EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Posttransplant lymphoproliferative disease is a major complication following solid-organ transplant. We summarize the relation of Epstein-Barr virus to this complication and discuss its treatment in pediatric patients.

Key words : Epstein-Barr virus, Posttransplant lymphoproliferative disease, Solid-organ transplant, Transplantation

Posttransplant lymphoproliferative disease (PTLD) comprises a wide spectrum of lymphoid and plasmacytic proliferations occurring after solid-organ or hematopoietic stem cell transplant. It causes significant mortality and morbidity in pediatric liver transplant recipients. The reported overall pediatric incidence of PTLD is 6% to 20%, and the mortality is as high as 20%. However, recent reviews give incidence rates of less than 5% and very low mortality. The entity of PTLD was first described in a renal transplant recipient in 1968,¹ but the term "PTLD" was introduced in 1984 by Starzl and colleagues.²

The development of PTLD is the consequence of an imbalance between immunosuppression and immunosurveillance. The risk of graft rejection has dropped, thanks to the use of potent immunosuppressive agents, which have resulted in longer survival in transplant patients. However, the impairment of T-cell function that results from the immunosuppression required to prevent allograft rejection places transplant patients at risk for PTLD. Most cases of PTLD are associated with Epstein-Barr virus (EBV) infection and represent a spectrum of diseases ranging from polyclonal PTLD to lymphoma.

Pathology
According to the 2008 World Health Organization classification, PTLDs are stratified into 4 groups: (1) early-type PTLDs, (2) polymorphic PTLDs, (3) monomorphic PTLDs, and (4) classical Hodgkin lymphoma.³ Early-type PTLDs are nondestructive lymphoplasmacytic proliferations. Polymorphic PTLDs are the most challenging. They are destructive lymphoplasmacytic proliferations, positive for cluster of differentiation 20 (CD20) and CD30, and negative for CD15, but they do not fulfill the criteria of malignant lymphoma. Monomorphic PTLDs are straightforward to diagnose because they meet the criteria of lymphoma originating from B cells or T cells, diffuse large-B cell lymphoma, Burkitt lymphoma, or plasmablastic lymphoma. Most are of the B-cell phenotype, although 10% to 15% are of T-cell origin; rarely, they meet the criteria for Hodgkin lymphoma. A transition from early PTLD through polymorphic PTLD to monomorphic PTLD is possible. Histology may show overlap between several categories, and PTLDs can present as different subtypes in different locations in the same patient. Clinically, PTLD involves extranodal sites. The allograft and the gastrointestinal tract are frequently involved; however, PTLD may occur at any site, including the skin and the central nervous system.³

Epstein-Barr virus and posttransplant lymphoproliferative disease
Seventy percent of PTLDs are associated with infection or reactivation of EBV. Healthy children exhibit a strong immune response against EBV, mainly by cytotoxic T cells, resolving the infection. In patients with chronic immunosuppression and depressed T-cell function, EBV replicates and drives B cells to immortalization. Asymptomatic Epstein-Barr viremia progresses to infectious mononucleosis and PTLD in these patients. Lymphoproliferation driven by EBV may even progress to overt lymphoma. Most frequently, PTLDs related to EBV infections occur in the first 1 to 2 years after liver transplant (80% of patients). However, PTLD is not exclusively associated with EBV infection; EBV-negative PTLDs are being increasingly recognized, usually developing late after transplant, but the cause is presently unknown. “Hit-and-run” EBV infection, other infectious agents, and chronic immune triggering by the graft have been proposed as possible underlying mechanisms in these EBV-negative patients.⁴

The risk factors for PTLD reportedly include high levels of immunosuppression and development of EBV infection after transplant. A higher incidence is seen in EBV-seronegative pediatric patients receiving a transplant from an EBV-seropositive donor. Young age appears to be a risk factor, especially when patients with extrahepatic biliary atresia receive grafts from older living donors. The era of the transplant and the use of immunosuppressant regimens and antilymphocyte therapies are also reportedly important. However, these risk factors may reflect center effects.⁵

Treatment for recurrent acute rejection also puts patients at risk for PTLD. The risk of symptomatic EBV infection and PTLD is greater in patients with more than 1 rejection episode in the first year after transplant. The impact of the graft is also important: grafts containing large amounts of lymphatic tissue transfer EBV-positive lymphocytes from donor to recipient. The risk of PTLD is higher in haploidentical hematopoietic stem cell transplant patients than in recipients of heart-lung or multivisceral organ transplants. Small bowel transplant has a higher risk of PTLD than liver, pancreas, kidney, and matched hematopoietic stem cell transplant.

Posttransplant lymphoproliferative disease presents with a variety of symptoms in young children after acquired primary EBV infection and in older children after EBV reactivation. Although extranodal disease is commonly seen (75%-85%), solid-organ grafts may also be involved in 15% to 30% of patients. Central nervous system lymphoma is seen in 10% to 15% of patients, who report headaches or focal neurologic symptoms.

Clinical presentation
Posttransplant lymphoproliferative disease often presents in a nonspecific way; if it is not suspected clinically, it is a major challenge to diagnose at the early stage. The initial symptoms are mainly constitutional and systemic, including unexplained fever or night sweats, malaise, weight loss, or anorexia. Other frequent symptoms are sore throat and swollen lymph nodes. A clinician can encounter allograft-specific symptoms such as jaundice and abdominal pain in patients with liver involvement. Gastrointestinal PTLD may cause abdominal pain, gastrointestinal bleeding, nausea, vomiting, and diarrhea. Lung involvement and enlarged mediastinal lymph nodes may cause shortness of breath, and cough; in kidney dysfunction, pain in the lumbar area and hematuria are the reported signs and symptoms. Physical examination may reveal signs of pallor, lymphadenopathy, subcutaneous nodules, tonsillar enlargement or inflammation, hepatosplenomegaly, or focal neurologic signs. Sometimes, PTLD presents as mass lesions found on imaging obtained for other reasons.

The diagnostic workup for suspected PTLD includes a complete blood count and differential, platelet count, electrolytes, albumin, calcium, blood urea nitrogen, creatinine, liver function tests, uric acid, lactate dehydrogenase, quantitative immunoglobulins, and stool for occult blood. Hypoalbuminemia and eosinophilia are important findings and may indicate PTLD. In patients with suspected PTLD, serology for EBV (anti-Epstein-Barr virus nuclear antigen, anti-viral capsid antigen) should be obtained. An elevated EBV viral load in the peripheral blood (by EBV polymerase chain reaction) is a valuable test. Chest radiography (anteroposterior and lateral); computed tomography (CT)-positron emission tomography (PET) of the neck, chest, abdomen, and pelvis; and core needle or excisional biopsy of any lesions are helpful for diagnosis. The use of F18-fludeoxyglucose PET-CT has become the standard for staging and for assessment of response and remission. It is superior to CT in evaluating both nodal and extranodal involvement.

The EBV-encoded RNA in situ hybridization technique can determine the association between EBV and PTLD; this test and CD20 immunohistochemistry studies of tissue samples are performed by a pathologist. Gastrointestinal endoscopy, bone scanning, bone marrow biopsy, brain CT and magnetic resonance imaging, and lumbar puncture are other investigational modalities used to diagnose PTLD.

There have been significant changes in the treatment of pediatric liver transplant recipients since the early reports of PTLD. New immunosuppressive drugs and the increased use of living-related donors may increase the risk of developing PTLD. However, the reported incidences of PTLD and symptomatic EBV infection have been decreasing in pediatric liver transplant patients concomitantly with reductions in the overall level of immunosuppression. Less steroid use, development of molecular monitoring of EBV infection, and proper response to this infection (lowering immunosuppression and giving antiviral treatment) are the underlying reasons for this decrease.⁶

Treatment
Different approaches are used for treating PTLD, including reduced immunosuppression, destruction of the malignant clone cells, and suppression of the Epstein-Barr viral load. The general recommendation is for reduction of immunosuppression and waiting for 2 to 4 weeks, unless there is concurrent rejection or true malignancy. Reduction of immunosuppression augments T-cell function, usually leading to lesion regression in 23% to 86% of patients. Regression is more common in early lesions and in polymorphic PTLD.

The use of anti-CD20 humanized chimeric monoclonal antibody (rituximab) after reducing immunosuppression is standard therapy for most patients with CD20-positive PTLD. Outcomes have been significantly improved with the integration of early rituximab therapy. Rituximab directly targets B-cell proliferation, as its binding to CD20 induces apoptosis of B-lymphocytes. About 50% of patients with PTLD after solid-organ transplant can be successfully treated with single-agent rituximab therapy. A 20% relapse rate is seen 7 months after stopping rituximab. Rituximab has adverse effects, including hypogammaglobulinemia and opportunistic infections.

Patients with CD20-negative monomorphic PTLDs (including plasmablastic, plasma cell myeloma, and T-cell lymphoma) and those with primary central nervous system lymphomas are usually treated like their immunocompetent counterparts. A low dose of cyclophosphamide (600 mg/m²/cycle) with prednisolone and rituximab (375 mg/m² weekly for 6 cycles) results in a high complete or partial-response rate in resistant cases. Surgery is typically limited to patients with isolated bulky lesions, intestinal perforation, or airway compression. Radiotherapy and more intensive chemotherapy are restricted to patients with refractory or recurrent disease, T-cell lymphoma, Hodgkin-like PTLD, or central nervous system PTLD.

Donor lymphocyte infusion and the administration of EBV-specific T-lymphocytes is only available in some clinics, and both are still considered investigational therapies.7 Acyclovir and ganciclovir inhibit DNA replication of EBV in vitro; however, neither agent has in vivo activity against EBV. Despite this fact, most transplant centers use acyclovir or ganciclovir, orally or intravenously, for their theoretical benefit against lytic EBV populations. Passive transfer of antibodies against EBNA with intravenous immunoglobulin treatment is used in some centers.

Although PTLD is a life-threatening complication after pediatric liver transplant, prompt and appropriate treatment with the agents mentioned above can result in a good outcome.

Volume: 15 Issue: 2 March 2017 - Supplement - 2

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