Post-transplant lymphoproliferative disorders (PTLDs) are lymphoid proliferations that arise in patients who have undergone solid organ or bone marrow transplantation (1). PTLDs are heterogeneous, encompassing a broad spectrum of histologic, immunophenotypic, and genetic findings that, in part, correlate with clinical behavior.

Polymorphic B-cell hyperplasia; polymorphic B-cell lymphoma.

The epidemiologic features of patients with PTLD are essentially those of patients who undergo organ transplantation. These, of course, will differ according to the underlying diseases leading to transplant, the type of transplant, and the differences in patient populations at various transplant centers. Here, we focus on the epidemiologic features involved in the risk of developing PTLD.

The overall frequency of PTLDs in the current era, including patients who have received all types of organ transplant, is approximately 2% (2). The frequency of developing PTLD is greatest during the first year after transplant. Opelz and colleagues (3) reported the highest relative risk of PTLD in the first year, and it was highest for patients who received a heart–lung or lung allograft. The incidence then tapered off in the second year, and continued to decrease over time.

A number of risk factors for developing PTLD are known, and these are summarized in Table 80.1. The type of organ transplant is an important risk factor. For patients who receive a solid organ transplant, those receiving more than one organ (e.g., heart and lung, lung and intestine) have a higher overall frequency of PTLD than patients receiving a single organ. Intestinal transplant recipients appear to have the greatest risk of developing PTLD, in up to 10% of patients, followed by those who have liver (4.3%), lung (2.5%), heart (2.3%), pancreas (2.1%), and kidney (<1%) allografts (4,5,6,7,8,9). The overall risk of PTLD in patients receiving a bone marrow or stem cell transplant is 0.5% to 1% (10,11).

These differences in frequency of PTLD are most likely attributable to differences in immunosuppressive regimens used for transplant recipients. These differences include the cumulative amount of immunosuppression, including induction and rejection therapy, and the types of therapeutic agents employed in these regimens. For example, the latency interval from time of transplant to PTLD is substantially shorter in patients treated with cyclosporine A, antithymocyte globulin (ATG), or OKT3 monoclonal antibody compared with patients treated with azathioprine (12,13,14).

Other risk factors are known for PTLD (Table 80.1). Patient age is important, with younger patients having a higher frequency of PTLD. For example, pediatric patients undergoing liver transplantation have a frequency of PTLD that is at least double the frequency of PTLD in adults (3,7). Lack of previous exposure to Epstein-Barr virus (EBV) also increases the risk of developing PTLD (7,15,16,17). Recipients who are EBV seronegative have a substantially (10–50-fold in various studies) increased risk of developing PTLD (7,17). Age and previous exposure to EBV are probably not independent factors, as younger patients are more often seronegative for EBV. The number of EBV+ lymphocytes in the allograft, typically highest in intestinal allografts, possibly may be involved in risk of PTLD (4). The male-to-female ratio in PTLD patients is approximately 2:1, suggesting that males are at greater risk than females; the explanation for this is uncertain. Diseases affecting the host also can increase the risk of developing PTLD. For example, patients with primary immunodeficiency diseases have an increased risk of lymphoproliferative disorders that is independent of organ transplantation (Chapter 79). Other diseases, such as cystic fibrosis and hepatitis C, are reported to increase the risk of PTLD, presumably also by affecting host immunosurveillance (18,19). In patients undergoing bone marrow transplantation, a human leukocyte antigen (HLA) mismatched allograft, T-cell depletion of the allograft, and patients who require immunosuppressive therapy for graft versus host disease all have increased risk of PTLD (10,20). The latter factor overlaps with risk attributable to the cumulative amount of immunosuppression described earlier. Last, it seems reasonable to suggest that underlying host biology may play a role in increasing risk of PTLD. Cytokine polymorphisms associated with impaired host cellular immunity have been suggested to be associated with increased risk of PTLD (21). Other host factors, and their overall role, are likely to be elucidated in the future.

The pathogenesis of PTLD is most likely highly variable, as these disorders are very heterogeneous at the histologic, immunophenotypic, and molecular levels, and presumably reflect pathogenetic differences. Here, we focus primarily on B-cell PTLDs, as some aspects of their pathogenesis are known, unlike PTLD of T- or NK-cell lineage, as well as Hodgkin lymphoma, which are poorly understood.

B-cell PTLD, including EBV+ and EBV– cases, arise from germinal center (GC) or post-GC B cells. This has been shown by assessing these lesions for somatic mutations of the Ig variable region genes (22). These mutations have been identified in approximately 75% of polymorphic and 90% of monomorphic PTLDs. Virtually all monomorphic PTLDs of Burkitt lymphoma type and 25% of diffuse large B-cell lymphoma (DLBCL) type have ongoing mutations (manifested by intraclonal heterogeneity) and therefore are thought to arise from GC centroblasts. In contrast, approximately 75% of polymorphic PTLD and 65% of monomorphic PTLD/DLBCL have stable
Ig somatic mutations consistent with origin from post-GC B cells (22).

Immunohistochemical staining for the combination of BCL-6, MUM1, and CD138 is an alternative approach that has been used to ascertain the cell of origin of B-cell PTLDs. Lesions that arise from a GC B cells are BCL-6+, MUM1+/-, CD138-; those arising from late GC B cells are BCL-6-, MUM1+, CD138-; and those that arise in post-GC B cells are BCL-6-, MUM1+, CD138+. Using this approach, approximately 65% of polymorphic PTLD arise from late GC B cells and 35% from post-GC B cells. Most of the monomorphic PTLD of DLBCL type that arise from post-GC B cells have immunoblastic features. The small number of PTLDs without Ig somatic mutations has a post-GC immunophenotype.

Donor versus host origin has been assessed in PTLDs. In patients who have received solid organ allografts, over 90% of PTLDs are of host origin. In contrast, in patients who have received bone marrow or stem cell allografts, most PTLDs are of donor origin. As the therapy for bone marrow or stem cell transplantation requires ablation of the host bone marrow and replacement by donor cells, it is not surprising that most PTLDs are of donor origin (1). Currently, donor versus host origin of PTLD has no therapeutic significance, and there is no consensus that this information has prognostic meaning.

As was reviewed by Thompson and Kurzrock (23), approximately 80% of all B-cell PTLDs are EBV+, including virtually all PTLD of early type and over 90% of PTLDs of Hodgkin lymphoma type. The evidence supporting a pathogenetic role for EBV in PTLD is abundant. Serum EBV antibody titers and blood EBV DNA load typically increase in patients prior to the onset of PTLD (24,25). Conversely, the numbers of EBV+ cytotoxic T cells often drop prior to onset of PTLD (26). Treating PTLD patients with EBV-specific T cells can induce remission or significant responses in some patients (27). Analysis of EBV terminal repeat regions by Southern blot analysis in PTLDs has shown that the virus is often present in monoclonal form (28). This finding suggests that EBV is present in a precursor cell prior to development of PTLD, implicating its role in the early onset of PTLD. Finally, experimental studies have shown that EBV can transform germinal center B cells (29).

The exact mechanisms by which EBV can transform B cells are an area of active investigation. Epstein-Barr virus latent membrane protein (LMP) has the capacity to transform B cells in vitro and may activate members of the tumor necrosis factor (TNF) receptor family (30). Both LMP-1 and LMP-2A can mimic B-cell receptor signals and CD40, the latter a member of the TNF receptor family (31). The nuclear factor (NF)-κB and mammalian target of rapamycin (mTOR) pathways are activated in PTLDs (32,33). A more detailed molecular understanding of the molecular events in PTLDs is clearly needed.

The overall effect of EBV infection is to transform B cells, thereby prolonging their survival in a host in whom normal T-cell immunosurveillance is compromised by immunosuppressive therapy. Initially, EBV+ B cells are polyclonal, but the extended half life of virally infected B cells increases the likelihood that molecular aberrations will develop that confer a growth advantage, leading to evolution of a monoclonal B cell population. Additional molecular events can then also occur as the B-cell clone further evolves. Data show that a subset of PTLDs has microsatellite instability due to defective DNA mismatch-repair mechanisms (34). This would predispose affected PTLDs to additional molecular alterations.

Approximately 20% of B-cell PTLDs are negative for EBV (35). Epstein-Barr virus-negative PTLD is more common in patients who have received a kidney allograft. At the University of Pittsburgh, the relative frequency of EBV– B-cell PTLDs increased markedly after the year 1990 (35). Although differences in the immunosuppressive regimens used are an obvious possibility, this is not proven, and the reasons for the increased frequency of EBV– PTLDs are currently unknown.

The interval from the time of transplant to onset of PTLD is highly variable and depends on the type of allograft, the EBV status of the PTLD, and the immunosuppressive regimen (1,4,6). Post-transplant lymphoproliferative disorders tend to arise most quickly in patients who have received a bone marrow or stem cell transplant, usually within 6 months. For patients receiving a solid organ transplant, the time interval to onset of PTLD tends to be longer, which correlates with EBV status. Epstein-Barr virus-positive PTLDs usually develop within the first year, whereas EBV– PTLDs occur a median of 50 months after transplant (35). The interval from transplant to PTLD is much shorter in patients who receive cyclosporine A, usually 10 to 18 months, compared with azathioprine, at approximately 4 years (1,12,13,14).

The clinical presentation of patients with PTLD is highly variable and correlates with the just mentioned factors, as well as histologic and immunophenotypic findings of the PTLD itself (1,4,6,36). Early lesions tend to occur in relatively younger patients (compared with patients with polymorphic and monomorphic PTLD) and are common in patients who were EBV– prior to transplant. These patients can present with mild flu-like symptoms or have a severe infectious mononucleosis-like clinical syndrome. Early lesions have a tendency to involve the head and neck region, particularly Waldeyer ring tissues. In contrast, patients with polymorphic and particularly monomorphic PTLDs present more like lymphomas in immunocompetent patients. These PTLD patients commonly have fever, lymphadenopathy, and evidence of extranodal involvement. Extranodal disease occurs in up to 75% of patients and can be bulky. A wide variety of extranodal sites can be involved by PTLDs.

A shift appears to have occurred in the distribution of PTLD that correlates with changes in immunosuppressive regimens. In the past, in patients treated with conventional immunosuppressive regimens (e.g., azathioprine), PTLDs predominantly involved extranodal sites. The gastrointestinal tract and brain were often involved in patients with monomorphic PTLD (37,38,39). Although extranodal sites of PTLD are still common, lymphadenopathy is more common in patients treated with cyclosporine A and other more recently developed therapeutic agents (e.g., OKT3) (1,4,5).

In patients who receive solid organ allografts, PTLDs can be either localized or generalized. In approximately one-quarter
of patients, the PTLD can involve the allograft and, in some patients is confined to the allograft (1,38). Allograft involvement is more frequent in PTLDs that arise within the first year. In bone marrow/stem cell allograft recipients who develop PTLD, the disease is generalized. Bone marrow involvement by PTLD can cause one or more cytopenias.

The prognosis of patients with PTLD is variable. A unique feature of PTLDs is that some lesions regress when the immunosuppressive treatment is reduced or discontinued (40). A trial reduction in the dose of immunosuppression by 50% is commonly the first step (36). Early lesions often regress spontaneously and virtually always regress following a reduction in immunosuppression. A substantial subset of polymorphic PTLDs also can regress with reduction of immunosuppression, but this is less common or more transient in patients with monomorphic PTLDs (41,42,43). Compared with EBV+ PTLDs, EBV– PTLDs regress less commonly after reduction of immunosuppression, but approximately 25% of these cases can do so (35). The prognosis of patients with T-and NK-cell PTLDs is particularly poor, with a median overall survival of 6 months (44).