Some Problems With Posttransplant Lymphoproliferative Disease

Although skin cancers are the most common posttransplantation malignancies, lymphomas and lymphoproliferations are the most important group as regards mortality and morbidity (1–2). There has been much controversy about the classification of lymphomas in the general population. The diagnostic dilemma is greatly increased in organ allograft recipients whose lymphoid tissues are exposed to numerous foreign antigens, including those of the allograft, heterologous ALG or antithymocyte globulin, heterologous monoclonal antibodies such as OKT3, a multiplicity of infectious agents, and a variety of medications. As a result, the nonspecific term posttransplant lymphoproliferative disease (PTLD) has been adopted (1–2). This covers a bewildering heterogeneity of lesions ranging from benign hyperplasias to frankly malignant lymphomas. A simplified subclassification (3) includes the following categories: 1. Hyperplasias—including infectious mononucleosis and plasma cell hyperplasias 2. Neoplasias a. Polymorphic b. Monomorphic (including B, T, natural killer, and null cell lymphomas) c. Other (including myeloma, plasmacytoma, and Hodgkin’s disease) Myeloma/plasmacytoma and Hodg- kin’s disease are uncommon in transplant patients, comprising 4% and 3%, respectively, of 1931 PTLD cases in the Cincinnati Transplant Tumor Registry (CTTR) (1–2). Hyperplastic PTLDs are polyclonal in origin, whereas all neoplastic PTLDs contain a monoclonal component, which can be detected by sensitive assays (3). In the past, it was believed that monoclonality indicated that a lesion would not respond to reduction/withdrawal of immunosuppressive therapy. However, both hyperplastic PTLDs (polyclonal) and polymorphic PTLDs (monoclonal) may respond to such therapy, whereas monomorphic PTLD (monoclonal) is unlikely to regress (3). In many published reports it is not clear whether the lesions were hyperplasias or neoplasias. Theoretically patients with hyperplasias have a better prognosis than those with neoplasias, but histologically benign lesions can behave in a malignant fashion in immunosuppressed patients. Several factors predispose patients to the development of PTLD (1–3). The study by Swerdlow et al. (this issue) is important because they used epidemiologic techniques to quantify several risk factors, at least in cardiac and cardiopulmonary recipients. Intense immunosuppression is a well-recognized major cause. Often three, four, or even five immunosuppressive agents are administered over a short time span. Whenever a new immunosuppressive agent is introduced there is a “learning curve” while we discover how to use it in appropriate doses, especially when it is added to combinations of other immunosuppressive medications. An increased frequency of PTLD was noted after the introduction of ALG, then cyclosporine, then OKT3, and with limited experience tacrolimus and mycophenolate mofetil (1–2). The role of more intense immunosuppression is raised by Swerdlow’s study, which found a greater risk of PTLD after two transplants than after one. Nonrenal allograft recipients (such as heart or lungs) are more likely to develop PTLDs than renal recipients (1–2). Heavy immunosuppressive therapy is often used in the former group to reverse rejection to save their lives, whereas with severe rejection of kidney allografts physicians can discontinue immunosuppression and return the patients to dialysis. Thus, when neoplasms in recipients of nonrenal organs were compared with those in renal recipients, PTLDs comprised 45% in the former group compared with only 12% in the latter (1–2). These findings are reinforced by reports that although PTLD occurs in less than 1% of renal recipients it involves 3% of heart, 3% of liver, 8% of lung, and 19% of intestinal recipients (3). Swerdlow’s group emphasizes that studies that calculate the percentage of transplant patients in whom PTLD occurred are of limited value, because, unlike epidemiologic techniques that take into consideration person-years at risk, the above percentages do not allow for the length of follow-up of each patient in a study. Approximately 90–95% of PTLDs are positive for Epstein-Barr virus (3), but in Swerdlow’s study 17% were EBV negative. A risk factor for development of PTLD is seronegative status at the time of the transplantation. In one study 11% of seronegative pediatric and 5% of seronegative adult recipients developed PTLD, whereas the corresponding figures in their seropositive counterparts were 0% and 2%, respectively (4). Swerdlow’s study quantitates the risk, which was raised 10-fold in individuals who were EBV negative before transplantation compared with EBV-positive individuals. Some investigators suggest that high loads of EBV in the peripheral blood may presage the onset of PTLD (4). Some studies suggest that cytomegalovirus infection may be a cofactor with EBV, either by causing further immunosuppression or, perhaps, in other ways. The CTTR data show that pediatric organ transplant recipients had a disproportionately high incidence of PTLD compared with adults (1–2). When neoplasms in pediatric patients were compared with those in adults, PTLDs comprised 53% in the former group compared with 15% in the latter (1–2). Swerdlow found a strongly decreasing risk of PTLD with increasing age. A major reason is that primary EBV infections are more common in childhood than in adults and in immunosuppressed patients are likely to result in PTLD (1–2). Swerdlow states that primary infection is more likely to lead to PTLD than is reactivation infection. Furthermore 61% of pediatric patients in the CTTR who developed PTLDs received nonrenal organ allografts and therefore more intense immunosuppressive therapy (1–2). Another reason why PTLDs are more common in pediatric recipients is that children have relatively more lymphoid tissue, which may undergo neoplastic change when subjected to appropriate stimuli (1–2). Increasingly, two distinct types of PTLD are being recognized (3–5). The first occurs early after transplantation, usually within the first and, to a lesser extent, in the second posttransplantation year. The disease is usually associated with EBV infection and children, in particular, are affected. Reduction of immunosuppressive therapy and administration of antiviral agents are two major treatments. The second type occurs 25–300.5 months after transplantation. In one study of 15 cases, the median time of appearance was 79 months after transplantation (5). Most patients were adults but a few were children. The lesions were often EBV negative (5). In Swerdlow’s study, all tumors were EBV negative, despite a careful search for the virus and its proteins, and notwithstanding that the patients were EBV seropositive before transplantation. The lesions were invariably clonal and some showed rearrangement of the c-myc oncogene (5). Reduction of immunosuppressive therapy was ineffective in patients with monomorphic lesions, and patients did not respond well to chemotherapy because of infectious complications and resistant disease (5). The median survival of patients with monoclonal disease was 7 months (5). The etiology of these PTLDs is probably very different from the early-occurring EBV-positive PTLDs. Swerdlow postulates an uncommon infection. Infection with HTLV-I, which can cause lymphomas, and is endemic in Japan and the Caribbean, was identified in only one PTLD in the CTTR (1–2). Chronic hepatitis C infection has been linked to some lymphomas in the general population, but no such connection has yet been reported in transplant recipients. Other possible causes include loss of immune surveillance; chronic antigenic stimulation of a partially immunosuppressed immune system; and chronically impaired immunoregulation (1–2). More studies are needed to determine what factors, in addition to the immunosuppressed state and EBV infection, contribute to the development of PTLD (1–2). For example, although large numbers of transplant patients are at risk for PTLD, only a small percentage actually develop it. Perhaps certain HLA groups may determine susceptibility or resistance to its development. Similar lesions occur in two states of immunodeficiency unrelated to the use of immunosuppressive drugs (1–2). Lymphomas are the most common neoplasms seen in naturally occurring immunodeficiency disorders, whereas 2% of patients with acquired immunodeficiency syndrome develop these lesions. In both disorders, the distribution of the lesions (for example, central nervous system involvement) resembles that seen with PTLDs. An interesting feature is that many acquired immunodeficiency syndrome-related lymphomas are EBV negative. Another problem that needs to be addressed is that of T-cell PTLDs. Eighty-five percent of PTLDs in the CTTR that were studied immunologically are of B-cell origin, but almost 15% (currently 117 cases) were of T-cell origin (1–2). Although EBV has been isolated from some T-cell PTLDs, much needs to be learned about the etiology of these lesions. Acknowledgments. The author thanks numerous colleagues, working in transplant centers throughout the world, who have generously contributed data concerning their patients to the Cincinnati Transplant Tumor Registry.