Practice Essentials
Posttransplant lymphoproliferative disease (PTLD) is a well-recognized complication of both solid organ transplantation (SOT) and allogeneic hematopoietic stem cell transplantation (HSCT). It is one of the most common posttransplant malignancies. [1]
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 EBV infection. In cases of primary infection, EBV may be acquired from the donor graft or, less commonly, from environmental exposure. While T-cell lymphoproliferative disorders that are not typically associated with EBV infection also occur after SOT and HSCT, the vast majority are B-cell proliferations.
In the current classification scheme, which derives in part from the work of a multidisciplinary panel that met in Seville, Spain in 2009, the term PTLD is also applied to posttransplantation infectious mononucleosis and plasma cell hyperplasia (reactive hyperplasias). [2] When the term PTLD is not qualified, it refers to neoplastic disease. The 2016 World Health Organization (WHO) classification system recognizes 6 major histopathologic subtypes of PTLD, as follows [3] :
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Plasmacytic hyperplasia PTLD
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Infectious mononucleosis PTLD
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Florid follicular hyperplasia PTLD
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Polymorphic PTLD
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Monomorphic PTLD (B- and T-/NK-cell types)
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Classical Hodgkin lymphoma PTLD
Most cases of PTLD occur within the first posttransplant year. The more intensive the immunosuppression used, the greater the risk of PTLD and the earlier it tends to occur.
PTLD can assume a wide range of guises: it may present as localized or disseminated disease, and it can mimic relatively benign conditions. Thus, a high degree of clinical vigilance and an awareness of its highly variable presentation are required if the diagnosis is not to be missed. See Presentation.
The diagnosis of PTLD is made by histopathologic evidence of lymphoproliferation, commonly with the presence of EBV DNA, RNA, or protein detected in tissue. See Workup.
The cornerstone of initial management of PTLD is reduction or withdrawal of immunosuppression, which in some situations may reverse the lymphoproliferative process. This potential for reversibility with reduction of immunosuppression distinguishes PTLD from neoplastic lymphoproliferative disorders that occur in immunocompetent patients.
Reduction of immunosuppression also carries the risk of inducing allograft dysfunction or loss and is not always feasible, depending on the grafted organ or clinical situation. Patients need to be made aware of the risks of both the disease its treatment.
Rituximab is a standard of care for CD20+ PTLD that has not responded adequately to reduction of immunosuppression. Preemptive treatment with rituximab is recommended for patients with EBV DNA detected in blood. Rituximab may be used alone or in combination with chemotherapy. Other potential treatments include the following:
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Surgical excision of the lesion
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Localized radiation therapy
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Antiviral therapy
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Immunoglobulin therapy
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Cytotoxic T lymphocytes
See Treatment and Medication.
Pathophysiology
The vast majority of cases of posttransplant lymphoproliferative disease (PTLD) are caused by Epstein-Barr virus (EBV) infection. [4, 5] EBV is a herpes virus that is thought to infect up to 95% of the population by adulthood. [6]
Primary infection with EBV in childhood usually results in mild, self-limiting illness. [6] In immunocompetent older children and adults, EBV infection causes infectious mononucleosis. [7] Once EBV infection occurs, the virus persists in a person for life, latently in B-cell lymphocytes and chronically replicating in the cells of the oropharynx. [8]
EBV was discovered in the 1960s by electron microscopy of cells cultured from a Burkitt lymphoma. [9] Subsequently, EBV has also been associated with non-Hodgkin lymphoma and oral hairy leukoplakia in patients with HIV infection and with nasopharyngeal carcinoma, particularly in patients from Southeast Asia. [7, 10, 11]
Structurally, the EBV genome is enclosed in a nuclear capsid surrounded by a glycoprotein envelope.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 immunocompetent patients, proliferation of transformed B cells usually is controlled by cytotoxic T cells. This is not the case, however, with patients who are immunosuppressed. [6]
During latency, the viral genome adopts an episomal configuration and expresses only 9 proteins. This change in gene expression creates increased difficulty for T-cell recognition, facilitating persistent EBV infection. Latency occurs in resting memory B cells. The 9 EBV proteins expressed during latency are the latent membrane proteins LMP-1, LMP-2A, and LMP-2B and the nuclear antigens EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, and EBNA-LP.
LMP-1 is considered an oncogene. Its expression results in increased levels of CD23, which is a B-cell activation antigen. LMP-1 also induces expression of bcl-2, an inhibitor of apoptosis in infected cells. LMP-2 prevents EBV reactivation in latently infected cells. EBNA-1 maintains 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. [6]
The lymphoproliferative tissue from most cases of PTLD has detectable EBV DNA and expression of 3 antigens in particular: EBNA-1, EBNA-2, and LMP-1. Two of these 3 proteins usually are not expressed in other EBV-related malignancies and so may be distinguishing features. Of note, the classic t(8;14) or t(8;22) chromosomal translocations observed in Burkitt lymphoma are often not detected in the tumors of patients with PTLD, even in cases of monomorphic/monoclonal B cell lymphoproliferations. [8, 12, 13]
Carriage of certain HLA-E alleles has been shown to affect host response to EBV. Individuals with the HLA-E∗0103/0103 genotype are less likely to experience infectious mononucleosis from primary EBV infection, compared with those with the HLA-E∗0101/0101 genotype, but are significantly more likely to develop EBV-positive PTLD. In contrast, transplant recipients with symptomatic EBV reactivations but without PTLD were significantly more likely to have the HLA-E∗0101/0101 genotype. [14]
Along with transplant recipient genotypes, the EBV strain may affect the risk of PTLD. In hosts with the HLA-E∗0103/0103 genotype, EBV strains that encode for the LMP-1 peptide variants GGDPHLPTL and GGDPPLPTL are associated with symptomatic EBV reactivation and progression to PTLD. [14]
EBV infection normally results in both a humoral and cellular immune response by the host. Cellular immunity—CD4 and CD8 T cells and natural killer cells—is thought to be more important in controlling proliferation of infected B lymphocytes. Antibodies produced to viral capsid and nuclear proteins facilitate the diagnosis of EBV infection. In individuals who are immunocompetent, these mechanisms prevent outgrowth of EBV-infected lymphocytes. The immunosuppression required to prevent graft rejection post transplantation impairs T-cell immunity, potentially allowing for uncontrolled proliferation of EBV-infected B-cells, which may result in a spectrum of B-cell proliferations that range from hyperplasia to true lymphoma. [15, 16, 17, 18]
Carriage of certain HLA-E alleles has been shown to affect host response to EBV. Individuals with the HLA-E∗0103/0103 genotype are less likely to experience infectious mononucleosis from primary EBV infection, compared with those with the HLA-E∗0101/0101 genotype, but are significantly more likely to develop EBV-positive PTLD. In contrast, transplant recipients with symptomatic EBV reactivations but without PTLD were significantly more likely to have the HLA-E∗0101/0101 genotype. [19]
In the initial stages of PTLD, proliferation is polyclonal. With mutation and selective growth, the lesion becomes oligoclonal and, later, monoclonal. Lymphocytes from patients treated with cyclosporine following transplantation do not exhibit an appropriate T-cell response to EBV-infected B cells in vitro. The activity of natural killer cells also is reduced for several months following transplantation, contributing to the impairment of the most important regulator of proliferation: cellular immune response. [5, 20, 21]
The mechanisms that cause EBV-negative PTLD are not well understood. This disorder often has a later onset, monomorphic histology, and a more aggressive course than EBV-positive PTLD, suggesting that it may have a different pathophysiology. [22, 23]
Epidemiology
Frequency
The frequency of posttransplant lymphoproliferative disease (PTLD) depends largely on the type of transplant received and the immunosuppression that the particular transplant requires. Primary EBV infection, such as may develop in an EBV-seronegative recipient who receives an allograft from an EBV-seropositive donor, is recognized as probably the most significant risk factor for developing PTLD. It is therefore not surprising that in general, PTLD rates are reported to be higher in pediatric transplant recipients than in adult transplant recipients. [24, 25, 26, 27]
The incidence of PTLD varies with the type of transplanted allograft. Reported rates are higher in heart, heart-lung, and small bowel transplants than in kidney and liver transplants. This presumably reflects in part the need for more intense immunosuppression to maintain certain types of allografts. The site of lymphoproliferative disease also depends on the type of graft. The lungs are frequently a site of involvement in patients undergoing heart-lung or heart-alone transplantation. Similarly, in small bowel transplants, the grafted bowel is commonly a site of PTLD. In cardiac transplants, the heart itself seldom is involved.
Kidney transplantation
A French kidney transplant registry consisting of data from adult patients who were enrolled prospectively from 1998 through 2007 found a 1% incidence of PTLD after 5 years, which increased to 2.1% by 10 years post transplantation. The more recently the transplant was performed, however, the less likely the recipient was to develop PTLD. [23]
In a Canadian single-center cohort study that included 1642 patients who received kidney transplants from 2000 through 2012, the incidence rate of PTLD was 0.18 cases per 100 person-years. EBV mismatch between donor and recipient was a strong risk factor. [28]
A report from the Organ Procurement and Transplantation Network (OPTN) of the United States reported PTLD incidence following kidney transplantation ranging from 0.6-1.5%. This study found an association between Medicare status, white race, and receipt of T-cell–depleting antibodies with the development of PTLD. A November 2012 report from the US OPTN found an incidence rate of 1.58 cases of PTLD per 1000 patient years post transplantation. [29]
In pediatric kidney transplant recipients, the reported incidence of PTLD ranges from 4.4-6.9%, with a wide range of times until onset—from less than 6 months to greater than 3 years. [30, 31] The majority of cases reported were B-cell proliferations. Age younger than 5 years at the time of transplantation and EBV-positive allograft donor to an EBV-seronegative recipient both significantly increased the risk ratio for developing PTLD. Many of the cases occurred while patients were still receiving steroids for immunosuppression.
Heart transplantation
In adults, heart transplantation is associated with approximately a 5% cumulative incidence of PTLD. Some reports have suggested that it may be as high as 8.9%. [32] Many reports of PTLD in heart transplant patients are single-institution studies and thus there may be greater variation seen in these reports compared with registry or cooperative studies. The US OPTN reports a rate of 2.24 cases of PTLD per 1000 patient years post heart transplantation. [29]
In children, the rate of PTLD following heart transplantation is even higher. Manlhiot et al found a 13% rate of PTLD at 4 years after pediatric heart transplantation at the Hospital for Sick Children at the University of Toronto. In this study, higher EBV load and longer induction of immunosuppression were associated with greater risk for PTLD.
Liver transplantation
An analysis of the Scientific Registry of Transplant Recipients of the United States reported PTLD rates of approximately 1% following liver transplantation in adult and pediatric recipients. The US OPTN reports a rate of 2.44 cases of PTLD per 1000 patient years post liver transplantation.
A retrospective analysis from the Mayo Clinic of 1206 orthotopic liver transplants (OLT) reported a cumulative incidence of PTLD of 1.1% at 18 months and 4.7% at 15 years. The authors suggest that previous reports of a lower incidence of PTLD late after OLT may warrant further examination as survival of OLT recipients improves. [33]
A retrospective study of 431 adult liver transplant recipients by Zimmerman et al reported that 11 (2.6%) patients developed PTLD. Multivariate analysis in that study revealed that pretransplant steroid treatment and liver transplantation for autoimmune hepatitis were risk factors for developing PTLD. [34]
More recent reports of PTLD in pediatric liver transplant recipients show rates that range from 3.8-4.7%. This is improved from earlier studies that reported PTLD rates as high as 5-15% for pediatric liver transplant. [35] The higher incidence of PTLD that was initially observed with tacrolimus as compared with cyclosporine [36] has more recently been attributed to the earlier practice of targeting higher tacrolimus levels. With greater experience using this immunosuppressive agent and targeting of lower therapeutic levels, tacrolimus no longer appears to be associated with a higher incidence of PTLD in pediatric liver transplant recipients.
Lung transplantation
Lung transplantation is associated with a relatively high rate of PTLD, with an incidence of approximately 5%. The median time to development of PTLD has been reported to be between 12 and 40 months, depending on the study. A report of 705 lung transplant recipients identified 34 cases of PTLD, for an incidence of 4.8%. [37] Among the 17 patients diagnosed within 11 months of transplantation, 85% had polymorphic PTLD and the most common site involved was the allograft, in 71% of the patients. PTLD that developed late was typically monomorphic and was more likely to involve the GI tract (39%) than the lung allograft (28%). The US OPTN reports a rate of 5.72 cases of PTLD per 1000 post transplantation patient years, with most cases occurring less than 1 year post transplantation.
HSCT
In the setting of HSCT, PTLD rates vary greatly depending on the conditioning regimen and the amount of T-cell depletion involved in either the conditioning or the product provided. Rates as high as 71% have been reported in the setting of very extreme T-cell depletion. More recently, however, rates of PTLD in adult HSCT range from 0.2% with no T-cell depletion to 1.7% with antithymocyte globulin treatment. [22]
Similar results are seen in pediatric HSCT. PTLD occurs in less than 1% of non–T-cell–depleted grafts from matched siblings, compared with as high as 30% of patients with unrelated or HLA-mismatched donors when extensive T-cell depletion of the donor bone marrow is performed. Other risk factors for PTLD in HSCT recipients include treatment of graft versus host disease with antithymocyte globulin or anti–T-cell monoclonal antibodies. [38]
Prognosis
PTLD represents a heterogeneous group of tumors, ranging from B-cell hyperplasia to immunoblastic lymphoma, the latter portending a grim prognosis. [3, 39, 40] All PTLD, however, irrespective of histology, is potentially life-threatening.
The presentation and clinical course for PTLD may be quite variable. At one end of the spectrum is fulminant disease with diffuse involvement, which may result in the rapid demise of the patient. At the other end of the spectrum are localized lesions that may be indolent and slow growing over months. The former tends to occur early post transplantation after primary EBV infection and often involves the allograft itself. Late-onset PTLD tends to be monoclonal, EBV-negative, and often more refractory to therapy. [20]
In a retrospective review of 32 adult and pediatric SOT patients with PTLD, the 5-year survival rate was 59%. [39] Nearly half of the patients were diagnosed within the first year following transplantation. Characteristics associated with poorer survival were diagnosis within the first year post transplantation, monoclonal tumors, and presentation with an infectious mononucleosis–like syndrome.
While advances in the diagnosis and treatment of PTLD have improved outcomes for patients with PTLD, studies continue to report high rates of mortality from PTLD. A series of adult kidney and heart transplant recipients reported by Wasson et al in 2006 had a mortality rate of 26.6%. Similarly, a more recent report of pediatric kidney transplant patients also found a 25% mortality rate related to PTLD. [31]
Central nervous system (CNS) involvement in EBV-PTLDs portends a very poor prognosis. In a case series of CNS PTLDs after HSCT, 7 of the 9 patients died a median of 17 days from diagnosis. [41]
Several studies have attempted to identify prognostic factors for PTLD outcomes. For example, Evens et al identified hypoalbuminemia as a strong prognostic factor in their multicenter study of 80 adult SOT recipients with PTLD. Similarly, Khedmat and Taheri performed a literature review and found evidence to suggest that CD20-positive PTLD portends earlier disease appearance and inferior outcome.
LeBlond et al applied the non-Hodgkin lymphoma International Prognostic Index (IPI) to a series of 61 adult patients with PTLD following kidney, lung, liver, or heart transplantation to analyze factors that may be predictive for shorter survival. In univariate analysis, the following were found to be poor prognostic features:
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Performance status (PS) ≥2
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Increased number of sites involved (ie, >1 vs 1)
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Primary central nervous system (CNS) involvement
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T-cell origin
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Monoclonality
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Nondetection of EBV in the tumor
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Treatment based on chemotherapy (in addition to reduction in immunosuppression)
In multivariate analysis, PS less than 2 and decreased number of disease sites (ie, 1 vs >1) both were associated with improved survival. These determinants were used to identify 3 levels of risk stratification in terms of survival probability. For intermediate-risk patients (ie, PS ≥2 or 2 or more sites), median survival time with treatment was 34 months. For high-risk patients (ie, PS ≥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 system was found to be more helpful in determining prognosis for PTLD patients than the IPI used for immunocompetent patients with non-Hodgkin lymphoma.
Although a number of prognostic scores have been proposed in different transplantation populations, none has been externally validated or widely adopted. The rarity and clinical diversity of the disease, as well as the nature of the reporting of PTLD cases, which is often retrospective and from single-institution studies, have contributed to the challenge of developing and validating a universally accepted system of risk classification.
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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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Biopsy of gingival tissue (400 X). Epstein-Barr virus encoded RNA (EBER) study shows numerous positive cells, which is consistent with posttransplant lymphoproliferative disease (PTLD).
