eMedicine Specialties > Transplantation > Complications
Posttransplant Lymphoproliferative Disease
Updated: Oct 22, 2008
Introduction
Background
Posttransplant lymphoproliferative disorder (PTLD) is a well recognized, although relatively uncommon, complication of both solid organ and allogeneic bone marrow transplantation. In most cases, PTLD is associated with Epstein-Barr virus (EBV) infection of B cells, either as a consequence of reactivation of the virus posttransplantation or from primary posttransplantation EBV infection acquired from the donor. While T-cell lymphoproliferative disorders not associated with EBV infection have also been documented after solid organ and bone marrow transplantation, the vast majority are B-cell proliferations.
A diagnosis of PTLD is made by having a high index of suspicion in the appropriate clinical setting; histopathological evidence of lymphoproliferation on tissue biopsy; and the presence of EBV DNA, RNA, or protein in tissue. Most cases of PTLD are observed in the first posttransplant year. The more intense the immunosuppression used, the higher the incidence of PTLD and the earlier it occurs. The cornerstone of successful treatment of PTLD is reduction or withdrawal of immunosuppression, which inherently carries the risk of allograft dysfunction or loss. This reversibility, partial or complete, with reduction of immunosuppression, differentiates PTLD from the lymphoproliferative disorders observed in patients who are immunocompetent. Other treatment modalities that can be employed additionally include surgical excision of the lesion, localized radiation therapy, combination chemotherapy, monoclonal antibodies, interferon therapy, and the use of immunoglobulin and cytotoxic T lymphocytes.
The American Society for Transplantation recently recommended that the term PTLD should be applied to posttransplantation infectious mononucleosis and plasma cell hyperplasia (reactive hyperplasias). When the term PTLD is not qualified, it should refer to neoplastic disease. Neoplastic diseases include polymorphic lymphoma, polymorphic B-cell hyperplasia, or lymphomatous PTLD. Histology must demonstrate lymphoproliferation that disrupts the architecture of the tissue, oligoclonal or monoclonal cell lines, and the presence of EBV in the tissue.
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Pathophysiology
EBV is a herpes virus that is thought to infect as much as 95% of the adult population. Primary infection with EBV usually results in mild, self-limiting illness in childhood and the clinical syndrome of infectious mononucleosis in adults. It was found over 3 decades ago by electron microscopy of cells cultured from a Burkitt lymphoma. Since 1968, it has been known to cause infectious mononucleosis and has been associated with non–Hodgkin lymphoma and oral hairy leukoplakia in patients with HIV infection and with nasopharyngeal carcinoma, particularly in Southeast Asia.Structurally, EBV comprises the EBV genome enclosed in a nuclear capsid, which in turn is surrounded by a glycoprotein envelope. Once a person is infected with EBV, the virus persists for life as a result of latency in B-cell lymphocytes and chronic replication in the cells of the oropharynx.
The EBV genome is a linear DNA molecule that encodes for approximately 100 viral proteins that are expressed during replication. The CD21 molecule on the surface of the B cell is the target receptor of the EBV glycoprotein envelope. Infection of B-cell lymphocytes with EBV results in either viral replication and B-cell lysis (ie, lytic replication) or a transformation of the cell with only partial EBV genome expression (ie, latency). Cell transformation is associated with B-cell activation and continuous proliferation. In patients who are immunocompetent, proliferation of these transformed B cells usually is controlled by cytotoxic T cells. This is not the case, however, with patients who are immunosuppressed.
The viral genome expresses only 9 proteins during latency, when it adopts an episomal configuration. This creates increased difficulty for T-cell recognition, facilitating persistent EBV infection, which is thought to occur in resting memory B cells. The 9 proteins expressed are EBV latent membrane proteins ([LMP], ie, LMP-1, LMP-2A, LMP-2B) and EBV nuclear antigens ([NA], ie, EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, EBNA-LP). LMP-1 is considered to be an oncogene. Its expression results in increased levels of CD23, which is a B-cell activation antigen. LMP-1 also is known to induce expression of bcl-2, which inhibits apoptosis of an infected cell. LMP-2 prevents reactivation of EBV in latently infected cells. EBNA-1 is responsible for maintaining the episomal configuration of the latent virus. EBNA-2 up-regulates the expression of LMP-1 and LMP-2, which are necessary for transformation of the B cell.
Almost all lymphoproliferative disease tissue has demonstrated the presence of EBV DNA. Analysis indicates expression of 3 antigens in particular—EBNA-1, EBNA-2, and LMP-1. Two out of these 3 proteins usually are not expressed in other EBV-related malignancies and so are distinguishing features. Of note, the classic 8;14 or 8;22 translocations observed in Burkitt lymphoma are not observed in patients with PTLD.
EBV infection results in both a humoral and cellular immune response by the host. Cellular immunity is thought to be the more important of the 2 in terms of regulation and control of proliferation of the infected B lymphocytes by means of CD4 and CD8 cytotoxic T cells and natural killer cells. Antibodies to viral capsid and nuclear proteins are produced, the presence of which facilitates the diagnosis of EBV infection. In individuals who are immunocompetent, these mechanisms work well to prevent outgrowth of EBV-infected lymphocytes. In patients who are immunodeficient, a number of factors compromise these mechanisms.
The immunosuppression required to preserve graft function posttransplantation results in impairment of T-cell immunity and allows for uncontrolled proliferation of EBV-infected B cells, resulting in monoclonal or polyclonal plasmacytic hyperplasia, B-cell hyperplasia, B-cell lymphoma, or immunoblastic lymphoma. Immune surveillance is impaired. As discussed above, this outgrowth usually is regulated by cytotoxic T cells and natural killer cells.
In the initial stages, the proliferation is polyclonal. With mutation and selective growth, the lesion becomes oligoclonal and, later, monoclonal. Cyclosporin was demonstrated many years ago to actually promote the proliferation of B lymphocytes in vitro. Additionally, lymphocytes from patients treated with cyclosporin following transplantation do not exhibit an appropriate T-cell response to EBV-infected B cells in vitro. The activity of natural killer cells is reduced for several months posttransplantation, impairing cellular immune response—the most important regulator of proliferation.
Frequency
United States
See international frequency below.
International
Cohen (1991) reviewed cases of PTLD in the literature involving renal, cardiac, heart-lung, liver, and bone marrow transplantation. In the case of renal allografts, 60% of patients developed PTLD within 6 months of transplantation, but the mean time was 32 months. He noted that patients treated with cyclosporin had a mean time to development of PTLD of 5 months. Survivors were more likely to have a shorter time interval to development of PTLD than those who died, they were more likely to have polyclonal lesions and B-cell hyperplasia, and they were more likely to have involvement of graft or lymph nodes.
In cardiac transplantation, the incidence of PTLD ranged from 4.9-13%, which almost certainly reflects the need for greater immunosuppression in these patients. The time interval between transplantation and the development of PTLD was 2 years, but 50% had a diagnosis of PTLD within 6 months of receiving their allograft. Most of the cases were monoclonal. Again, in patients treated with cyclosporin, the mean time to development of PTLD was 5 months.
In heart-lung transplantation, the interval between transplantation and diagnosis of PTLD was 2 months, although the number of patients considered was small.
In liver transplantation, the incidence was 2%. Sixty seven percent of patients developed PTLD within 1 year of transplantation, and the mean interval was 27 months. Those who survived were more likely to have polyclonal lesions.
Allogeneic bone marrow transplantation–related PTLD had an incidence of 1.6%. This was much higher if the patient had received mismatched T cell–depleted bone marrow (24%) or if the patient had received anti–T-cell monoclonal antibodies for graft versus host disease (17%). The mean time interval from transplantation to a diagnosis of PTLD was 5 months. The indication for bone marrow transplantation in those who survived was more likely to be for nonmalignant disease.
Shapiro et al found an overall incidence of PTLD of 1.9% in a population of 1316 patients undergoing kidney transplants at the University of Pittsburgh from 1989-1997.1 The incidence in adults was 1.2%, with a much higher incidence in pediatric patients (ie, 10.1%). The time interval to diagnosis of PTLD ranged from less than 1 month to 49 months in adults. The 1- and 5-year patient and graft survival rates in adults were 93% and 86% and 80% and 60%, respectively.
In children, the 1- and 5-year patient and graft survival rates were 100% and 100% and 100% and 89%, respectively. The immunosuppressive regimen was tacrolimus based, and treatment consisted of discontinuing, or significantly reducing, immunosuppression plus concomitant ganciclovir therapy. In the adult group, 10 patients lost their allograft, and 2 died of PTLD-related complications. No pediatric deaths occurred, and only 1 allograft was lost. The authors concluded that although PTLD is more common in renal transplant pediatric recipients receiving tacrolimus, they have a more favorable prognosis.
Srivastava et al found an incidence of PTLD of 7.1% in pediatric renal transplant recipients.2 These patients all received intense immunosuppression with antilymphocyte globulin/antilymphocyte globulin, methylprednisolone, cyclosporine, and mycophenolate mofetil or azathioprine, thus rendering them at high risk for development of PTLD. All additionally had received prophylactic acyclovir.
Mortality/Morbidity
PTLD forms a heterogenous group of tumors, ranging from B-cell hyperplasia to immunoblastic lymphoma, the latter portending a more grim prognosis. All PTLD, however, irrespective of histology, is potentially, and frequently, fatal. Mortality rates as high as 60-100% have been cited. The presentation and clinical course are variable. At one end of the spectrum is aggressive disease with diffuse involvement, resulting in rapid demise of the patient; at the other end of the spectrum are localized lesions that are indolent and slow growing over months, as opposed to days or weeks. The former occur early in the posttransplantation period and are more often polyclonal lesions. Late-onset PTLD tends to be monoclonal and heralds a worse prognosis.
Hauke et al reported their experience with PTLD occurring in patients after solid organ transplantation.3 In this retrospective review of 32 patients, the 5-year survival rate was 59%, with 45% of patients diagnosed within the first year following transplantation. Six out of 8 patients surgically treated remain alive and disease free. Characteristics associated with poorer survival were diagnosis within the first year posttransplant, monoclonal tumors, and presentation with an infectious mononucleosis–like syndrome.
LeBlond et al, in a series of 61 patients who had undergone kidney, lung, liver, or heart transplantation, found that factors predictive for shorter survival (univariate analysis) in PTLD included a performance status (PS) greater than or equal to 2, increased number of sites involved (ie, > 1 versus 1), primary central nervous system (CNS) involvement, T-cell origin, monoclonality, nondetection of EBV in the tumor, and treatment based on chemotherapy (in addition to reduction in immunosuppression).4
In multivariate analysis, PS less than 2 and decreased number of disease sites (ie, 1 versus >1) both were associated with improved survival. These determinants were used to identify 3 levels of risk in terms of survival probability. For intermediate-risk patients (ie, PS ³ 2 or 2 or more sites), median survival time with treatment was 34 months. For high-risk patients (ie, PS ³ 2 and 2 or more sites), median survival time was 1 month. Survival time for low-risk patients (ie, PS <2 and <2 sites) was not defined. This risk stratification is helpful in determining prognosis, in addition to other variables, which is discussed later. In any case, PTLD is a serious adverse complication of transplantation and immunosuppression, and, regardless of the histology, prompt and effective treatment is required.
Clinical
History
Whether PTLD presents as localized or disseminated disease, the tumors are aggressive and rapidly progressive and often are fatal. Clinical presentation is very variable and includes fever (57%), lymphadenopathy (38%), gastrointestinal symptoms (27%), infectious mononucleosis–like syndrome that can be fulminant (19%), pulmonary symptoms (15%), CNS symptoms (13%), and weight loss (9%). Patients may report fever, weight loss, anorexia, lethargy, sore throat, swollen glands, diarrhea, abdominal pain, shortness of breath, neurological symptoms, or symptoms that initially would not suggest a diagnosis of PTLD.The most common sites for involvement are lymph nodes (59%), liver (31%), lung (29%), kidney (25%), bone marrow (25%), small intestine (22%), spleen (21%), CNS (19%), large bowel (14%), tonsils (10%), and salivary glands (4%). T-cell lymphoproliferative disorders not associated with EBV infection tend to occur at extranodal sites. Reports exist of PTLD presenting in the oral cavity.
Raut et al described a patient who received an allogeneic bone marrow transplant for chronic myeloid leukemia complicated by severe chronic graft versus host disease, for which he was treated with cyclophosphamide and mycophenolate mofetil.5 The patient reported soreness of the gum. Biopsy results of the tissue revealed a diagnosis of non-Hodgkin lymphoma. For patients who have received either solid organ transplantation or allogeneic bone marrow transplantation and who are immunosuppressed as prophylaxis against graft rejection or graft versus host disease, a high index of suspicion and vigilance is required for prompt and timely diagnosis. A diagnosis of PTLD is entertained more easily in a patient who has undergone transplantation recently and who presented with fever, unexplained weight loss, lymphadenopathy, and hepatosplenomegaly.
Consider the case of a patient who underwent combined renal-pancreas transplant at the authors' institution and who reported symptoms of numbness and soreness of the gum 5 months after the combined renal-pancreas transplantation. An initial diagnosis of gingivitis was made, but histopathology of the affected tissue demonstrated B-cell hyperplasia. Immunoperoxidase stain demonstrated EBV-positive B cells, confirming a diagnosis of PTLD. His case was managed by surgical excision of the lesion and reduction in immunosuppression. He remains euglycemic, with good renal graft function, and no evidence of disease recurrence.
The incidence of PTLD varies with the type of transplanted allograft. It is much higher in heart or heart-lung transplants, presumably reflecting the need for more intense immunosuppression in these patients. In terms of lymphoproliferative disease occurring in the allograft itself, it depends on the graft in question. The lungs very frequently are a site of involvement in patients undergoing heart-lung, or heart alone, transplant. In cardiac transplant, the heart itself seldom is involved. In renal allografts, the graft kidney is affected approximately one third of the time, which is similar to graft involvement rates in liver and bone marrow transplant cases.
In patients who undergo bone marrow transplantation, risk factors for the development of PTLD include the development of graft versus host disease treated with antithymocyte globulin or monoclonal antibodies, total-body irradiation, T-cell depletion of donor marrow, and human leukocyte antigen (HLA) mismatch.
Higher risk of developing PTLD and earlier occurrence posttransplantation have been shown to occur with more intense immunosuppression. The total burden of immunosuppression appears to be a very significant factor in determining risk. Swinnen et al (1990) examined the incidence of PTLD in patients undergoing cardiac transplant and using OKT3 (murine monoclonal anti-CD3 antibody) as immunosuppression and found an incidence of 6.2% in patients who had received a dose of 75 mg or less. The mean time to development of PTLD was 11 months, compared with an incidence of 35.25% and a mean interval of 1.5 months in patients who received doses of greater than 75 mg. With prednisolone and azathioprine alone, the mean time to developing PTLD is 50 months. Cyclosporin therapy reduced this to 5 months. Use of tacrolimus and use of antilymphocyte globulins have been associated with much earlier and more frequent presentation of PTLD.
Cox et al addressed the incidence PTLD in pediatric patients undergoing liver transplant and found that the use of tacrolimus was associated with a higher incidence of PTLD (19% versus 3%) compared to cyclosporin.6
Other risk factors that have been identified as predictive for the development of PTLD include recipient pretransplant EBV seronegativity and donor EBV seropositivity. The incidence of PTLD has been found to be significantly higher in patients who are EBV seronegative pretransplant, compared with those who are seropositive (23.1% versus 0.7% in Cockfield's 1993 analysis7 ). Presumably, EBV is transmitted from donor to recipient via the graft at a time of considerable immunosuppression for the recipient, or the patient develops primary EBV infection unrelated to donor EBV status. However, experience at the University of Pittsburgh indicates that, in the case of intestinal transplantation, the incidence of PTLD is as high in patients who are EBV seropositive pretransplantation as in patients who are seronegative.
Physical
See History discussion.
Causes
See Pathophysiology discussion and History discussion.
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Further Reading
Keywords
posttransplant lymphoproliferative disorder, PTLD, Epstein-Barr virus, EBV, immunosuppression, bone marrow transplantation, solid organ transplantation, posttransplantation infectious mononucleosis, posttransplantation plasma cell hyperplasia, posttransplantation reactive hyperplasias, polymorphic lymphoma, polymorphic B-cell hyperplasia, lymphomatous PTLD
