AUTHOR AND EDITOR INFORMATION

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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.

Click here to complete a Medscape CME activity on a patient with PTLD.

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 ³2 or 2 or more sites), median survival time with treatment was 34 months. For high-risk patients (ie, PS ³2 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

Section 3 of 11  

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• Clinical
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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.

DIFFERENTIALS

Section 4 of 11  

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• Differentials
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Other Problems to be Considered

PTLD can present in a wide variety of ways. The differential diagnosis should include any condition that would be on the differential diagnosis appropriate for those particular symptoms in any patient. Patients who are immunosuppressed, in addition to being at risk for lymphoproliferative disease, are at risk for all of the same conditions as patients who are immunocompetent. For example, if a patient who is immunosuppressed presents with fever, pharyngitis, and cervical lymphadenopathy, the differential diagnosis might include streptococcal infection, infectious mononucleosis, and PTLD.

WORKUP

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Lab Studies

• Rooney et al investigated methods that could be used for early identification of PTLD and, therefore, earlier and more successful treatment in patients receiving bone marrow transplant.⁸ They postulated that spontaneous outgrowth of EBV-positive peripheral blood mononuclear cells in culture would be associated reliably with the development of disseminated lymphoproliferative disease. Additionally, they looked at the relationship between EBV DNA levels in peripheral blood lymphocytes and disease onset.
• • They were able to demonstrate that the ability of EBV-infected peripheral blood lymphocytes to grow out rapidly in culture showed a 100% correlation with the emergence of lymphoproliferative disease. Outgrowth was detectable several weeks before the disease was apparent clinically.
  • They concluded that large numbers of EBV-transformed B cells are likely to circulate in the blood prior to disease onset. They also deemed that measurement of EBV DNA levels in the peripheral blood appeared to be a useful marker for those patients at high risk of development of PTLD.
  • These factors alone, or in combination, potentially are potent predictors of patients at high risk for the development of PTLD. Positive results would prompt early therapeutic intervention. The authors sampled peripheral blood every 1-2 months after bone marrow transplantation but suggested that more frequent sampling would be more informative.
• The EBV status of the recipient usually is established pretransplantation. Donor EBV status is not always sought routinely because the incidence of infection with EBV in the general population is so high.
• • In primary EBV infection, EBV viral capsid antigen (VCA) immunoglobulin M (IgM) titers are elevated. Reactivation of EBV infection is characterized by more than a 4-fold rise in EBV VCA immunoglobulin G (IgG) titers, compared with previously recorded EBV VCA IgG titers. No change in titer suggests past infection.
  • These tests can be performed as part of a PTLD workup. Elevated titers of antibodies to VCA have been identified in recipients of solid organ grafts who developed PTLD. Note that absence of change in EBV antibody titers does not exclude a diagnosis of PTLD. However, increases in EBV viral load in the peripheral blood have been detected in patients prior to the onset of lymphoproliferative disease, and a decrease in these levels has occurred following effective treatment of PTLD. EBV viral load can be monitored by means of polymerase chain reaction (PCR).
• Evaluation of tumor for the presence of EBV is very important. Nondetection of EBV is associated with tumors that present late, usually are monoclonal, and are more resistant to treatment. They are more likely to be disseminated and are less likely to achieve complete remission. T-cell PTLD usually is not associated with EBV infection and does not respond to immunosuppression dose reduction. It carries an unfavorable prognosis. Polyclonal lesions, however, have a more favorable prognosis. They, unlike monoclonal lesions, tend to occur early and are responsive to reduction of immunosuppression. Primary CNS involvement is associated with significantly higher mortality rates, 88% at 6 months in one study. CNS disease requires intrathecal therapy or localized radiation therapy because intravenous chemotherapy and monoclonal antibodies do not cross the blood-brain barrier adequately.
• Lactate dehydrogenase (LDH) measurements in LeBlond's 2001 series did not correlate with survival data.⁴ High levels of LDH simply may represent cell turnover, as opposed to being a marker of tumor load. However, if elevated, LDH levels may be useful in following disease progression or regression.

Imaging Studies

• Radiological evaluation includes computerized tomography scan of chest, abdomen, pelvis, and head, looking for evidence of hepatosplenomegaly, lymphadenopathy, or abnormal mass.

Other Tests

• In addition to a high degree of vigilance in the appropriate clinical setting, histological confirmation of lymphoproliferation is mandatory. It also requires demonstration of the presence of EBV DNA, RNA, or protein in the biopsied tissue. Histopathologically, the lesion may demonstrate plasmacytic hyperplasia, B-cell hyperplasia, B-cell lymphoma, or immunoblastic lymphoma. Immunohistologic staining can be used to confirm the presence of EBV. In situ hybridization with the EBV-encoded RNA (Epstein-Barr early region [EBER]-1) probe (labels EBV-encoded RNA in infected cells) is a reliable means of detecting EBV in tissue. EBV viral load in the peripheral blood can be determined using PCR. High viral loads have been found in a high proportion of patients with PTLD, but a high EBV viral titre is not diagnostic. This test is not standardized, and not all patients with PTLD have a high viral load.

Procedures

• Obtaining bone marrow aspirate and biopsy is appropriate to determine if marrow is involved in the disease process. If a suspicion of CNS or neurological involvement exists, lumbar puncture should be performed for cerebrospinal fluid evaluation. In addition to the standard tests, the fluid should be analyzed using PCR for EBV DNA.
• Establishing the clonality of the lesion is important. Tumors can be monoclonal, oligoclonal, polyclonal, or mixed. Some lymphomas may appear polyclonal by surface immunoglobulin staining but are monoclonal by immunoglobulin rearrangement. Reports of patients with multiple disease sites, one lesion of which was monoclonal while a distant lesion was polyclonal, have occurred. Monoclonal PTLD has a worse prognosis, so multiple biopsy sites may be useful in defining prognosis in an individual with more than one lesion. Do not assume that if one site is polyclonal, all disease sites are polyclonal. PTLD does not demonstrate the 8;14 or 8;22 translocations associated with Burkitt lymphoma. PTLD cannot be differentiated into benign or malignant tumors. The mortality rate is high, independent of histology. With regard to T-cell lymphoproliferative disorders, these lesions predominantly are monoclonal.

Histologic Findings

Knowles et al have classified PTLD into the following 3 distinct categories: (1) plasmacytic hyperplasia, which arises most commonly in the oropharynx or lymph nodes and nearly always is polyclonal, with a lack of oncogene or tumor suppressor gene alteration; (2) polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma, which can be nodal or extranodal, nearly always are monoclonal, usually contain a single form of EBV, and lack oncogene or tumor suppressor gene alteration; and (3) immunoblastic lymphoma with widely disseminated disease, which is monoclonal, contains a single form of EBV, and contains alterations of 1 or more the oncogene or tumor suppressor genes.⁹

TREATMENT

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Medical Care

Starzl et al were the first to suggest reduction, or withdrawal, of immunosuppression as a treatment option for PTLD.¹⁰ This serves to allow the patient's natural immunity to recover and gain control over proliferating EBV-infected cells. Most patients with more benign PTLD respond well to this management approach. People with more malignant disease often respond inadequately to these measures, and more aggressive treatment is necessary.

Reduction or withdrawal of immunosuppression is the cornerstone for the treatment of EBV-driven B-cell PTLD, independent of histology, but the role and timing of other therapeutic modalities is less clear. Comparative data to evaluate these treatment options are deficient, and many reports are anecdotal. In patients who underwent solid organ transplant, a balance must be sought between reduction of immunosuppression and the risk of allograft rejection. In allogeneic bone marrow transplantation, graft versus host disease is a critical concern. This approach has resulted in complete and lasting resolution of the tumor in some cases. Additional measures that have been used include surgical excision of the lesion (which can be curative in cases of localized disease), antiviral therapy, radiation therapy and chemotherapy, alfa interferon, intravenous gamma globulin, cytotoxic T lymphocytes, and monoclonal antibodies, each with varying degrees of success.

In Cohen's 1991 review, two thirds of transplant recipients with PTLD whose cases were managed with reduction of immunosuppression survived, compared with an overall survival rate of 31%. Benkerrou et al reported complete regression in 40% of patients after reduction or discontinuation of immunosuppressive therapy.¹¹ Polyclonal lesions have a favorable prognosis. They, unlike monoclonal lesions, tend to occur early and are responsive to reduction of immunosuppression. A reduction in immunosuppressive therapy is not effective for CNS PTLD. Primary CNS involvement is associated with significantly higher mortality rates, 88% at 6 months in one study. CNS disease requires intrathecal therapy because intravenous chemotherapy and monoclonal antibodies do not cross the blood-brain barrier adequately. T-cell PTLD usually is not associated with EBV infection and does not respond to immunosuppression dose reduction.

The use of acyclovir for treatment of PTLD generally has been reported as not being of significant value. Acyclovir and ganciclovir both inhibit lytic EBV DNA replication in vitro. Ganciclovir is approximately 10 times more potent than acyclovir. However, the majority of EBV-infected cells in lymphoproliferative lesions are transformed B cells. Acyclovir inhibits the replication of linear EBV DNA and is ineffective against episomal EBV DNA, which is the conformation of the EBV genome in latent B lymphocytes, and so does not prevent their proliferation.

Srivastava et al report treatment of PTLD in a group of 84 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. Treatment involved reduced immunosuppression and ganciclovir/acyclovir. Chemotherapy was used in 1 patient and hyperimmune globulin in 2 patients resistant to first-line treatment. The PTLD resolved in all patients, and allograft function was universally preserved. Authors concluded that reduction of immunosuppression plus antiviral therapy is adequate treatment for PTLD in the majority of patients.

One group demonstrated acyclovir, in addition to reduction of immunosuppression, to be effective in the treatment of a polyclonal B-cell lymphoma, with dramatic regression of both patient symptoms and objective disease. The reduction in immunosuppression was suggested to assist in maintenance of the remission. However, one patient experienced an episode of allograft rejection 2 months later, which required treatment with steroids. Within 1 month, the PTLD had recurred. On this occasion, no regression of the tumor occurred in response to acyclovir.

Interferon alfa has been effective in the treatment of B-cell PTLD in some patients. Interferon functions as both a proinflammatory and antiviral agent. Because no prospective clinical trials have been conducted to date, many of the reports of its success are anecdotal.

Faro et al report the case of an 11-year-old boy who is EBV seronegative with emphysema of unknown etiology and who underwent double lung transplantation from a donor who is EBV seropositive.¹² He developed PTLD following treatment of an episode of severe rejection. Initial management was unsuccessful with reduction of immunosuppression and acyclovir therapy. Subsequent treatment with interferon alfa for a period of 9 months led to dramatic clinical and histologic improvement, with no evidence of recurrence of PTLD at 18 months.

Interferon alfa is recognized to inhibit the outgrowth of EBV-transformed B cells, and it decreases the oropharyngeal shedding of EBV. It also is known to inhibit T helper cells, which release cytokines (ie, interleukin [IL]-4, IL-6, IL-10) that promote B-cell proliferation. Faro also reported in the same study that interferon alfa therapy significantly decreased the levels of IL-4 and IL-10 messenger RNA (mRNA), which had been noted prior to interferon therapy to be markedly elevated in bronchoalveolar lavage cells.¹² The reduction in these cytokines correlated with the patient's improvement.

Shapiro et al describe 5 patients with monoclonal and polyclonal PTLD who were treated with interferon alfa and intravenous gamma globulin with good response.¹³ O'Brien and colleagues report a case of monoclonal nodal PTLD in a renal transplant recipient who did not respond to reduction in immunosuppression, acyclovir therapy, or intravenous immunoglobulin.¹⁴ The patient then was treated for a period of 3 months with subcutaneous injections of interferon alfa 3 times a week with good response and remained in remission 12 months after treatment.

Intravenous immunoglobulin has been used as adjunctive therapy in the management of PTLD. Deficiency or absence of antibody against one of the EBNAs in patients posttransplantation has been associated with the subsequent development of PTLD. Decreasing EBV viral load has been reported to be associated with increased levels of antibody against EBNAs. These 2 factors provide the rationale for the use of intravenous immunoglobulin in the management of PTLD. It has been used mainly in combination with interferon alfa.

A high mortality rate has been associated with the use of chemotherapy in the management of transplant-associated lymphoproliferative disease. In Cohen's (1991) review of the value of chemotherapy and radiotherapy for the treatment of PTLD in transplant recipients, neither chemotherapy nor radiotherapy demonstrated any survival advantage compared with overall survival rates of 31%. In fact, survival rates were worse, at 23% and 20%, respectively.

Swinnen et al, however, report a retrospective study of 19 cardiac transplant recipients with PTLD who initially were treated with reduced immunosuppression and acyclovir.¹⁵ The patients had all received OKT3 (ie, monoclonal anti–T-cell antibody) as part of their immunosuppressive regimen. A statistically significant reciprocal relationship exists between the dose of OKT3 used and time interval between transplantation and the onset of PTLD.

Six of the patients had polyclonal disease, and 13 had monoclonal. A large proportion of these patients presented early posttransplantation with diffuse and aggressive disease. Those who survived and did not respond to initial management were treated with the combination chemotherapeutic regimen ProMACE-CytaBOM (prednisone, Adriamycin, Cytoxan, etoposide, arabinoside cytosine, bleomycin, Oncovin, and methotrexate). Of the 8 patients who received chemotherapy, all had monoclonal disease. This regimen was felt to be adequately immunosuppressive to obviate the need to continue with other immunosuppressive agents during chemotherapy, and no episodes of graft rejection occurred. Seventy five percent of patients achieved a complete remission, and no cases of relapse occurred at 38 months.

The CHOP combination (cyclophosphamide, Adriamycin, Oncovin, and prednisone) has been used with high remission rates in cardiac transplant patients. However, the dose of doxorubicin in ProMACE-CytaBOM is half that used in CHOP, making ProMACE-CytaBOM less cardiotoxic and a more attractive therapeutic regimen. Although not used frequently now, ProMACE-CytaBOM also was effective for the treatment for non-Hodgkin lymphoma.

Anti-CD21 and anti-CD24 monoclonal antibodies have been used to treat PTLD following bone marrow and solid organ transplantation. LeBlond et al, in a single center study, used anti–B-cell monoclonal antibodies, in addition to reduction of immunosuppression, in a series of 12 patients with PTLD.¹⁶ Four of seven patients with monoclonal lesions and 4 of 5 patients with polyclonal PTLD achieved a complete remission.

Anti–B-cell antibodies were used by Fischer in 26 patients following bone marrow and solid organ transplantation.¹⁷ They received anti-CD21 and anti-CD24 monoclonal antibodies for a period of 10 consecutive days. Treatment was well tolerated, aside from transient neutropenia (granulocytes express CD24 molecules). Complete remission was achieved in patients who had oligoclonal lesions not involving the CNS. Patients with monoclonal lesions or CNS lesions either did not respond in the case of the former or relapsed in the case of the latter. The authors concluded that anti–B-cell antibodies could be effective treatment for severe, diffuse oligoclonal lesions confined outside the CNS.

Benkerrou et al reported the long-term outcome of severe, aggressive PTLD following bone marrow and solid organ transplantation treated with the same B-cell antibodies as Fischer.^{11, 17} Eligibility criteria included lymphoproliferations not responsive to reduction in immunosuppression or rapidly progressive disease. Complete remission was achieved in 61% of patients, with a relapse rate of 8%. The overall long-term survival rate was of the order of 46% at 61 months, although survival rates were lower among bone marrow transplant recipients (35%) compared with solid organ transplant patients (55%). They also identified as poor prognostic markers multivisceral disease, CNS involvement, and late-onset PTLD, which are findings that are consistent with results published by other authors.

Rituximab is a new anti-CD20 monoclonal antibody, which has been used to treat non-Hodgkin lymphoma. Milpied et al in France reported promising results, with response rates of 65%, in patients with PTLD treated with rituximab following solid organ transplantation.¹⁸

PTLD associated with EBV infection in bone marrow transplant recipients usually presents as B-cell lymphoma of donor origin, which often is aggressive, progressive, and fatal. Chemotherapy and radiation therapy are not effective. Papadopoulous et al postulated that the use of donor-leukocyte infusions might treat PTLD effectively in the allograft recipient.¹⁹ They based this hypothesis on the premise that the donor has cytotoxic T lymphocytes, which are presensitized to the EBV responsible for the lymphoproliferation in the recipient—the EBV being donor in origin. They studied 5 patients who developed malignant B-cell lymphoma after receiving T-cell depleted allogeneic bone marrow transplantation. EBV DNA was detected in each tissue sample. All patients achieved complete clinical and pathological remission in response to unirradiated infusions of donor leukocytes.

The EBV-specific cytotoxic T lymphocytes from the donor, in the case of bone marrow transplantation, have the capability of recognizing and destroying EBV-infected B cells in the recipient. Solid organ transplant patients, however, develop PTLD that can be recipient or donor in origin, which in each case would have to be determined before initiation of treatment. In the case of PTLD that is recipient in origin, to obtain cytotoxic T lymphocytes the recipient's T cells would need to be stimulated against EBV ex vivo—technology that is not yet available.

Strategies to prevent EBV infection posttransplantation also may be considered. Prophylactic measures may include screening of donors and recipients for baseline EBV data, risk stratification, and using grafts from donors who are EBV seronegative where possible for seronegative recipients. EBV may be transmitted in blood transfusions, so the use of leukocyte filters may reduce the risk of EBV transmission from blood products. The use of routine acyclovir as prophylaxis is felt to be largely ineffective, as reported by Trigg et al and others.²⁰

Darenkov et al reported a dramatic reduction in the incidence of PTLD in high-risk patients treated with antilymphocyte globulin when prophylactic therapy was administered in the form of ganciclovir (if donor/recipient were cytomegalovirus [CMV] positive) or acyclovir (if CMV negative) during anti–lymphocyte antibody therapy.²¹ Davis et al looked at the benefit of antiviral prophylaxis (intravenous ganciclovir followed by high-dose oral acyclovir) in kidney-pancreas and liver allograft recipients, again in the context of the use of antilymphocyte globulin.²² They found that the incidence of PTLD was lower with prophylactic antiviral treatment.

Birkeland et al reported that primary or reactivated EBV infection correlated with acute graft rejection and the incidence of PTLD.²³ They additionally found that the use of acyclovir (3200 mg/d for 3 mo posttransplantation) was protective against primary or reactivated EBV infection and that the addition of mycophenolate mofetil resulted in further reduction of infection or reactivation. These patients also had been treated with antilymphocyte globulin. Serial monitoring of EBV viral load may be beneficial in the recognition of early PTLD and could be used to prevent progression with the introduction of preemptive therapy.

Surgical Care

In addition to boosting the immune system by reducing immunosuppression, surgical resection or the use of localized radiation therapy has been of value in some patients with PTLD. For a lesion that is focal, this approach may be curative. Surgical management or focal radiation therapy is useful, especially for the treatment of localized complications of the disease. In Cohen's (1991) review, survival rates of the order of 74% were noted for patients treated by surgical excision of the lesion, compared with an overall survival rate of 31%. Field radiation therapy now is felt to be the most effective treatment for PTLD involving the CNS.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Numerous treatment options for PTLD exist. The general consensus is that immunosuppression should be reduced, or withdrawn, in the first instance; however, no strict guidelines exist for this process. The issue of which drug to withdraw or which drug to dose reduce is still an individual decision for the clinician. The aim is to achieve balance—to improve immune function to gain remission from lymphoproliferation while at the same time preserving the allograft. Many immunosuppressive drug combinations and permutations are used in practice, adding to the complexity. Reducing immunosuppression depends to a large degree on the allograft in question. In the case of renal transplantation, an option to cut the immunosuppression significantly or withdraw it altogether is available. If allograft rejection or failure ensues, an adequate form of replacement therapy is available. In the case of heart transplantation, serious allograft rejection and/or failure likely heralds patient demise.

Other treatment options already have been discussed (see Treatment). The second line of treatment varies, and the dose/duration of treatment depends on patient weight, response, complications, tolerance of treatment, and so forth. Bearing in mind that PTLD is an umbrella term that encompasses a wide spectrum of lymphoproliferative diseases, management of PTLD has to be tailored to the needs of the individual patient. Details provided regarding the medications below are to be regarded as general information. Doses or treatment durations provided here are not necessarily those utilized in the management of PTLD. Much of the information provided pertains to treatment of disease entities remote from PTLD. Many of these drugs have been used experimentally for the purpose of treating lymphoproliferative disease, and reports of their efficacy largely are anecdotal.

Drug Category: Immunosuppressive agents

Inhibit key factors that mediate immune reactions, which in turn decrease inflammatory responses.

Drug Category: Antiviral agents

Nucleoside analogs initially are phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit herpes simplex virus (HSV) polymerase with 30-50 times the potency of human alpha-DNA polymerase.

Drug Category: Immunomodulator agents

Rituximab (anti-CD20 monoclonal antibody) has been used primarily in the treatment of lymphoma; however, it has been reported to have successfully treated PTLD in some patients. Other monoclonal antibodies, such as anti-CD21, CD24, and anti-CD3 (OKT3), also have been used successfully for treatment of PTLD. Interferon alfa also has been used in the treatment of PTLD.

Drug Category: Antineoplastic agents

Disrupt DNA replication or cell division, thereby inhibiting cell growth and proliferation.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Follow-up of EBV viral load may provide useful information regarding disease status and the patient's response to treatment. Green at the University of Pittsburgh recommends weekly monitoring of EBV viral titers in the peripheral blood of patients with PTLD.²⁴ A declining viral load is suggestive of response to treatment. Persistently high or rising viral load suggests the presence of disease progression and the need for therapeutic modification. This especially is true if clinical, radiological, or other markers also support progression or lack of response to treatment. Serial physical examinations, radiological evaluation, and assessment for any evidence of allograft rejection are essential. Note that rebounds in viral load can occur with reintroduction of immunosuppression; these are less likely to represent a recurrence of disease in the absence of other findings. In any case, once cured, PTLD has a relapse rate of approximately 10%.
• Management of PTLD is somewhat of a balancing act between eradication and cure of the disease and preservation of graft function. The degree of graft loss that can be tolerated depends on the graft in question, and immunosuppression reduction/withdrawal has to be tailored accordingly, with due consideration of other treatment options. At this time, treatment has not been standardized beyond the generally accepted belief that reduction or withdrawal of immunosuppression is the backbone of management.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Transplantation and the accompanying immunosuppression put patients at risk for potentially fatal infection and malignancy. Transplant candidates must be fully informed of these risks as part of the consent process pretransplantation.
• PTLD can assume an astonishing number of guises. It can mimic relatively benign conditions in its presentation, so a high degree of clinical vigilance and an awareness of its highly variable presentation are required if the diagnosis is not to be missed.
• Treatment of PTLD risks allograft dysfunction. Patients need to be made aware that PTLD is a serious consequence of transplantation and immunosuppression, and it requires treatment; however, this treatment may result in the loss of the allograft.
• Failure to inform the patient of relevant risks and possible outcomes at every stage puts the physician at risk for medical litigation.
• Additionally, care must be taken on the part of the treating physician to consider a diagnosis of PTLD in patients who are immunosuppressed, even when clinical symptoms or signs are atypical, and to perform the appropriate diagnostic tests to exclude the diagnosis of PTLD.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Biopsy of gingival tissue (400 X) with hematoxylin and eosin stain demonstrates polymorphous infiltrate of atypical lymphoid cells, which is consistent with posttransplant lymphoproliferative disease (PTLD).
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