Posttransplant lymphoproliferative disorder after living donor liver transplant: are we improving incidence and outcome?

Posttransplant lymphoproliferative disorders (PTLDs), a group of B-cell (and less frequently, T-cell) lymphomas, develop as a complication of immunosuppression in patients undergoing organ transplant [1]. The first report of PTLD was in 1969 [2] by Penn and colleagues, but since then, it has been reported after different kinds of organ transplant and has become an entity of interest and research worldwide. Since the initial description, PTLD has been shown to have a wide variation in clinical presentation, time of appearance, etiology, histopathology, and therapy. However, overall it represents a potentially life-threatening complication of transplant.

Fortunately, we are now in an era of impressive advances in the field of organ transplant in general and liver transplant in particular. In this respect, one of the major achievements in this field over the past 20 years has been the success of live donor liver transplant (LDLT), first performed in the pediatric population in 1989 [3] and later successfully implemented in adults. LDLT has facilitated access to life-saving liver transplants for patients with end-stage hepatic diseases who otherwise had to remain on long waiting lists in order to receive an organ from a deceased donor. There are several biological advantages to LDLT, compared to cadaver organs, including the fact that there are less inflammatory events in the immediate postoperative transplant period and consequently less susceptibility to acute graft rejection. Furthermore there are also fewer allo-immune responses and less long-term impairment of graft function [4].

In this issue of Leukemia and Lymphoma, Kataoka et al. attempt, for the first time, to establish the true incidence of PTLD and outline the clinical characteristics of this disorder, after adult-to-adult live donor liver transplant [5]. Now, are they indeed able to answer the crucial question of whether improvement of transplant procedures is translated into fewer transplant-related complications such as PTLD? Are we truly improving in respect to the incidence and development of PTLD after LDLT? In their report, Kataoka et al. retrospectively analyze data on 323 patients who had undergone LDLT at a single institution from 1996 to 2007. Only three of the 323 patients developed PTLD, with a cumulative incidence of 0.8% at 5 years and 1.6% at 10 years. All three cases, had hepatitis C virus (HCV) related cirrhosis, leukocyte antigen-mismatched donors, and notably exhibited distinct clinical features of late-onset PTLD that was Epstein–Barr virus (EBV)-negative [5].

This study does not have enough statistical power to derive definitive conclusions about whether there is a lower incidence of PTLD. However, these results suggest that this may be so, and that we are moving to a new pattern of presentation with less early-onset EBV-related disease and more cases with a later onset (occurrence later than a year after transplant) [6,7], which are EBV-negative [5]. Whereas in the past most, if not all, the cases of adult PTLD were associated with EBV infection, it is now apparent that there are other co-factors that may be present in the immune-suppressed adult population which favor the development of the disease. One of these factors, proposed by Mañez et al. [8], could be the association and correlation with cytomegalovirus (CMV) infection in the peri-transplant period. However, effective CMV prophylaxis has probably overcome this possible association today, and other co-factors are still being sought.

Optimal staging evaluation for patients with this entity remains unclear. Kataoka et al. performed positron emission tomography-computed tomography (PET-CT) scans in two patients and were able to identify lesions that were not detected by conventional CT scans. The authors conclude that PET scans may be more sensitive for initial staging of PTLD. However, although other studies [9,10] have reported the higher sensitivity of PET-CT in these disorders, PTLD is regarded as a heterogeneous disease and has a variety of histopathological forms of presentation, ranging from polyclonal inflammatory-like proliferation to frank monoclonal lymphoma. As a result, the role of interpretation of positive PET scans in this setting and for different lymphoma subtypes still needs to be firmly established in larger cohorts of patients. PET imaging may represent a better imaging modality than conventional CT scans in this patient population, who frequently have impaired renal function related to the chronic immunosuppressive therapy given and are not good candidates to receive radio-contrast dye during the conventional imaging procedures. However, until further data regarding its positive and negative predictive value are available, PET-CT scan cannot be recommended as the primary imaging modality for the entire group of patients with PTLD.

Regarding therapy for this disorder, is there a current standard treatment regimen for PTLD after liver transplant? In this report by Kataoka et al. [5], the three patients received different chemotherapy or immunotherapy combinations. In this regard it is widely accepted that the first therapeutic step to be taken should be the reduction of immunosuppression, but what is the minimum reduction to introduce? And when is it necessary to combine this approach with another modality? Here again, the therapeutic approach will be determined by the localization of the PTLD, the timing of its appearance, and whether the clinical presentation is aggressive or not [11,12].

In summary then, the article by Kataoka et al. is intriguing in that it suggests that the LDLT approach results in a lower incidence of PTLD compared with cadaveric transplant, and that the disease may be biologically distinct in this group. Further follow-up will be required to confirm this and to determine the optimal imaging and therapeutic modalities for this challenging group of lymphomas.