Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation

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Abstract

Post-transplant lymphoproliferative disorders (PTLD) are a well-recognised and potentially fatal complication after solid organ transplantation. They include a spectrum of disorders ranging from benign hyperplasia to invasive malignant lymphoma. The majority of cases are associated with Epstein Barr virus (EBV)-driven tumour formation in B cells and are a consequence of the detrimental effect of immunosuppressive agents on the immune-control of EBV. This review provides an update on the pathogenesis and clinical features of PTLD after solid organ transplantation and discusses recent progress in management. Reduction in immunosuppressive therapy remains a key component of therapy for EBV-positive PTLD and may lead to remission in early disease. Chemotherapy is used when reduced immunosuppression fails to control early disease and as initial therapy for many cases of late disease. Unfortunately, the mortality for PTLD that fails to respond to a reduction in immunosuppression remains high. Newer treatments include manipulation of the cytokine environment, B lymphocyte depleting antibodies and adoptive T cell immunotherapy using allogeneic or autologous EBV-specific cytotoxic T lymphocytes. Although early results appear promising, well-designed clinical trials are needed to assess the efficacy of these novel approaches. EBV vaccination may in the future prove an effective prophylaxis against EBV-driven PTLD but until then, avoiding excessive immunosuppressive therapy may help minimise the risk of PTLD.

Introduction

Post-transplant lymphoproliferative disorders (PTLD) are a well-recognised and potentially life-threatening complication after solid organ transplantation. There is no universally accepted definition of the term PTLD but it is most commonly used to describe a wide spectrum of lymphoproliferative disorders after solid organ and haematopoietic cell transplantation that range from infectious mononucleosis and lymphoid hyperplasia to highly invasive malignant lymphoma. PTLD after solid organ transplantation nearly always originates from recipient lymphoid cells whereas after bone-marrow or stem cell transplantation, PTLD is usually of donor origin. Most cases of PTLD after both solid organ and haematopoietic cell transplantation are associated with Epstein Barr virus (EBV) that leads to uncontrolled B cell proliferation and tumour formation. Although there are many similarities between PTLD after solid organ transplantation and after haematopoietic cell transplantation, only the former is considered further in this review.

PTLD is a relatively common malignancy after transplantation and is seen in up to 10% of all solid organ transplant recipients [1]. It is the most common form of post-transplant malignancy in children and in adults it is the second most common malignancy after skin cancer [2], [3]. In both children and adults it is the most common cause of cancer-related mortality after solid organ transplantation and the reported overall mortality for PTLD often exceeds 50% [4], [5], [6]. There have been several informative reviews of PTLD published elsewhere over the last 2 years (see [7], [8], [9], [10]). This review provides an update on the pathogenesis and clinical features of PTLD after solid organ transplantation and discusses recent progress in management.

Section snippets

Pathological classification of PTLD

PTLD encompasses a wide spectrum of lymphoproliferative disorders with differing pathogenesis, histological appearance and clinical behaviour. In Europe and the U.S., about 85% of PTLD are of B cell lineage [4], [11] and most of these (over 80%) are associated with EBV infection [12]. Around 10–15% of PTLD are of T cell lineage, around 30% of which are associated with EBV [12]. Other haematopoietic cell lineages, such as natural killer cells, may very occasionally give rise to PTLD [13], [14].

The role of EBV in the development of PTLD

EBV is closely involved in the pathogenesis of PTLD and the majority of cases of PTLD arise in response to primary infection with EBV or to re-activation of previously acquired EBV [6], [18], [19]. EBV belongs to the gamma herpes virus family and over 95% of the world's population acquire EBV in childhood or early adolescence [20]. Infection in normal individuals is often asymptomatic, though it may result in a self-limiting, benign lymphoproliferative syndrome termed infectious mononucleosis.

Incidence

The incidence of PTLD after solid organ transplantation is markedly different in children and adults and also varies according to the type of organ transplant. In adult recipients, PTLD has been reported to occur in 1–2.3% of kidney transplants, 1–2.8% of liver transplants, 1–6.3% of heart transplants, 2.4–5.8% of heart-lung transplants, 4.2–10% of lung transplants and up to 20% of small bowel transplants [4], [10], [11], [31], [32], [33], [34], [35]. The incidence of PTLD is significantly

Immunosuppressive agents and PTLD

PTLD arises, in large part, as a consequence of the potent immunosuppressive agents necessary to prevent allograft rejection. The number of different immunosuppressive agents available for use after organ transplantation has increased markedly over the last two decades and most recipients receive multiple agents. The effect of different immunosuppressive protocols on the development of PTLD has been examined in two large cohort studies. Libertiny et al. [35] reported a single centre analysis of

Clinical features

The clinical presentation of PTLD is highly variable. Most patients present with fever (seen in 50%), lymphadenopathy (seen in 30%) or non-specific symptoms such as tonsillitis (particularly children) and weight loss [17]. Around 15% of patients present as an emergency with intestinal perforation [17]. A small group of patients present with fulminant PTLD characterised by disseminated systemic disease that clinically resembles septic shock [45]. PTLD may involve the lymph nodes or extranodal

Diagnosis of PTLD

The diagnosis of PTLD should be based on histological examination of biopsy tissue. Excision biopsy is preferable and needle biopsy should only be performed where excision of affected tissue in not practicable. Fine needle aspiration and cytology is not adequate for classifying PTLD and has little role. Tissue should be subjected to standard histology, examined for the presence of EBV by immunostaining or in-situ hybridisation, cellular infiltrates characterised by relevant phenotypic markers

Treatment

The management of PTLD poses a major therapeutic challenge and although there is reasonable agreement about the overall principles of treatment, there is still considerable controversy about the optimal treatment of individual patients. It is important that treatment is directed by an oncologist/haemaologist with an interest in lymphoma working closely with the appropriate transplant clinicians. Treatment can be considered under a number of different headings (Table 2).

Prophylaxis of EBV and PTLD

Most PTLD arises as a consequence of EBV infection and prophylactic measures should include avoiding over-immunosuppression of the recipient, in particular avoiding anti-lymphocyte preparations which are a significant risk factor. Other ways of preventing or controlling EBV infection, such as antiviral agents, EBV vaccination and in-vitro generated EBV-specific CTL lines are currently under development. In EBV seronegative recipients avoiding transplantation with an organ from an EBV positive

Conclusion

PTLD remains a serious complication after solid organ transplantation and most cases are EBV-related B cell tumours resulting from impaired immunity due to immunosuppressive therapy. Reduction in immunosuppressive treatment is a key component of therapy and may lead to remission in early disease. Chemotherapy is standard therapy when reduced immunosuppression fails to control early disease and as initial therapy for most cases of late disease. Manipulation of the cytokine environment, the use

Anna Taylor is a research fellow in the Department of Surgery, University of Cambridge. After qualifying in medicine at the University of Sheffield, she undertook surgical training at Cambridge and is currently working towards a Ph.D. in transplantation immunology from the University of Cambridge.

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  • Cited by (0)

    Anna Taylor is a research fellow in the Department of Surgery, University of Cambridge. After qualifying in medicine at the University of Sheffield, she undertook surgical training at Cambridge and is currently working towards a Ph.D. in transplantation immunology from the University of Cambridge.

    Robert Marcus is a consultant haematologist at Addenbrookes NHS Trust. He qualified in medicine at UCL and pursued postgraduate training in haematology in London. He was appointed as a consultant haematologist in 1987 and directs the Lymphoma service at Addenbrookes Hospital and in the West Anglia Cancer Network. He has a particular interest in the use of antibodies in the therapy of lymphoma.

    J. Andrew Bradley is Professor of Surgery at the University of Cambridge, UK. He is an honorary consultant surgeon and clinical director of transplantation at Addenbrooke's hospital, Cambridge. After qualifying in medicine at the University of Leeds, he undertook surgical training in Leeds and Glasgow. He obtained a Ph.D. from the University of Glasgow and was based at the Western Infirmary, Glasgow until moving to Cambridge in 1997.

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