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Diagnosis of posttransplantation lymphoproliferative disorder by endomyocardial biopsy in a cardiac allograft recipient.

Posttransplantation lymphoproliferative disorder is a serious complication of organ transplantation. This disorder has been linked to Epstein-Barr virus infections and can involve the transplanted organ. In the past the diagnosis of posttransplantation lymphoproliferative disorder in heart transplant recipients involving the transplanted organ was made primarily at autopsy. A case of a patient with posttransplantation lymphoproliferative disorder in whom the diagnosis was made initially by endomyocardial biopsy with confirmation by application of molecular techniques on mediastinal lymph node tissue and who was subsequently treated successfully is reported.

Biopsy↗

Primary intraocular posttransplantation lymphoproliferative disorder.

We report a case of posttransplantation lymphoproliferative disorder manifesting as an isolated, unilateral iris tumor. A 2-year-old boy who had undergone liver transplantation for biliary atresia at age 4 months was seen with a 2-month history of an enlarging iris nodule. Histopathologic examination of the iris lesion demonstrated a mixed population of lymphoid cells. To our knowledge, this is the youngest patient with posttransplantation lymphoproliferative disorder isolated to the eye.

Biliary Atresia↗

Constitutive activation of Jak/STAT proteins in Epstein-Barr virus-infected B-cell lines from patients with posttransplant lymphoproliferative disorder.

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is a major complication after bone marrow and solid organ transplantation. The disease encompasses a spectrum of abnormal, Epstein-Barr virus (EBV)-associated B-cell proliferations. We have previously shown that EBV-infected, spontaneous lymphoblastoid cell lines (SLCL) derived from PTLD patients require autocrine interleukin (IL)-10 to proliferate. To determine if cytokine signal transduction is involved in the autonomous growth of the SLCL, the activation states of the Jak/STAT signaling pathway proteins were analyzed in three different SLCL, termed JB7, MF4, and VB4. METHODS: The tyrosine phosphorylation (P-tyr) states of the Janus kinases (Jaks) and signal transducers and activators of transcription (STAT) proteins were examined by immunoprecipitation and immunoblot. Activated STAT dimer formation was determined by electromobility shift assays. RESULTS: All three SLCL, but not the Daudi Burkitt's lymphoma B-cell line, expressed the four known Jak kinases constitutively tyrosine phosphorylated, with particularly high levels of P-tyr Jak1 in the JB7 line. STAT1 and STAT3, but not STAT2 or STAT5, are also constitutively activated in all SLCL. The ability of the activated STAT proteins to form DNA-binding dimers was confirmed by electromobility shift assay. The SLCL, but not the Daudi line, express activated STAT complexes composed of STAT1 and STAT3. Another EBV-infected B-cell line, isolated from a lymph node biopsy after kidney transplantation, is phenotypically similar to the other SLCL in both surface antigen and activated STAT1 and STAT3 expression. CONCLUSION: These data support the presence of a constitutively active autocrine signaling pathway consistent with IL-10 in the SLCL.

Antigens, CD↗

Polymorphism of the CD30 promoter microsatellite repressive element is associated with development of primary cutaneous lymphoproliferative disorders.

Lymphomatoid papulosis is a preneoplastic cutaneous lymphoproliferative disorder characterized by overexpression of CD30, a member of the tumor necrosis factor receptor superfamily. CD30 signaling is known to have an effect on the growth and survival of lymphoid cells. Therefore, we hypothesized that the development of lymphomatoid papulosis and progression to an associated neoplasm such as cutaneous and systemic anaplastic large cell lymphoma may reflect an underlying genetic defect. In this study, we determined that two allelic forms of the CD30 promoter microsatellite repressive element, designated 30M377 and 30M362, are associated with the development of lymphomatoid papulosis and CD30+ lymphomas in lymphomatoid papulosis patients, respectively. These findings suggest that allele-specific differences in the control of CD30 transcription may determine the pathogenesis of the spectrum of CD30+ cutaneous lymphoproliferative disorders.

Boston↗

Membrane receptors and their redistribution in lymphoproliferative disorders.

Lymphoid cells from 20 patients with lymphoproliferative disorders, including chronic lymphocytic leukemia, hairy cell leukemia, Sezary syndrome, lymphoma, and lymphadenitis, were studied for redistribution of surface membrane immunoglobulins (SmIg) and concanavalin A (Con-A) receptors. Fluorescein-labeled polyvalent goat anti-human immunoglobulin and fluoresceinated concanavalin A were used as ligands. Results were similar with both ligands. The highest percentage of capping of ligand-membrane receptors was noted in mononuclear cells from patients with "hairy" cell leukemia: from 24% to 90%. These cells showed moderate to marked fluorescein activity and were able to cap within 15 min at 4 degrees C. Chronic lymphocytic leukemia cells showed a weak fluorescein stain with a very low percentage of cells (0%--16%) capping. Lymph node cells from patients with lymphoma demonstrated moderate to strong fluorescein activity with only an average of 3% of the cells capping; while lymphoid cells from patients with lymphaedenitis showed an average of 27.5% capping and moderate fluorescein activity. Capping of Con-A receptors in mononuclear cells from patients with Sezary syndrome was poor (0%--14%) with moderate fluorescein intensity. This report demonstrates difference in density and mobility of binding sites for SmIg and Con-A on the surface membrane of lymphoid cells from various subclasses of lymphoproliferative disorders. These differences may assist in the differential diagnosis and classification of these conditions.

Cell Membrane↗

Lymphoproliferative disorder involving the cervix in a patient being treated with FK-506.

FK-506 is an immunosuppressive agent used mainly to prevent allograft rejection in organ transplant patients. Recently, it has been applied as a treatment for patients with autoimmune disorders. An entity called posttransplant lymphoproliferative disorder (PTLD) is a well-recognized result of immunosuppression in transplant patients receiving long-term immunosuppression. This disorder is a complication of treatment with FK-506 in 0.7 to 1.6% of transplant patients and is usually of B-cell origin. A majority of patients have serologic evidence of EBV infection. We report a case of a patient receiving long-term FK-506 therapy for multiple sclerosis who developed lymphoproliferative disorder involving the cervix. We will discuss the possible role of FK-506 initiation of this tumor.

Adult↗

Present nosography of lymphoproliferative disorders.

The present nosography of lymphoproliferative disorders is continuously in progression. Until now, a number of data regarding cytomorphological, cytochemical, immunological and molecular biological findings demonstrated importance in diagnostic and prognostic evaluation.

Deltaretrovirus Infections↗

The atypical lymphoproliferative disorders: tissue expression.

The atypical lymphoproliferative disorders (ALDs) represent one of the most intriguing problems in diagnostic histopathology. In fact, there is no sharp distinction between benign and malignant lesions within this group of diseases and the name ALD reflects this doubt. New developed molecular and genetic techniques probably will help to solve this diagnostic problem.

Diagnosis, Differential↗

Hepatitis C virus (HCV) infection and lymphoproliferative disorders

Several infectious agents have been associated with development of lymphoproliferative disorders. Among these is hepatitis C virus (HCV), which infects more than 200 million people worldwide. HCV infection has been linked to progression of type II mixed cryoglobulinemia (MC) syndrome and has also been suggested to contribute to development of B-cell non-Hodgkin's lymphoma (NHL). Mechanisms responsible for development of lymphoproliferative disorders among HCV-positive patients remain unclear. Accumulating evidence supports a model in which chronic stimulation of B-cells by antigens associated with HCV infection causes nonmalignant B-cell expansion that may evolve into B-cell NHL. The course of disease among HCV-positive B-cell NHL patients may be complicated by coinfection with other infectious agents. This possibility has been explored by studies that have investigated potential interactions between HCV and human immunodeficiency virus (HIV) as well as between HCV and Epstein-Barr virus (EBV). Further characterization of the mechanisms by which HCV promotes development of lymphoproliferative disorders may improve diagnosis, classification, and treatment of these conditions.

Antiviral Agents↗

Posttransplantation lymphoproliferative disorders (PTLD): current perspectives.

Posttransplant lymphoproliferative disorders (PTLDs) are a family of lymphoid hyperplasias and neoplasias that occur in the context of organ transplantation and immunosuppression. A strong association exists with Epstein-Barr virus (EBV) infection of the B lymphocyte. This review summarizes clinical and pathological aspects of these lesions and explains the terminology used to describe them. Clinical diagnosis and therapy, including experimental approaches, are outlined. Patient outcomes from published series are given. The clinical heterogeneity and the need to individualize therapy for these patients are stressed.

Adjuvants, Immunologic↗

Low-dose radiation for posttransplant lymphoproliferative disorder.

Initial treatment for posttransplant lymphoproliferative disorder (PTLD) usually involves discontinuation of immunosuppressants. Anti-CD20 monoclonal antibody and/or antivirals are typically employed for persistent disease. Chemotherapy is generally reserved as a final option. The role of radiation therapy, and doses required, have not been well established. Low-dose involved field radiation therapy was used in three pediatric bone marrow transplant (BMT) patients with biopsy-proven PTLD. One patient received a matched T-cell-depleted BMT for dyskeratosis congenita. Two patients with acute myelogenous leukemia received an unrelated umbilical cord blood transplant, and a matched-related allogeneic BMT. All patients required intubation for respiratory distress due to PTLD. Initial treatment was discontinuation or decrease in FK-506. Anti-CD20 antibody was started in all patients, and foscarnet in one patient. All patients were treated with three 150-cGy fractions, for a total dose of 450 cGy. Time from BMT to development of PTLD was 4, 2, and 32 months, respectively. Duration of observation on initial medical therapy prior to irradiation was 11 days, 12 days, and 1 day, respectively. The radiation was well tolerated with no acute complications. Two patients were extubated at 8 and 4 days postradiation, respectively. The first patient had complete radiographic resolution of the mass and adenopathy at 4 months after radiation. The second died of pulmonary hemorrhage and disseminated aspergillosis infection, but had significant regression of disease in the irradiated area 15 days after radiation. The third had pronounced shrinkage of his mediastinal mass. A biopsy was taken of a persistent mass 4 months after radiation, with no evidence of lymphoproliferative disease. These cases demonstrate that low-dose radiation for PTLD is effective for palliation and produces a durable response with no acute toxicity.

Adult↗

Infectious complications associated with alemtuzumab use for lymphoproliferative disorders.

BACKGROUND: Alemtuzumab is an emerging therapy for refractory lymphoproliferative disorders. The associated long-term risks of infection remain poorly defined. METHODS: From July 2001 through December 2003, all patients who received alemtuzumab for the treatment of lymphoproliferative disorders at 1 institution underwent a retrospective evaluation to document infectious complications until death or end of follow-up in October 2004. Alemtuzumab recipients who underwent allogeneic hematopoietic stem cell transplantation were compared with a concurrent cohort who also underwent allogeneic hematopoietic stem cell transplantation but did not receive alemtuzumab. RESULTS: Twenty-seven patients were identified (21 with chronic lymphocytic leukemia and 6 with plasma cell disorders). The overall mortality was 37%, with 7 of 10 deaths being related to infection. Significant opportunistic infections occurred in 9 patients (43%) with chronic lymphocytic leukemia, including cytomegalovirus, progressive multifocal leukoencephalopathy, adenovirus, toxoplasmosis, and acanthamaebiasis. Thirty nonopportunistic infections in 22 patients (82%) were also identified. The 3 deaths related to nonopportunistic infections all involved Enterococcus species bacteremia. When compared with a concurrent chronic lymphocytic leukemia cohort that underwent allogeneic hematopoietic stem cell transplantation, alemtuzumab recipients had an incidence of cytomegalovirus reactivation of 66.7% (6 of 9 patients), compared with 37% in the non-alemtuzumab group (10 of 27 patients; P = .15), and an incidence of post-transplant opportunistic infections (excluding herpesviruses) of 44.4% (compared with 29.6% in the non-alemtuzumab group; P = .41). CONCLUSIONS: Despite the use of herpesvirus and Pneumocystis pneumonia prophylaxis, serious infectious complications occur in patients receiving alemtuzumab for lymphoproliferative disorders. Infectious complications are more varied and diverse in patients receiving alemtuzumab than has been reported in trials to date.

Adult↗

Post-transplant lymphoproliferative disorder presenting as epistaxis.

An unusual case of epistaxis resulting from post-transplant lymphoproliferative disorder is described. A 30-year-old woman who had undergone renal transplantation 12 years previously presented with profuse, posterior, unilateral epistaxis. The initial findings, workup and treatment are presented. A post-nasal space (PNS) mass was detected and biopsy showed this to be an Epstein-Barr virus-positive polymorphous B-cell post-transplant lymphoproliferative disorder. Computed tomography findings showed a polypoid lesion protruding from the sphenoethmoidal recess and filling the left PNS. Post-transplant lymphoproliferative disorder is well known to involve tonsil tissue. Commonly, this is the first presentation of the disease in children. However, until now post-transplant lymphoproliferative disorder has not been described in the PNS or nasal cavity presenting as epistaxis. We conclude that all transplant patients presenting with epistaxis should be followed up for an accurate examination of the PNS and nasal cavity after the acute episode.

Adult↗

Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD).

Post-transplant lymphoproliferative disorders (PTLD) are a life-threatening complication following solid organ transplantation. Treatment with rituximab, a humanized anti-CD20 monoclonal antibody, has proved to be a promising approach and shown a low toxicity profile. Between February 1999 and April 2002, we conducted a multicentre phase II trial investigating rituximab as single agent in 17 patients with PTLD. Transplanted organs were heart (n = 5), kidney (n = 4), lung (n = 4) and liver (n = 4). Patients were treated with four weekly doses of 375 mg/m(2) of rituximab. The mean follow-up time is 24.2 months. Histology was distributed in 10 diffuse large cell-, 2 marginal zone-, 1 Burkitt-like lymphoma, 1 Hodgkin-like PTLD and 3 polymorphic lymphoproliferations. Therapy was well tolerated and no severe adverse events were observed. The mean overall survival period is 37.0 months with 11 patients still living. In total, 9 patients (52.9%) achieved a complete remission, with a mean duration of 17.8 months. Partial remission was observed in 1 patient, minor remission in 2 patients, no change in 3 patients and 1 patient experienced progressive disease. Two patients relapsed, at intervals 3 and 5 months after obtaining complete remission. Rituximab proved to be well tolerated and effective in the treatment of PTLD.

Adult↗

Posttransplantation lymphoproliferative disorder: endoscopic findings.

BACKGROUND: Posttransplantation lymphoproliferative disorder (PTLD) may manifest a variety of nonspecific symptoms and must be suspected in the patient who undergoes solid organ transplantation. Common sites of occurrence include the gastrointestinal tract, the central nervous system, and lymphoid tissue of the oral pharynx, mediastinum, and mesentery. The large incidence of gastrointestinal involvement provides an opportunity for endoscopic diagnosis. This is the description of a characteristic endoscopic finding in patients who have undergone liver transplantation who are under evaluation for suspected PTLD. METHODS: During a 2-year period, 27 liver transplantations were performed in 24 pediatric patients. Fourteen patients underwent endoscopic evaluation. Indications for endoscopy included abdominal pain, vomiting, hematemesis, irritability, growth failure, anemia, occult blood loss, and suspected PTLD. Biopsy specimens were obtained from any endoscopically detected abnormality and from the duodenum, gastric antrum, esophagus, terminal ileum, cecum, and rectum. Specimens with suspected PTLD were evaluated with Epstein-Barr virus latent membrane stain. RESULTS: Six patients were found to have a characteristic lesion, which was raised, rubbery, and erythematous, with a central ulceration. Lesions were singular or multiple and ranged from 5 to 15 mm in diameter. Microscopic evaluation revealed a monotonous proliferation of lymphocytes. All specimens were positive for Epstein-Barr virus latent membrane protein stain. Stains for cytomegalovirus were negative. Biopsy specimens from the eight patients without identified characteristic lesions were negative for PTLD. CONCLUSIONS: Panendoscopy is a useful tool for the diagnosis and treatment of gastrointestinal PTLD. Endoscopy is easily accomplished, may provide an instantaneous result if the characteristic lesion is identified, and provides tissue for disease classification. Patients with unexplained gastrointestinal signs or symptoms should undergo panendoscopy for suspected PTLD.

Adolescent↗

Posttransplant lymphoproliferative disorders in transplant recipients.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation, with a reported incidence between 0.8% and 32%. The incidence of PTLD mainly depends on the transplanted organ, the immunosuppressive drugs, the viral serology, and the age of the recipient. The aim of our study was to analyze our patients diagnosed with PTLD. Among 1040 transplantations, including 931 renal, 14 heart, 55 liver and 40 allogeneic peripheral blood stem cell (PBSC), 8 patients (7 male, 1 female) were diagnosed with PTLD. Five patients had undergone renal, one cardiac, one liver, and one PBSC transplantations. Four patients were diagnosed within the first year of transplantation. Six patients presented with abdominal disease, one with convulsions, and one with peripheral lymph node involvement. According to the World Health Organization classification system, six patients were diagnosed as diffuse large B-cell lymphoma, one patient Burkitt's lymphoma, and one polymorphic PTLD. At the time of diagnosis, 7 patients showed positive Epstein-Barr virus (EBV) and cytomegalovirus (CMV) Ig G and negative Ig M; one patient, positive EBV Ig M and negative CMV Ig G and M. EBV viral load was extremely high in the plasma of two patients by polymerase chain reaction. One of these patient's pathologic tissue revealed positive EBV DNA, which was not detected in six of the other eight patients. This patient was an 8-year-old boy diagnosed with Burkitt's lymphoma at 31 months after liver transplantation. Seven patients died of disease or complications of chemotherapy. Only one patient survived after the diagnosis of PTLD. In conclusion, even with treatment the mortality rate was high among our patients with PTLD. To decrease the incidence of PTLD and related mortality, risk factors must be evaluated in multicenter studies.

Adult↗

Adhesion molecules in B-chronic lymphoproliferative disorders.

In B-chronic lymphoproliferative disorders (B-CLD) adhesion molecules (AM) have been investigated in order to explain the variable biologic behavior and dissemination patterns and to assess their contribution to the differential diagnosis and prognosis of these diseases. The main AM studied either by immunohistochemistry on lymph node sections or by flow cytometry in blood and bone marrow specimens are L-selectin, CD11a/CD18 (LFA-1), CD54 (ICAM-1), CD44 (HCAM), CD11c/CD18 (gp150/95), and CD49d/CD29 (VLA-4). Among B-CLD, hairy-cell leukemia (HCL) and follicular lymphoma (FL) show a uniform AM expression pattern. Thus, HCL is characterized by high CD54, CD44, VLA-4, CD11c, and CD18 and by low or absent CD11a and L-selectin, whereas FL confined to the lymph nodes is characterized by high CD11a, CD18, and CD54 expression. Diffuse growth and dissemination of FL is associated with alteration in the AM profile. Mantle-cell lymphoma (MCL) seems to be characterized by low or absent L-selectin and CD11c and high CD54 expression, especially compared with B-chronic lymphocytic leukemia (B-CLL). B-CLL is the most heterogeneous among all B-CLD with respect to AM expression. In general, low LFA-1 and CD54, high L-selectin and CD44, and variable CD11c characterize B-CLL. Cases with splenomegaly as their prominent feature bear high CD11a, CD18, CD29, and CD11c on the surface of the leukemic cells. Small lymphocytic lymphoma (SLL) shares the same AM phenotype with B-CLL, with the possible exception of LFA-1, which is strongly expressed on SLL cells. LFA-1 and CD54 are more frequently positive in lymphoplasmacytic lymphoma (LPL) as compared with B-CLL. Splenic lymphoma with villous lymphocytes differs from B-CLL by its high LFA-1, VLA-4, and CD54 and low L-selectin expression, whereas its high LFA-1 positivity can differentiate it from HCL. Surface and soluble AM have been investigated as possible prognostic markers in these diseases. Conflicting data exist concerning the prognostic significance of surface AM. However, high soluble (s)CD44 and CD54 levels in B-CLL and non-Hodgkin's lymphomas (NHL) are considered as adverse prognostic factors.

Antigens, CD↗

Humanized anti-CD20 monoclonal antibody (Rituximab) treatment for post-transplant lymphoproliferative disorder.

INTRODUCTION: Post-transplant lymphoproliferative disorders (PTLD) is a consequence of Epstein-Barr virus (EBV) infection and is a B-cell hyperplasia with CD-20 positive lymphocytes. The treatment of PTLD includes reduction/withdrawal of immunosuppression and chemotherapy. This study reports our center experience with humanized monoclonal antibody against CD-20 (Rituximab) for the treatment of PTLD. MATERIAL AND METHODS: Eight cases of PTLD after solid organ transplantation [six kidney, one kidney/pancreas (KP) and one liver] occurred between September 1998 and October 2001. The mean time between transplant and the diagnosis of PTLD was 57.3 months (range 3 months to 10 yr). Five patients underwent cadaveric transplant, five males and six were Caucasians with mean age of 48 yr (range 20-67 yr). RESULTS: The clinical presentation was as follows: lymphadenopathy--5, gastrointestinal bleeding--2 and tonsillar enlargement--1. The diagnosis was made by a lymph node biopsy in five, a gastric ulcer biopsy in two and a tonsillar biopsy in one case. Six of them had polymorphous, two had monoclonal B-cell lymphoma, and all were positive for CD-20. Six were related to EBV, documented by latent membrane protein (LMP) or Epstein-Barr encoded RNA (EBER) staining. Immunosuppression at the time of PTLD diagnosis consisted of tacrolimus in six cases and cyclosporine A (CsA) in two with mycophenolate mofetil (MMF) and azathioprine--3 each and sirolimus--1. Rituximab was administered at a dose of 375 mg/m2 once a week for 4 wk. There were no side effects seen with this therapy. Immunosuppression was reduced in all patients. Complete remission was observed in seven cases (one required two courses). One patient who did not respond received chemotherapy. Patients were followed for a mean period of 22.5 months (range 10-45 months post-PTLD diagnosis. At the last follow-up all eight patients were alive, seven with a functioning graft and one on maintenance dialysis. Three of these patients had been in remission for more than 2.5 yr. CONCLUSION: Rituximab is an effective agent in the treatment of PTLD without the morbidity characteristic of chemotherapy. Chemotherapy should be reserved only for those refractory to Rituximab therapy.

Adult↗