1. P s t n p n l h po frted e s
o tr s l ty o rl ai i a e
-a a mp ie v s

2. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 3
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/apme
Review Article
Post-transplant lymphoproliferative disease
S. Rajagopalan
Consultant, Department of Nephrology, Apollo Hospital, Chennai, India
article info abstract
Article history: Post-transplant lymphoproliferative disorder/disease (PTLD) is a B-cell proliferation dis-
Received 16 January 2013 order following infection with EpsteineBarr virus due to therapeutic immunosuppression
Accepted 18 January 2013 after organ transplantation. The more intense the immunosuppression, the higher the
Available online 30 January 2013 incidence of PTLD and the earlier it occurs. The cornerstone of successful treatment of
PTLD is reduction or withdrawal of immunosuppression.
Keywords: Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
Transplant
Immunosuppression
EBV
B cells
PTLD
Transplant patients may develop infectious mononucleosis- immunosuppression in these patients. In terms of lympho-
like lesions or polyclonal polymorphic B-cell hyperplasia due proliferative disease occurring in the allograft itself, it de-
to EpsteineBarr virus (EBV) infection. Some of these B cells pends on the graft in question. The lungs very frequently are
may undergo mutations which will render them malignant, a site of involvement in patients undergoing heart-lung, or
giving rise to a lymphoma. Most cases of PTLD are observed in heart alone, transplant. In cardiac transplant, the heart itself
the first post-transplant year. Reduction of immunosup- seldom is involved. In renal allografts, the graft kidney is
pression inherently carries the risk of allograft dysfunction or affected approximately one third of the time, which is similar
loss. The reversibility, partial or complete, with reduction of to graft involvement rates in liver and bone marrow trans-
immunosuppression, differentiates PTLD from the lympho- plant cases.
proliferative disorders observed in patients who are immu- The incidence in renal transplant recipients is around 1 per
nocompetent. Studies have documented the adverse impact cent, a risk of lymphoma about 20 times greater than in the
of subclinical CMV (cytomegalovirus) and EBV viremia on graft general population. The two main aetiological mechanisms
function.1 are EBV infection and immunosuppression. EBV infection can
be detected in about 90 per cent of patients and is almost al-
ways a primary infection. Thus, seronegative recipients are
1. Epidemiology, morbidity and mortality those predominantly at risk and this explains why children
are commonly affected in contrast to lymphoma in the gen-
The incidence of PTLD varies with the type of transplanted eral population.
allograft. It is much higher in heart or heart-lung transplants, Swinnen et al examined the incidence of PTLD in patients
presumably reflecting the need for more intense undergoing cardiac transplant and using OKT3 (murine
E-mail address: drrajagopalan_s@apollohospitals.com.
0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.apme.2013.01.014

3. 58 a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 3
monoclonal anti-CD3 antibody) as immunosuppression and retrospective review of 32 patients, the 5-year survival rate
found an incidence of 6.2% in patients who had received a dose was 59%, with 45% of patients diagnosed within the first year
of 75 mg or less. The mean time to development of PTLD was 11 following transplantation. Six out of 8 patients surgically
months, compared with an incidence of 35.25% and a mean treated remain alive and disease free. Characteristics asso-
interval of 1.5 months in patients who received doses of ciated with poorer survival were diagnosis within the first year
greater than 75 mg. With prednisolone and azathioprine alone, post-transplant, monoclonal tumors, and presentation with
the mean time to developing PTLD is 50 months. Cyclosporin an infectious mononucleosis-like syndrome.6
therapy reduced this to 5 months. Use of tacrolimus and use of LeBlond et al, in a series of 61 patients who had undergone
antilymphocyte globulins have been associated with much kidney, lung, liver, or heart transplantation, found that factors
earlier and more frequent presentation of PTLD.2 predictive for shorter survival (univariate analysis) in PTLD
Majority of PTLDs are of non-Hodgkin’s lymphoma subtype included a performance status (PS) greater than or equal to 2,
and makeup about 93% of lymphoma encountered in this increased number of sites involved (i.e., >1 versus 1), primary
setting. Out of those 86% of post-transplant lymphomas are of central nervous system (CNS) involvement, T-cell origin,
B-cell origin and about 14% of lymphomas are of T-cell origin, monoclonality, nondetection of EBV in the tumor, and treat-
whereas less than 1% are of null cell origin.3 ment based on chemotherapy (in addition to reduction in
Cohen (1991) reviewed cases of PTLD in the literature immunosuppression).7
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 2. Pathophysiology
mean time was 32 months. He noted that patients treated
with cyclosporin had a mean time to development of PTLD of 5 The disease is an uncontrolled proliferation of B lymphocytes
months. Survivors were more likely to have a shorter time following infection with EpsteineBarr virus. EBV is a herpes
interval to development of PTLD than those who died, they virus that is thought to infect as much as 95% of the adult
were more likely to have polyclonal lesions and B-cell hyper- population. Primary infection with EBV usually results in mild,
plasia, and they were more likely to have involvement of graft self-limiting illness in childhood and the clinical syndrome of
or lymph nodes.4 infectious mononucleosis in adults. It was found over 3 de-
Shapiro et al found an overall incidence of PTLD of 1.9% in cades ago by electron microscopy of cells cultured from
a population of 1316 patients undergoing kidney transplants a Burkitt lymphoma. Since 1968, it has been known to cause
at the University of Pittsburgh from 1989 to 1997. The inci- infectious mononucleosis and has been associated with non-
dence in adults was 1.2%, with a much higher incidence in Hodgkin lymphoma and oral hairy leukoplakia in patients
pediatric patients (i.e., 10.1%). The time interval to diagnosis of with HIV infection and with nasopharyngeal carcinoma, par-
PTLD ranged from less than 1 month to 49 months in adults. ticularly in Southeast Asia.
The 1- and 5-year patient and graft survival rates in adults Once a person is infected with EBV, the virus persists for
were 93% and 86% and 80% and 60%, respectively. The authors life as a result of latency in B-cell lymphocytes and chronic
concluded that although PTLD is more common in renal replication in the cells of the oropharynx. The EBV genome is
transplant pediatric recipients receiving tacrolimus, they have a linear DNA molecule that encodes for approximately 100
a more favorable prognosis.5 viral proteins that are expressed during replication. The CD21
PTLD forms a heterogenous group of tumors, ranging from molecule on the surface of the B-cell is the target receptor of
B-cell hyperplasia to immunoblastic lymphoma, the latter the EBV glycoprotein envelope. Infection of B-cell lympho-
portending a more grim prognosis. All PTLD, however, irre- cytes with EBV results in either viral replication and B-cell
spective of histology, is potentially, and frequently, fatal. lysis (i.e., lytic replication) or a transformation of the cell with
Mortality rates could be as high as 60e100%. The presentation only partial EBV genome expression (i.e., latency). Cell trans-
and clinical course are variable. At one end of the spectrum is formation is associated with B-cell activation and continuous
aggressive disease with diffuse involvement, resulting in proliferation. In patients who are immunocompetent, prolif-
rapid demise of the patient; at the other end of the spectrum eration of these transformed B cells usually is controlled by
are localized lesions that are indolent and slow growing over cytotoxic T cells. This is not the case, however, with patients
months, as opposed to days or weeks. The former occur early who are immunosuppressed.
in the post-transplantation period and are more often poly- The viral genome expresses only 9 proteins during latency,
clonal lesions. Late-onset PTLD tends to be monoclonal and when it adopts an episomal configuration. This creates
heralds a worse prognosis. Polyclonal lesions, however, have increased difficulty for T-cell recognition, facilitating persis-
a more favorable prognosis. They, unlike monoclonal lesions, tent EBV infection, which is thought to occur in resting
tend to occur early and are responsive to reduction of memory B cells. The 9 proteins expressed are EBV latent
immunosuppression. Primary CNS involvement is associated membrane proteins ([LMP], i.e., LMP-1, LMP-2A, LMP-2B) and
with significantly higher mortality rates, 88% at 6 months in EBV nuclear antigens ([NA], i.e., EBNA-1, EBNA-2, EBNA-3A,
one study. CNS disease requires intrathecal therapy or local- EBNA-3B, EBNA-3C, EBNA-LP). LMP-1 is considered to be an
ized radiation therapy because intravenous chemotherapy oncogene. Its expression results in increased levels of CD23,
and monoclonal antibodies do not cross the blood-brain bar- which is a B-cell activation antigen. LMP-1 also is known to
rier adequately. induce expression of bcl-2, which inhibits apoptosis of an
Hauke et al reported their experience with PTLD occurring infected cell. LMP-2 prevents reactivation of EBV in latently
in patients after solid organ transplantation. In this infected cells. EBNA-1 is responsible for maintaining the

4. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 3 59
episomal configuration of the latent virus. EBNA-2 up-regu- may be seen with isolated or multiple tumors often involving
lates the expression of LMP-1 and LMP-2, which are necessary the gastrointestinal tract, the lungs, or the allograft. Finally,
for transformation of the B-cell. one may see an EBV-negative type of PTLD which is of late
EBV infection results in both a humoral and cellular im- onset and clinically resembles non-Hodgkin’s lymphoma. In
mune response by the host. Cellular immunity is thought to be those patients with localized organ involvement, the brain is
the more important of the two in terms of regulation and frequently involved, much more often than in lymphoma in
control of proliferation of the infected B lymphocytes by the general population.
means of CD4 and CD8 cytotoxic T cells and natural killer Whether PTLD presents as localized or disseminated dis-
cells. Antibodies to viral capsid and nuclear proteins are pro- ease, the tumors are aggressive and rapidly progressive and
duced, the presence of which facilitates the diagnosis of EBV often are fatal. Clinical presentation is very variable and in-
infection. In individuals who are immunocompetent, these cludes fever (57%), lymphadenopathy (38%), gastrointestinal
mechanisms work well to prevent outgrowth of EBV-infected symptoms (27%), infectious mononucleosis-like syndrome
lymphocytes. In patients who are immunodeficient, a number that can be fulminant (19%), pulmonary symptoms (15%), CNS
of factors compromise these mechanisms. Production of an symptoms (13%), and weight loss (9%). Patients may report
interleukin-10, an endogenous anti-T cell cytokine, has also fever, weight loss, anorexia, lethargy, sore throat, swollen
been implicated. glands, diarrhea, abdominal pain, shortness of breath, neu-
The immunosuppression required to preserve graft function rological symptoms, or symptoms that initially would not
post-transplantation results in impairment of T-cell immunity suggest a diagnosis of PTLD. The most common sites for
and allows for uncontrolled proliferation of EBV-infected involvement are lymph nodes (59%), liver (31%), lung (29%),
B cells, resulting in monoclonal or polyclonal plasmacytic kidney (25%), bone marrow (25%), small intestine (22%), spleen
hyperplasia, B-cell hyperplasia, B-cell lymphoma, or immuno- (21%), CNS (19%), large bowel (14%), tonsils (10%), and salivary
blastic lymphoma. Immune surveillance is impaired. As dis- glands (4%).
cussed above, this outgrowth usually is regulated by cytotoxic T
cells and natural killer cells.
In the initial stages, the proliferation is polyclonal. With 4. Evaluation
mutation and selective growth, the lesion becomes oligoclonal
and, later, monoclonal. Cyclosporin was demonstrated many A diagnosis of PTLD is made by having a high index of suspi-
years ago to actually promote the proliferation of B lympho- cion in the appropriate clinical setting; histopathological evi-
cytes in vitro. Additionally, lymphocytes from patients treated dence of lymphoproliferation on tissue biopsy; and the
with cyclosporin following transplantation do not exhibit an presence of EBV DNA, RNA, or protein in tissue.
appropriate T-cell response to EBV-infected B cells in vitro. The EBV status of the recipient usually is established pre-
The activity of natural killer cells is reduced for several transplantation. Donor EBV status is not always sought rou-
months post-transplantation, impairing cellular immune tinely because the incidence of infection with EBV in the
responsedthe most important regulator of proliferation. general population is so high. In primary EBV infection, EBV
Depletion of T cells by use of anti-T-cell antibodies (ATG, ALG viral capsid antigen (VCA) immunoglobulin M (IgM) titers are
and OKT3) in the prevention or treatment of transplant elevated.
rejection further increases the risk of developing post- Reactivation of EBV infection is characterized by more than
transplant lymphoproliferative disorder. a 4-fold rise in EBV VCA immunoglobulin G (IgG) titers, com-
Other risk factors that have been identified as predictive for pared with previously recorded EBV VCA IgG titers. No change
the development of PTLD include use of OKT3, anti- in titer suggests past infection.
lymphocyte globulin, recipient pretransplant EBV seronega- These tests can be performed as part of a PTLD workup.
tivity and donor EBV seropositivity. The incidence of PTLD has Elevated titers of antibodies to VCA have been identified in
been found to be significantly higher in patients who are EBV recipients of solid organ grafts who developed PTLD. The
seronegative pretransplant, compared with those who are absence of change in EBV antibody titers does not exclude
seropositive (23.1% versus 0.7%) in Cockfield’s 1993 analysis.8 a diagnosis of PTLD. However, increases in EBV viral load in
However, experience at the University of Pittsburgh, in the the peripheral blood have been detected in patients prior to
case of intestinal transplantation, the incidence of PTLD is as the onset of lymphoproliferative disease, and a decrease in
high in patients who are EBV seropositive pretransplantation these levels has occurred following effective treatment of
as in patients who are seronegative. PTLD. EBV viral load can be monitored by means of polymer-
ase chain reaction (PCR). High viral loads have been found in
a high proportion of patients with PTLD, but a high EBV viral
3. Presentation and clinical features titer is not diagnostic. This test is not standardized, and not all
patients with PTLD have a high viral load.9
PTLD usually presents as one of four clinical syndromes. An In addition to a high degree of vigilance in the appropriate
onset similar to acute infectious mononucleosis with con- clinical setting, histological confirmation of lymphoprolifera-
stitutional upset and tonsilar and cervical lymph node tion is mandatory. Histopathologically, the lesion may dem-
enlargement is the most common mode of presentation dur- onstrate plasmacytic hyperplasia, B-cell hyperplasia, B-cell
ing the first year. Second a fulminating picture with wide- lymphoma, or immunoblastic lymphoma. The pathological
spread infiltration and ominous prognosis can present within diagnosis of PTLD is based on the WHO classification and in-
weeks of the transplant. Later, a more indolent presentation cludes 4 main categories: (1) early lesions, (2) polymorphic

5. 60 a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 3
Nondetection of EBV is associated with tumors that present
late, usually are monoclonal, and are more resistant to treat-
ment. They are more likely to be disseminated and are less
likely to achieve complete remission (Fig. 2).
Establishing the clonality of the lesion is important. Tu-
mors can be monoclonal, oligoclonal, polyclonal, or mixed.
Some lymphomas may appear polyclonal by surface immu-
noglobulin 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 can-
not be differentiated into benign or malignant tumors. The
Fig. 1 e Biopsy of gingival tissue, with haematoxylin and mortality rate is high, independent of histology.
eosin stain demonstrates polymorphous infiltrate of With regard to T-cell lymphoproliferative disorders, these
atypical lymphoid cells, which is consistent with post- lesions predominantly are monoclonal.
transplant lymphoproliferative disease (PTLD). T-cell PTLD usually is not associated with EBV infection
and does not respond to immunosuppression dose reduction.
It carries an unfavorable prognosis.
PTLD, (3) monomorphic PTLD, and (4) classic Hodgkin lym- Radiological evaluation includes computerized tomogra-
phoma (Fig. 1).10 phy scan of chest, abdomen, pelvis, and head, looking for
In practice, a clear separation between the different sub- evidence of hepatosplenomegaly, lymphadenopathy, or
types is not always possible; early lesions, polymorphic PTLD, abnormal mass.
and monomorphic PTLD probably represent a spectrum of T-cell lymphoproliferative disorders not associated with
diseases.11 EBV infection tend to occur at extranodal sites. Reports exist of
Immunohistologic staining can be used to confirm the PTLD presenting in the oral cavity.
presence of EBV. In situ hybridization with the EBV-encoded Gastrointestinal PTLD usually involves the small and large
RNA (EpsteineBarr early region [EBER]-1) probe (labels EBV- intestine and most common presentation is fever, abdominal
encoded RNA in infected cells) is a reliable means of detect- pain or perforation.12
ing EBV in tissue. It also requires demonstration of the pres- It has been observed that gastric PTLD is more common in
ence of EBV DNA or protein in the biopsied tissue. renal allograft recipients compared to other solid organ
Fig. 2 e EBV early RNA (EBER) in PTLD tissue.

6. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 3 61
transplantation but the exact cause of this difference is not dose of OKT3 used and time interval between transplantation
well understood.13 and the onset of PTLD. Six of the patients had polyclonal dis-
ease, and 13 had monoclonal. A large proportion of these pa-
tients presented early post-transplantation with diffuse and
5. Treatment aggressive disease. Those who survived and did not respond to
initial management were treated with the combination che-
Starzl et al were the first to suggest reduction, or withdrawal, motherapeutic regimen ProMACE-CytaBOM (prednisone,
of immunosuppression as a treatment option for PTLD.14 This Adriamycin, Cytoxan, etoposide, arabinoside cytosine, bleo-
serves to allow the patient’s natural immunity to recover and mycin, Oncovin, and methotrexate). Of the 8 patients who
gain control over proliferating EBV-infected cells. Most pa- received chemotherapy, all had monoclonal disease. This
tients with benign PTLD respond well to this management regimen was felt to be adequately immunosuppressive to
approach. People with malignant disease often respond obviate the need to continue with other immunosuppressive
inadequately to these measures, and more aggressive treat- agents during chemotherapy, and no episodes of graft rejection
ment is necessary. A reduction in immunosuppressive ther- occurred. Seventy five per cent of patients achieved a complete
apy is not effective for CNS PTLD. remission, and no cases of relapse occurred at 38 months.2
T-cell PTLD usually is not associated with EBV infection The CHOP combination (cyclophosphamide, Adriamycin,
and does not respond to immunosuppression dose reduction. Oncovin, and prednisone) has been used with high remission
Additional measures that have been used include surgical rates in cardiac transplant patients. However, the dose of
excision of the lesion (which can be curative in cases of doxorubicin in ProMACE-CytaBOM is half that used in CHOP,
localized disease), antiviral therapy, localized radiation ther- making ProMACE-CytaBOM less cardiotoxic and a more
apy and chemotherapy, alfa interferon, intravenous gamma attractive therapeutic regimen.
globulin, cytotoxic T lymphocytes, and monoclonal anti- Benkerrou et al reported the long-term outcome of severe,
bodies, each with varying degrees of success. aggressive PTLD following bone marrow and solid organ trans-
Acyclovir and ganciclovir both inhibit lytic EBV DNA rep- plantation treated with B-cell antibodies, anti-CD21, anti-CD24.
lication in vitro. Ganciclovir is more potent than acyclovir. Eligibility criteria included lymphoproliferations not responsive
However, the majority of EBV-infected cells in lymphoproli- to reduction in immunosuppression or rapidly progressive dis-
ferative lesions are transformed B cells. Acyclovir inhibits only ease. Complete remission was achieved in 61% of patients, with
the replication of linear EBV DNA and is ineffective against a relapse rate of 8%. The overall long-term survival rate was of
episomal EBV DNA, which is the conformation of the EBV the order of 46% at 61 months, although survival rates were
genome in latent B lymphocytes. lower among bone marrow transplant recipients (35%) com-
Interferon alfa has been found effective in the treatment of pared with solid organ transplant patients (55%). They also
B-cell PTLD in some patients. It functions as both a proin- identified as poor prognostic markers multivisceral disease,
flammatory and antiviral agent. Interferon alfa inhibits the CNS involvement, and late-onset PTLD, which are findings that
outgrowth of EBV-transformed B cells, and decreases the are consistent with results published by other authors.18
oropharyngeal shedding of EBV. It inhibits T helper cells, Rituximab, an anti-CD20 monoclonal antibody, has been
which release cytokines (i.e., interleukin IL-4, IL-6, IL-10) that used to treat non-Hodgkin lymphoma. Milpied et al in France
promote B-cell proliferation.15 reported promising results, with response rates of 65%, in
Intravenous immunoglobulin has been used as adjunctive patients with PTLD treated with rituximab following solid
therapy in the management of PTLD. Deficiency or absence of organ transplantation.19 According to Gross et al, rituximab
antibody against one of the EBNAs in patients post-trans- can be combined with low-dose chemotherapy to create
plantation has been associated with the subsequent devel- a safe and effective treatment for pediatric patients who
opment of PTLD. Decreasing EBV viral load has been reported have EpsteineBarr virus and PTLD following solid-organ
to be associated with increased levels of antibody against transplantation.20
EBNAs. These 2 factors provide the rationale for the use of Papadopoulous et al postulated that the use of donor leu-
intravenous immunoglobulin in the management of PTLD. It kocyte infusions might treat PTLD effectively in the allograft
has been used mainly in combination with interferon alfa.16,17 recipient. They based this hypothesis on the premise that the
A high mortality rate has been associated with the use of donor has cytotoxic T lymphocytes, which are presensitized
chemotherapy in the management of transplant-associated to the EBV responsible for the lymphoproliferation in the
lymphoproliferative disease. In Cohen’s (1991) review of the recipientdthe EBV being donor in origin. They studied 5 pa-
value of chemotherapy and radiotherapy for the treatment of tients who developed malignant B-cell lymphoma after
PTLD in transplant recipients, neither chemotherapy nor receiving T-cell depleted allogeneic bone marrow trans-
radiotherapy demonstrated any survival advantage compared plantation. EBV DNA was detected in each tissue sample. All
with overall survival rates of 31%. In fact, survival rates were patients achieved complete clinical and pathological remis-
worse, at 23% and 20%, respectively. sion in response to unirradiated infusions of donor leuko-
Swinnen et al, however, report a retrospective study of 19 cytes.21 The EBV-specific cytotoxic T lymphocytes from the
cardiac transplant recipients with PTLD who initially were donor, in the case of bone marrow transplantation, have the
treated with reduced immunosuppression and acyclovir. The capability of recognizing and destroying EBV-infected B cells
patients had all received OKT3 (i.e., monoclonal anti-T-cell in the recipient. Solid organ transplant patients, however,
antibody) as part of their immunosuppressive regimen. A sta- develop PTLD that can be recipient or donor in origin, which in
tistically significant reciprocal relationship exists between the each case would have to be determined before initiation of

7. 62 a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 3
treatment. In the case of PTLD that is recipient in origin, to references
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