antigen-matched CTL banks and the anti-CD20 monoclonal antibody therapy, MabThera. Furthermore, studies involving other EBV-associated disorders have described the potential benefit of adoptive transfer of EBV-specific CTLs for Hodgkin's disease, nasopharyngeal carcinoma, chronic active EBV infection, and Burkitt's lymphoma. The challenges of tailor-making therapies for individual diseases and EBV antigen expression latencies are highlighted, in addition to considering vaccination strategies for optimal treatment.