The IPTA Nashville consensus conference on post-transplant lymphoproliferative disorders after solid organ transplantation in children: IV-consensus guidelines for the management of post-transplant lymphoproliferative disorders in children and adolescents.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders (PTLD) after pediatric solid organ transplantation. This report addresses the outcomes of deliberations by the PTLD Management Working Group. A strong recommendation was made for reduction in immunosuppression as the first step in management. Similarly, strong recommendations were made for the use of the anti-CD20 monoclonal antibody (rituximab) as was the case for chemotherapy in selected scenarios. In some scenarios, there is uncoupling of the strength of the recommendations from the available evidence in situations where such evidence is lacking but collective clinical experiences drive decision-making. Of note, there are no large, randomized phase III trials of any treatment for PTLD in the pediatric age group. Current gaps and future research priorities are highlighted.

Choledochal cyst in two pediatric heart transplant patients.

Choledochal cyst is a relatively uncommon entity in Western countries. No reports of choledochal cyst in heart transplant patients have been reported to date. We report two cases of choledochal cyst in pediatric heart transplant recipients, one with post-transplant lymphoproliferative disorder (PTLD) within the cyst. The first patient had abdominal pain, increased liver enzymes and was seropositve for Epstein-Barr virus. A choledochal cyst with PTLD was removed 4 years after heart transplantation. The second patient presented 14 years after heart transplantation with a choledochal cyst that was excised for severe abdominal pain. This previously unreported association between choledochal cysts in conjunction with PTLD and heart transplantation is interesting and a possible common pathogenesis is proposed. The management and alternative treatments were briefly noted. We recommend an aggressive treatment for patients with suspected choledochal cyst after heart transplantation because of the increased potential for malignant transformation.

Classical Hodgkin lymphoma-type PTLD after solid organ transplantation in children: a report on 17 patients treated according to subsequent GPOH-HD treatment schedules.

Post-transplant lymphoproliferative disease (PTLD) is a severe complication after solid organ transplantation (SOT). Classical Hodgkin lymphoma-type (HL-) PTLD is a rare subtype, and systematic data on treatment and prognosis are lacking. We report on 17 pediatric patients with classical HL-PTLD. HL-PTLD developed late at a median of 8.1 years after SOT. It was commonly EBV-positive (16/17) and expressed both CD30 (all tumors) and CD20 (8/17 tumors). Patients were treated with chemotherapy +/- involved field radiotherapy (IF-RT) according to the respective GPOH-HD protocol tailored by stage and LDH. Overall survival at 2 and 5 years was 86% with 81% of patients surviving event-free. Six patients had additional rituximab treatment; in two it was given as upfront monotherapy and in four was given concurrently with their chemotherapy. Rituximab monotherapy did not lead to long-term remission. In conclusion, treatment of HL-PTLD with classical HL chemotherapy is effective and tolerable. New treatment modalities such as CD30-targeted or EBV-specific agents may diminish toxicity.

Oncogenic γ Herpesviruses EBV and HHV8 in Kidney Transplantation.

Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8) are γ herpesviruses associated with post-transplant malignancies in kidney transplant recipients. EBV is associated with post-transplantation lymphoproliferative disorder (PTLD), with increased risk in EBV-seronegative patients on intensified immunosuppression. Human herpesvirus-8 is associated with Kaposi's sarcoma (KS), with an increased risk in certain patient populations. Diagnosis of PTLD and KS relies on tissue biopsy. The mainstay of therapy for both PTLD and Kaposi's sarcoma is a reduction of immunosuppression, and in the case of PTLD, consideration of rituximab. Chemotherapy, radiation therapy, or surgery is provided for disseminated or recalcitrant disease. The prognoses vary depending on the type of malignancy identified and stage of disease.

Epstein-Barr virus lymphoproliferative disorders after liver transplantation.

Post-transplant lymphoproliferative disorders (PTLD) represent a spectrum of histological and immunological abnormalities, ranging from benign polyclonal B-cell hyperplasia to monoclonal malignant lymphoma. The important role of Epstein-Barr virus (EBV) in PTLD in liver transplant patients, particularly in pediatric recipients, is reviewed. Understanding the risks of EBV infection, the clinical presentations and diagnosis of PTLD, and its pathophysiology are crucial to the management of these disorders. Current treatment methods have resulted in better outcomes of these disorders, which in the past were uniformly fatal.

Case report: an unusal cause of stridor in a post-liver transplant 6-year old.

Polymorphic lymphoproliferative disorder is a recognised cause of upper airway obstruction in children [N. Sculerati, M. Arriga, Ann. Otol. Rhinol. Laryngol 99 (1990) 445-450]. It is associated with long-term immunosuppression therapy and frequently with Epstein-Barr virus (EBV) infection [D.W. Hanto, Annu. Rev. Med. 46 (1995) 381-394; B.D. Fletcher, H.E. Heslop, H.C. Kaste, S. Bodner, Upper airway obstruction and pulmonary abnormalities due to lymphoproliferative disease following bone marrow transplantation in children, Pediatr. Radiol. 28 (1998) 492-496]. The prevalence in reported series ranges from 4 to 13% among post-transplant children [M. Ho, R. Jaffe, G. Miller, Transplantation 45 (1988) 719-727; G.B. Hammer, S. Cao, M.G. Boltz, A. Messner, Anesthesiology 89 (1998) 263-265; B.V. Lattyak, P. Rosenthal, Post-transplant lymphoproliferative disorder presenting in the head and neck, Laryngoscope 108 (1998) 1195-1198]. This condition may present in the transplanted allograft, the gastrointestinal tract, the head and neck, and in particular in the upper airway. Previously reported cases of upper airway obstruction have been in the supraglottis, Waldeyer's ring, the glottis, and one case of an intra tracheal mass [M. Ho, R. Jaffe, G. Miller, Transplantation 45 (1988) 719-727; G.B. Hammer, S. Cao, M.G. Boltz, A. Messner, Anesthesiology 89 (1998) 263-265]. We report a case of post-transplant lymphoproliferative disorder in the sub-glottis causing acute upper airway obstruction with negative (EBV) serology.

Treatment and prognosis of post-transplant lymphoproliferative disease.

Post-transplant lymphoproliferative diseases (PTLDs) are a clinically and morphologically heterogeneous group of lymphoid proliferations. They represent a life-threatening complication of solid organ transplantation. The mechanisms of their pathogenesis are not yet fully understood. A combination of impaired immunity, oncogenic consequences of immunosuppressive therapy and EBV infection may play a role. Studies on incidence, treatment and prognosis are difficult because of the small number of cases occurring at each transplant center and the lack of reliable classification. Overall mortality remains high even though 25% of patients require no other measure than reduction in immunosuppression which must be the first step of treatment. Several treatments are currently used but more adequate classification as well as multicenter studies are urgently needed because many questions remain with regard to therapeutic strategy. Late-onset monoclonal tumors may be treated by conventional chemotherapy, while EBV-positive PTLDs may benefit from other approaches such as antiviral therapies or immunologic modulation of tumor functions.

Post-transplant lymphoproliferative disorder.

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is increasingly recognized as a serious complication of solid organ transplantation in both children and adults. Factors associated with increased risk of PTLD include mismatch of recipient and donor EBV serologic status (seronegative recipient with seropositive donor), and intensive drug-induced immunosuppression. METHODS AND RESULTS: We searched MEDLINE for articles published since 1970 to January 2009. Search terms included posttransplant lymphoproliferative disorder, immunosuppression, posttransplant malignancy, treatment, antiviral agents, rituximab, interferon alpha, chemotherapy, radiation, surgery. Studies in English of adult and pediatric populations after solid organ transplantation were selected and analyzed. CONCLUSION: Screening of patients at risk and balancing the intensity of immunosuppression against the risk of allograft rejection could reduce the risk of developing PTLD. In patients who develop PTLD, the severity and extent of disease should be examined and an individualized treatment plan including immunosuppression reduction and other agents should accordingly be chosen.

Malignancy after solid organ transplantation: an overview.

With improving survival following solid organ transplantation, clinicians must be aware of post-transplant complications. One increasingly frequent complication is the development of malignancy after transplantation. The most common malignancies encountered in the post-solid organ transplant setting are nonmelanoma skin cancers, post-transplant lymphoproliferative disorders, and Kaposi's sarcoma (KS). The pathogenesis of these tumors is likely related to the immunosuppressive drugs used post-transplantation and subsequent viral infection. Treatment involves modification of the immunosuppressive drug regimen, resection of localized disease, and chemotherapy. We present the second reported case of a patient with lung transplantation who developed KS in the lung graft.

Diagnosis and management of posttransplant lymphoproliferative disorder in solid-organ transplant recipients.

The Epstein-Barr virus (EBV) has a pivotal pathophysiologic role in the development of most lymphoproliferative disorders that occur after solid-organ transplantation. The term "EBV-associated posttransplant lymphoproliferative disorder" (PTLD) includes all clinical syndromes of EBV-associated lymphoproliferation, ranging from uncomplicated posttransplant infectious mononucleosis to true malignancies that contain clonal chromosomal abnormalities. PTLDs are historically associated with a high mortality rate in patients who have a monoclonal form of the disorder. Recently described approaches to pathology, diagnosis, treatment, and preventive strategies of PTLD, however, have the potential to improve outcome.

European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.6.1. Cancer risk after renal transplantation. Post-transplant lymphoproliferative disease (PTLD): prevention and treatment.

GUIDELINES: A. In the first year after organ transplantation, recipients are at the greatest risk of developing lymphoproliferative diseases (PTLDs), which are induced most often by Epstein-Barr virus (EBV) infection, and patients should therefore be screened prior to or at the time of transplantation for EBV antibodies. B. In the rare cases (<5%) where the recipient is EBV seronegative, he or she has a 95% likelihood of receiving an organ from an EBV-seropositive donor, which translates into a high risk of primary EBV infection with seroconversion soon after transplantation. In such cases, the recipient should receive a prophylactic antiviral treatment with acyclovir, valacyclovir or ganciclovir, starting at the time of transplant and lasting for at least 3 months. The specific recommendations given for CMV prophylaxis could be applicable in this situation. C. The treatment of PTLD should be based on accurate pathology with extensive cell markers and phenotyping. The treatment modalities are as follows. Reduction of basal immunosuppression in all cases (either maintain only steroids, or decrease by at least 50% the anti-calcineurin drugs and stop other immunosuppressive drugs). In the case of EBV-positive B-cell lymphoma, antiviral treatment with acyclovir, valacyclovir or ganciclovir may be initiated for at least 1 month or according to the blood level of EBV replication when available. In the case of rare lymphomas from the mucosal-associated lymphoid tissue (MALT) with positive Helicobacter pylori, full eradication of H. pylori should be carried out with a validated protocol. Subsequent H. pylori prophylaxis should be implemented to avoid relapse. In the case of CD20-positive lymphomas, treatment with rituximab, a chimeric monoclonal antibody directed against CD20, should be carried out with one i.v. injection per week for 4 weeks. In the case of diffuse lymphomas or improper response to previous treatment, CHOP chemotherapy should be used alone or in combination with rituximab. The CHOP regimen is cyclophosphamide, doxorubicine, vincristine and prednisone. Complete cessation of immunosuppression with or without graft nephrectomy should also be considered.