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PubMed2003

CT of posttransplantation lymphoproliferative disorder in pediatric recipients of lung allograft.

OBJECTIVE: The purpose of this study was to determine the CT and clinical findings of posttransplantation lymphoproliferative disorder in pediatric lung allograft recipients. MATERIALS AND METHODS: We reviewed the medical records and CT examinations of 260 lung transplantations in pediatric patients and found 26 recipients who had 29 episodes of histologically proven posttransplantation lymphoproliferative disorder. The clinical and CT features of the disease, the time to diagnosis, and the outcomes were assessed. RESULTS: The clinical presentation of posttransplantation lymphoproliferative disorder varied from asymptomatic pulmonary nodules (14/29 [48%]) detected on chest CT to specific (organ-related) and nonspecific symptoms (15/29 [52%]). Intrathoracic posttransplantation lymphoproliferative disorder occurred in 20 (69%) of 29 cases and manifested as multiple pulmonary nodules (n = 17), alveolar infiltrates (n = 2), and combined nodules and infiltrates (n = 1). In eight (28%) of 29 cases, there was extraparenchymal disease, including adenopathy, pleural effusion, and esophageal thickening and erosions. Extrathoracic posttransplantation lymphoproliferative disorder occurred in 13 cases and involved the abdomen (n = 10), paranasal sinuses (n = 2), and brain (n = 1). In the abdomen, extranodal disease was more common than nodal disease and presented as bowel wall thickening, focal mass lesions, and splenomegaly. In 18 of 29 episodes of posttransplantation lymphoproliferative disorder, the histologic diagnosis was lymphoma. The median time to diagnosis after transplantation for the 29 episodes of posttransplantation lymphoproliferative disorder was 10 months. Thirteen of the 26 patients died. The median time of survival after the diagnosis of posttransplantation lymphoproliferative disorder was 17 months. CONCLUSION: Posttransplantation lymphoproliferative disorder in pediatric lung transplant recipients occurs with relatively high frequency in both the chest and abdomen, tends to have lymphomatous features, and results in substantial mortality rates.

Adolescent↗
PubMed2004

Positron emission tomography with fluoro-2-deoxy-D-glucose (FDG-PET) in the staging of post transplant lymphoproliferative disorder in lung transplant recipients.

Posttransplantation lymphoproliferative disorder (PTLD) is a histologic heterogeneous disease that complicates 4 to 8% of lung transplant recipients. Disease extent is an important prognostic factor and may affect therapy. Positron emission tomography with fluoro-2-deoxy-D-glucose (FDG-PET) has proven useful for staging high-grade lymphomas but is less accurate for staging low-grade and extranodal lymphoma. This study examined our initial experience using FDG-PET imaging to stage lung transplant recipients with posttransplantation lymphoproliferative disorder. FDG can show foci of uptake, particularly in extrathoracic sites, not seen by conventional imaging, which allows more accurate staging of disease thereby yielding useful prognostic information and guiding therapy.

Fluorodeoxyglucose F18↗
PubMed2002

Tailored chemotherapy for malignant lymphoma arising in the setting of posttransplant lymphoproliferative disorder after solid organ transplantation.

Posttransplant lymphoproliferative disorder is a clinical challenge. Traditional chemotherapy results in tumor response, but toxicity and transplant rejection limit survival. The authors treated seven patients with malignant lymphoma after organ transplant with chemotherapy tailored to individual patient response. Chemotherapy consisted of vincristine, cyclophosphamide, and prednisone, with or without doxorubicin (Adriamycin; Pharmacia & Upjohn, Peapack, NJ, U.S.A.), or the ProMACE-CytaBOM regimen. Six of seven patients (86%) showed a complete response to treatment, with five of seven (71%) alive disease-free at 9 to 72 months (mean 38.2) after treatment. The results show that chemotherapy tailored to individual patient response is a safe and effective therapy for malignant lymphoma arising in patients with posttransplant lymphoproliferative disorder.

Algorithms↗
PubMed1995

Polyclonal Epstein-Barr virus-associated lymphoproliferative disorder following autografting for chronic myeloid leukemia.

Epstein-Barr-associated lymphoproliferative disorders have been described as complications of immunodeficiency states including allogeneic BMT. There is, however, only one report in the English language literature of such a disorder after autografting. We report a 56-year-old man undergoing autologous BMT for CML in whom a rapidly progressive lymphoproliferative disorder showing the histology of typical post-transplant lymphoproliferative disorder with latent EBV presence developed at approximately 30 days after BMT. Therapy with corticosteroids, acyclovir and alpha-interferon was instituted and led to prompt resolution of symptoms and signs. There was no evidence of lymphoproliferative disease at 7 months after BMT. It is concluded that EBV-associated lymphoproliferative disorders may be a complication, albeit a rare one, of intensive therapy with autologous stem cell support.

Bone Marrow Transplantation↗
PubMed1994

Lymphoproliferative disorders of the lung: histopathology, clinical manifestations, and imaging features.

The lymphoproliferative disorders represent a spectrum of lymphoid abnormalities that can involve the chest. Plasma cell granuloma, pseudolymphoma, posttransplantation lymphoproliferative disorders, lymphoid interstitial pneumonia, and lymphomatoid granulomatosis involve the pulmonary parenchyma, whereas Castleman's disease, infectious mononucleosis, and angioimmunoblastic lymphadenopathy with dysproteinemia involve intrathoracic lymph nodes. Recent immunohistochemical techniques give us a better understanding of the lymphoproliferative disorders. Clinical and radiologic features often allow differentiation of the lymphoproliferative disorders from the more common aggressive lymphomas.

Female↗
PubMed1996

Tumorous intrahepatic lymphoproliferative disorder in transplanted livers.

OBJECTIVE: We describe the radiologic findings of lymphoproliferative disorder manifesting as an intrahepatic mass in hepatic transplant recipients. Three patients with focal intrahepatic masses due to lymphoproliferative disorder after transplantation were retrospectively identified. Clinical features and radiologic findings in these patients were reviewed in conjunction with pertinent cases from the literature. (Reports of lymphoproliferative disorder confined to the transplanted liver have been sporadic.) CONCLUSION: Factors supporting the diagnosis of tumorous intrahepatic lymphoproliferative disorder include presentation 4-12 months after transplantation; portal or periportal location; poorly defined extrahepatic periportal soft tissue; encasement or narrowing of the biliary ducts, hepatic artery, or portal vein; and serologic evidence of exposure to Epstein-Barr virus.

Aged↗
PubMed1999

Detection of immunoglobulin kappa light chain rearrangements by polymerase chain reaction. An improved method for detecting clonal B-cell lymphoproliferative disorders.

The clonal determination of B-cell lymphoproliferative disorders by immunoglobulin heavy chain (IgH) rearrangement by polymerase chain reaction (PCR) is widely used. However, few attempts have been made to detect immunoglobulin kappa light chain (Igkappa) gene rearrangement using PCR. We studied 145 cases of B-cell neoplasms, along with 58 atypical and 18 reactive lymphoproliferative disorders, using newly designed degenerate oligoprimers recognizing the framework 3 (FR3kappa) and the joint (Jkappa) regions of the Igkappa gene. PCR products were analyzed on nondenaturing polyacrylamide gel (ndPAGE). Clonal B-cell determination was further investigated using IgH rearrangement and t(11:14) or t(14:18). By combining these methods, we detected either clonality or translocation in 117 of 137 cases (85%) in mature B-cell neoplasms. The additional analysis of Igkappa rearrangement improved sensitivity from 66% to 85%. To investigate whether the Ig gene configuration could be characterized using Igkappa PCR in B-cell neoplasms showing severe breakdown of genomic DNA, 18 selected cases were analyzed. Successful amplification was detected in 72% of the cases using either FR3/2-JH and/or FR3Jkappa oligoprimers. Finally, clonality was detected in 21 of 58 atypical B-cell proliferations, and among them, the atypical marginal cell (54%) and atypical large cell (50%) proliferations showed the highest frequency of clonal immunoglobulin gene products. We concluded that PCR/ndPAGE analysis of Igkappa is a sensitive, rapid, and efficient method for assessing clonality in conjunction with IgH and specific translocation analysis. This approach is particularly useful in the characterization of B-cell lymphoproliferative disorders in archival material with poor preservation of the genomic DNA.

Clone Cells↗
PubMed2005

Lymphoproliferative disorders: prospects for gene therapy.

The lymphoproliferative disorders represent a large group of diseases with a significant variation in presentation and clinical course. There has been a trend of increasing incidence for some of these disorders, and despite advances in therapies, a significant number of patients either respond poorly or have early relapses. For this reason there is a need to investigate novel therapies to be used either alone or as adjunct treatment in combination with conventional therapies. Gene therapy is a relatively new field that takes advantage of our increased understanding of molecular biology with the aim of treating a variety of diseases including cancer. It is defined as the introduction of genetic material into cells for therapeutic intent. Methods to improve gene delivery efficiency have been the focus of a large amount of research and to date the optimal procedure uses viruses such as oncoretroviruses, lentiviruses, adenoviruses, adeno-associated viruses and herpes simplex viruses. There are four main gene therapy strategies that might be used for the treatment of lymphoproliferative disorders. First, immunotherapy using tumour vaccines or techniques to enhance the function of immune effector cells has been investigated with some success in patients with B-cell malignancies. Second, the introduction of prodrug-activated 'suicide' genes into cells has been explored, in particular in patients with post-transplantation lymphoproliferative disease. Third, direct lysis of tumour cells using viruses shows some early promise, especially in the treatment of B-cell disorders by manipulating the measles virus to target the CD20 antigen. Finally, anti-gene strategies such as anti-sense therapy, ribozymes, and most recently RNA interference, could be used to suppress expression of specific target genes. RNA interference in particular has tremendous potential and has been studied in the context of anaplastic large cell lymphoma as well as Epstein-Barr virus-associated malignancies. Whilst we are still in the early days of this field and to date results have been modest, there is still a significant potential for gene therapy to play a role in the future treatment of these disorders.

Animals↗
PubMed2005

Death receptor apoptosis signaling mediated by FADD in CD30-positive lymphoproliferative disorders involving the skin.

BACKGROUND: The CD30-positive lymphoproliferative disorders lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (C-ALCL), and systemic anaplastic large cell lymphoma (S-ALCL) are lesions that overlap clinically, histopathologically, and immunophenotypically. Their biologic behaviors, however, vary considerably. In particular, lesions of LyP regress spontaneously while those of S-ALCL persist and often progress. Apoptosis has been suggested as the mechanism by which the lesions of LyP regress, but the underlying signaling pathways remain unclear. In this study, we used newly developed activation state-specific antibodies to demonstrate apoptosis signaling through the death receptor-mediated pathway regulated by FADD and caspase 3. METHODS: Dual immunohistochemistry for CD30 and activated forms of FADD and caspase 3 was performed on cutaneous biopsy specimens from 27 patients with CD30-positive lymphoproliferative disorders involving the skin. The patients included 18 with primary cutaneous CD30-positive LPDs (15 with LyP and 3 with C-ALCL) and 9 with S-ALCL. RESULTS: The proportion of CD30-positive cells expressing activated FADD was significantly different between primary cutaneous CD30-positive lymphoproliferative disorders and S-ALCL (36.4% vs. 14.5%, P = 0.0083). Expression of cleaved caspase 3 was also significantly different between primary cutaneous lesions and S-ALCL (9.2% vs. 1.9%, P = 0.048). CONCLUSIONS: Although a larger number of cases should be studied to validate these results, these data provide evidence that differences in signaling through the death-receptor apoptosis pathway mediated by FADD may be responsible for the varying biologic behaviors of CD30-positive lymphoproliferative disorders involving the skin.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Donor origin of posttransplant lymphoproliferative disorder localized to a liver allograft: demonstration by fluorescence in situ hybridization.

SETTING: Posttransplant lymphoproliferative disorders in solid organ transplantation are mostly of recipient origin. We report an unusual case of posttransplant lymphoproliferative disorder following liver transplantation with localized limited involvement of the solid organ allograft. DESIGN: Tissues were obtained at the time of surgery and evaluated by immunohistochemistry, in situ hybridization, and fluorescence in situ hybridization with chromosome X and Y centromeric probes. PATIENT: A 53-year-old Hispanic man with hepatic failure due to hepatitis C virus who underwent orthotopic liver transplant from a female donor and developed posttransplant lymphoma in the transplanted liver. INTERVENTION: Withdrawal of immunosuppression, resection of liver allograft, and second transplant. RESULTS: This posttransplant lymphoproliferative disorder was clearly shown to be derived from Epstein-Barr virus-infected donor lymphoid cells. This was demonstrated by fluorescence in situ hybridization for X and Y chromosomes in paraffin sections in a sex-mismatched transplant. Despite aggressive histology (monoclonal B-cell immunoblastic lymphoma) and lack of response to withdrawal of immunosuppression, the posttransplant lymphoproliferative disorder was successfully managed by repeat liver transplantation without recurrence. CONCLUSION: Fluorescence in situ hybridization was used to prove donor derivation in a posttransplant lymphoma of the liver. Allograft-localized donor posttransplant lymphoproliferative disorder may represent a unique category with more favorable prognosis requiring different clinical management from other cases.

Female↗
PubMed2002

Crystal-storing histiocytosis involving the kidney in a low-grade B-cell lymphoproliferative disorder.

Intracellular crystal formation in histiocytes in multiple myeloma and other lymphoproliferative disorders is an uncommon presentation. In all cases, crystal formation is associated with accumulation of histiocytes containing light chain or immunoglobulin inclusions, and the disorder has been termed crystal-storing histiocytosis. We report a case of crystal-storing histiocytosis affecting the kidney with prominent infiltration of the mesangium by large mononuclear and multinuclear cells that contained eosinophilic crystalline material in the setting of a low-grade B-cell lymphoproliferative disorder. The interstitium did not contain similar crystal-containing histiocytes. On electron microscopy, the mononuclear and multinuclear cells in the mesangium were filled with rhomboid and needle-shaped crystals. Immunofluorescence studies showed the material to be positive for lambda light chains but negative for kappa light chains. To our knowledge, this is the first report of crystal-storing histiocytosis involving the kidney in a low-grade B-cell lymphoproliferative disorder with an immunophenotype of a marginal zone lymphoma and of exclusive expansion of the mesangium by infiltrating histiocytes containing needle-shaped and rhomboid crystals that were positive for lambda light chains. We report this case to illustrate an unusual finding of mesangial infiltration by crystal-storing histiocytes, and we review the literature of renal involvement by crystal-storing histiocytosis and crystal deposition in lymphoproliferative disorders.

B-Lymphocytes↗
PubMed1997

The clinical diversity and role of chemotherapy in lymphoproliferative disorder in liver transplant recipients.

BACKGROUND/AIMS: Post-transplant lymphoproliferative disorder is a well-documented complication with an incidence ranging from 2 to 10%, depending on the organ transplanted. Yet despite our increased understanding of the pathophysiology of this disease and the various treatments available, the mortality remains high at 60-80%. We present the clinical and histological features of ten adult liver transplant recipients with post-transplant lymphoproliferative disorder presenting over a 15-year period and review the therapeutic options. METHODS: CD20/CD45RO immunostaining was used for T/B-cell markers; polymerase chain reaction and in-situ hybridisation for Epstein-Barr virus genome detection; kappa/lambda immunostaining and gene rearrangement analysis for clonality. RESULTS: There were six females and four males (age range 24-56) with onset of post-transplant lymphoproliferative disorder-symptoms ranging from 3 to 72 months post transplant. Sites of post-transplant lymphoproliferative disorder included liver (n=4), lymph nodes (n=5), bone marrow (n=2), lungs (n=2), kidneys (n=2), brain, ovaries,: and pancreas (n=1). All lesions were classified as high-grade lymphoma, of B-cell lineage (9 tested); Epstein-Barr virus genome was detected in 7/10 cases. Three tumours were monoclonal; four were polyclonal and three undetermined. Treatment included immunosuppression reduction, antiviral therapy with acyclovir and/or chemotherapy (CHOP or VAPEC-B). Survival times for those patients not treated with chemotherapy were from 9 days to 30 months, whereas those receiving chemotherapy had remission times of 4 to 48 months. CONCLUSIONS: Longer-term remissions can be achieved in patients treated with systemic chemotherapy, although not without morbidity. Clonality assessment is important but treatment decisions should be based primarily on clinical features of progression, as polyclonal tumours can behave as aggressively as monoclonal tumours.

Adult↗
PubMed2006

Analysis of immunoglobulin heavy and light chain variable genes in post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorders (PTLD) derive from antigen-experienced B-cells and represent a major complication of solid organ transplantation. We characterized usage, mutation frequency and mutation pattern of immunoglobulin variable (IGV) gene rearrangements in 50 PTLD (polymorphic PTLD, n=10; diffuse large B-cell lymphoma, n=35; and Burkitt/Burkitt-like lymphoma, n=5). Among PTLD yielding clonal IGV amplimers, a functional IGV heavy chain (IGHV) rearrangement was found in 40/50 (80.0%) cases, whereas a potentially functional IGV light chain rearrangement was identified in 36/46 (78.3%) PTLD. By combining IGHV and IGV light chain rearrangements, 10/50 (20.0%) PTLD carried crippling mutations, precluding expression of a functional B-cell receptor (BCR). Immunohistochemistry showed detectable expression of IG light chains in only 18/43 (41.9%) PTLD. Failure to detect a functional IGV rearrangement associated with lack of IGV expression. Our data suggest that a large fraction of PTLD arise from germinal centre (GC)-experienced B-cells that display impaired BCR. Since a functional BCR is required for normal B-cell survival during GC transit, PTLD development may implicate rescue from apoptosis and expansion of B-cells that have failed the GC reaction. The high frequency of IGV loci inactivation appears to be a peculiar feature of PTLD among immunodeficiency-associated lymphoproliferations.

Apoptosis↗
PubMedDate not supplied

Immunological and genotypic analysis of human T gamma-lymphoproliferative disorders.

T gamma-lymphoproliferative disorders (T gamma-LPD) are rare diseases characterized by expansion of circulating elements with resemblance to large granular lymphocytes (LGL). We have studied 12 patients with T gamma-LPD. Morphological evaluation revealed 79-88% of LGL in non-adherent peripheral blood lymphocytes as assessed by light and electron microscopy. The most common features of the membrane phenotype included expression of T3, HNK-1 and AB8.28 (anti-Fc gamma); other surface markers of LGL (OKM1, B73.1, N901) were variably expressed or absent. Patients' LGL usually had little or no NK activity, with the exception of two patients who had values comparable to those of normal donors; in addition, cell preparations from all patients mediated antibody-dependent cellular cytotoxicity. The recent availability of the T cell receptor beta chain probes allowed us to investigate the lineage and the clonality of T gamma-LPD. Of the 12 patients analyzed, 10 displayed clonal rearrangements of T beta locus and expression of the T3 antigen, whereas the two remaining cases displayed a germ-line configuration of the T beta gene and no expression of the T3 antigen. We suggest that individual T gamma-LPD cases represent the clonal expansion of cells frozen at different stages of differentiation/activation within an individual hematopoietic LGL/NK lineage. These data suggest that either a subset of LGL or a particular step of differentiation may be related to the T cell lineage.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1998

Lymphoproliferative disorder after liver transplantation.

Lymphoproliferative disorder (LPD) is a well recognized complication of solid organ transplantation. It is associated with Epstein-Barr virus (EBV) infection and is often a fatal complication of immunosuppression. We report a 2.5-year-old boy who developed LPD presenting as small bowel lymphoma after liver transplantation. The patient had intermittent fever after transplantation and reactivation of latent EBV infection was documented by pre- and posttransplant serologic tests. About 5 months after his liver transplantation, the patient had sudden onset of abdominal pain and emergency laparotomy was performed for peritonitis. He proved to have multiple small bowel perforations caused by B cell lymphoma and died of multiple organ failure 9 days after operation, despite aggressive treatment and stopping immunosuppressive agents. We conclude that prevention of overimmunosuppression in pediatric recipients after liver transplantation and early detection and treatment of LPD are important to decrease this often-fatal complication.

Child, Preschool↗
PubMed1997

Presence of Epstein-Barr virus latency type III at the single cell level in post-transplantation lymphoproliferative disorders and AIDS related lymphomas.

AIMS: To investigate the expression pattern of Epstein-Barr virus (EBV) latent genes at the single cell level in post-transplantation lymphoproliferative disorders and acquired immunodefiency syndrome (AIDS) related lymphomas, in relation to cellular morphology. METHODS: Nine post-transplantation lymphoproliferative disorders and three AIDS related lymphomas were subjected to immunohistochemistry using monoclonal antibodies specific for EBV nuclear antigen 1 (EBNA1) (2H4), EBNA2 (PE2 and the new rat anti-EBNA2 monoclonal antibodies 1E6, R3, and 3E9), and LMP1 (CS1-4 and S12). Double staining was performed combining R3 or 3E9 with S12. RESULTS: R3 and 3E9 anti-EBNA2 monoclonal antibodies were more sensitive than PE2, enabling the detection of more EBNA2 positive lymphoma cells. Both in post-transplantation lymphoproliferative disorders and AIDS related lymphomas, different expression patterns were detected at the single cell level. Smaller neoplastic cells were positive for EBNA2 but negative for LMP1. Larger and more blastic neoplastic cells, sometimes resembling Reed-Sternberg cells, were LMP1 positive but EBNA2 negative (EBV latency type II). Morphologically intermediate neoplastic cells coexpressing EBNA2 and LMP1 (EBV latency type III), were detected using R3 and 3E9, and formed a considerable part of the neoplastic population in four of nine post-transplantation lymphoproliferative disorders and two of three AIDS related lymphomas. All samples contained a subpopulation of small tumour cells positive exclusively for Epstein-Barr early RNA and EBNA1. The relation between cellular morphology and EBV expression patterns in this study was less pronounced in AIDS related lymphomas than in post-transplantation lymphoproliferative disorders, because the AIDS related lymphomas were less polymorphic than the post-transplantation lymphoproliferative disorders. CONCLUSIONS: In post-transplantation lymphoproliferative disorders and AIDS related lymphomas, EBV latency type III can be detected by immunohistochemistry in a subpopulation of tumour cells using sensitive monoclonal antibodies R3 and 3E9. Our data suggest that EBV infected tumour cells in these lymphomas undergo gradual changes in the expression of EBV latent genes, and that these changes are associated with changes in cellular morphology.

Antibodies, Monoclonal↗
PubMed2002

Use of EBV PCR for the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients.

Epstein-Barr virus (EBV) is known to be involved in the majority of patients who develop post-transplant lymphoproliferative disorder after solid organ transplant. We conducted a retrospective study to determine the utility of qualitative and quantitative Epstein-Barr virus polymerase chain reaction (PCR) for the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients. Peripheral blood leukocytes obtained from 35 adult solid organ transplant patients consecutively referred for evaluation of possible post-transplant lymphoproliferative disorder, were tested by EBV PCR at the time of initial evaluation and at time points thereafter. Eighteen of 35 (51%) patients were ultimately diagnosed with post-transplant lymphoproliferative disorder by tissue biopsy. Fifteen of 18 (83%) patients were found to have EBER-1 positive tumors by in situ hybridization. EBV PCR was positive in 7 of 15 patients, suggesting a sensitivity of 39%. Seventeen patients without post-transplant lymphoproliferative disorder and three with EBER-1 negative post-transplant lymphoproliferative disorder all had negative EBV PCR tests, suggesting a specificity of 100%. We observed that declines in EBV DNA load were associated with response to therapeutic interventions, such as reduction in immunosuppression, rituximab therapy and chemotherapy. We conclude that peripheral blood EBV PCR may have a role in the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients.

Adult↗