Posttransplant Lymphoproliferative Disorders€¦ · developing a PTLD, although this correlation...

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Posttransplant LymphoproliferativeDisorders

Lead contributors:

Cristian Sánchez La Rosa, MDEmilio Rubulotta, MD

Centro de Educación Médica e Investigaciones Clínicas (CEMIC)Buenos Aires, Argentina

Translation:

Alex H. Beesley, Ph.D.Division of Leukaemia and Cancer Research,Telethon Institute for Child Health Research

Perth, Western Australia

A. Introduction

In the last 30 years, the development of new immunosuppressant

treatments has been a major therapeutic advance that has facilitated the

success of organ transplantation. The number of transplants performed has

constantly grown, even in developing countries, and has resulted in an increase

in the number of tumors observed in the transplanted population. This increase

is 3 to 5 times greater than that observed in the general population. It has been

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known for many years that there is a greater incidence of lymphoproliferative

processes in people with congenital, acquired, or pharmacologically induced

immunodeficiencies.1 Those that present in this way after immunosuppressive

therapy for organ transplant represent a heterogeneous group of mono- or

polyclonal proliferations, ranging from plasma hyperplasia to non-Hodgkin

lymphoma. These lymphoproliferative processes are clinically and

morphologically heterogeneous, and are known as posttransplant

lymphoproliferative disorders (PTLDs), which occasionally evolve into clinical

lymphoma.2 Lymphomas (50%) occur more frequently than cutaneous tumors

(20%) among pediatric transplant recipients, and the tumorsthe are more

common in adult patients.3

A. 1 Pathogenesis

A clear relationship exists between PTLDs and infection with EpsteinBarr

virus (EBV).2,4 It has been postulated that infection with this lymphotropic herpes

virus, whether primary infection or reactivation, could initially produce the

polyclonal expansion of B cells. Due to the suppression of T-cell

immunovigilance, which is caused by immunosuppression treatments,

mutations in oncogenes and tumor suppressor genes accumulate over time,

leading to the selection of malignant clones that continue to present episomal

EBV DNA.

Primary EBV infection can be asymptomatic, producing a clinical picture

of nonspecific or infectious mononucleosis. The infected individual maintains

anti-EBV IgG antibodies and the virus resides in the nasopharynx. The EBV

genome (DNA) encodes a number of proteins and molecules, each of which

possesses a specific function. Among the most important of these, from an

oncology point of view, are 3 latent membrane proteins (LMPs), 2 nuclear RNAs

(EBER1/2), and 6 transcription factors (EBNAs). EBNA1 is essential for viral

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maintenance, whilst LMP1 possesses oncogenic potential.4 The function of the

EBERs is only partially understood.

The expression of each of these proteins in normal and neoplastic cells is

different. Three types of expression or latency have been described that permit

the evasion of immune control mediated by cytotoxic lymphocytes. In all EBV-

infected individuals, with or without tumors, EBNA1 is expressed. Latency type I

is typical of Burkitt lymphoma, and is characterized by the sole expression of

EBER1/2. Type II demonstrates the expression of EBNA1, the EBERs, and the

LMPs1, 2A & 2B, and is characteristic of nasopharyngeal carcinoma, Hodgkin

lymphoma, and nasal lymphomas. Type III, which is typically observed in the

lymphoid processes of immunodeficient individuals, shows a pattern in which

all of the proteins are expressed.

A. Table 1EBV-associated pathology

B-lymphoid origin:Burkitt lymphomaB lymphomas in immunosuppressed individuals (HIV+

and/or post-transplant)

T/NK-lymphoid origin:T/NK lymphomasHydroa vacciniforme-like lymphoma

Others:Nasopharyngeal carcinomaHodgkin lymphoma (Hodgkin disease)

At the histological level, EBV can be detected by in situ hybridization

(ISH), essentially applied for the detection of EBERs, but can also be detected

with immunohistochemistry using anti-LMP1/2 and anti-EBNA1 antibodies, or by

southern blot, which allows the detection of clonality.4 In addition, one use real-

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time PCR to establish the correlation between EBV load and the risk of

developing a PTLD, although this correlation is not precise in patients with

profound immunodeficiency.5,6

Another important factor in the development of PTLD in transplant

recipients is the state of immunodeficiency that these patients present after

immunosuppressant treatment has been administered to them to prevent the

rejection of transplanted organs.7 The incidence of PTLD varies depending on

the type of transplanted organ, the age of the recipient, and the type of

immunosuppressant regimen. The incidence of PTLDs is around 1% in renal

transplant patients,8 up to 5% in hepatic transplant recipients,9,10 and

approximately 20% in cardiac or intestinal transplant recipients.11 The frequency

of PTLD in bone marrow transplant recipients varies depending on whether the

bone marrow is unmanipulated, in which case the risk is less than 1%, or

manipulated through T –lymphocyte depletion, when it can reach 7.5%.12 The

use of therapy against graft-versus-host disease (GVHD), especially with anti-T-

cell agents, advanced donor age, the use of total body irradiation (TBI) and the

involvement of non-HLA identical recipients/donors13 are risk factors for PTLD.

Of note, the recipients of non-HLA identical transplants with grafts depleted of

T cells have a higher risk of developing PTLDs, up to 15%,14 which is reduced

when umbilical cord blood is used instead.

Another important factor influencing the development of a PTLD is the

presence of an underlying disease. For example, patients who receive a bone

marrow transplant (BMT) for the treatment of congenital immunodeficiency

have an increased risk of developing PTLD compared to those who receive BMT

for other reasons. Shpilberg et al suggested that patients who receive liver

transplants because of underlying autoimmune disorders, such as autoimmune

hepatitis or primary biliary cirrhosis, may also have an increased risk of

developing PTLD.15

The frequency of PTLD occurrence also depends on the

immunosuppressive regimen administered to patients. For example, patients

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given combined treatments with anti-lymphocytic globulin, steroids, and

azathiopurine, with or without cyclosporine, are considered a low risk group,

provided that the levels are monitored. On the other hand, initial studies have

suggested that patients treated with tacrolimus may have an increased risk of

developing PTLDs, although this could not be completely confirmed.16-18

Other risk factors for immunocompromised transplant recipients

developing PTLDs include episodes of rejection warranting intensification of

immunosuppression, especially the therapeutic use of cellular antibodies

against T cells;19 negative EBV serology at the time of tranplantation;20,21

pulmonary or small intestinal transplant; and young age at the time of

transplant (particularly less than 5 years of age). The incidence of PTLD is

greatest in the first year after transplant, when T-cell immunity against EBV is at

its lowest.22 Pediatric patients have a higher incidence of PTLD than adult

patients receiving similar grafts.

A. References

1Norin S, Kimby E, Ericzon BG, Christensson B, Sander B, Soderdahl G, Hagglund H.Posttransplant lymphoma--a single-center experience of 500 liver transplantations. Med Oncol2004;21:273-284.2Lim WH, Russ GR, Coates PT. Review of Epstein-Barr virus and post-transplantlymphoproliferative disorder post-solid organ transplantation. Nephrology (Carlton)2006;11:355-366.3Penn I. De novo malignances in pediatric organ transplant recipients. Pediatr Transplant1998;2:56-63.4Cohen JI, Bollard CM, Khanna R, Pittaluga S. Current understanding of the role of Epstein-Barrvirus in lymphomagenesis and therapeutic approaches to EBV-associated lymphomas. LeukLymphoma 2008;49 Suppl 1:27-34.5Greenfield HM, Gharib MI, Turner AJ, Guiver M, Carr T, Will AM, Wynn RF. The impact ofmonitoring Epstein-Barr virus PCR in paediatric bone marrow transplant patients: can itsuccessfully predict outcome and guide intervention? Pediatr Blood Cancer 2006;47:200-205.6Tsai DE, Douglas L, Andreadis C, Vogl DT, Arnoldi S, Kotloff R, Svoboda J, Bloom RD, OlthoffKM, Brozena SC, Schuster SJ, Stadtmauer EA, Robertson ES, Wasik MA, Ahya VN. EBV PCR in thediagnosis and monitoring of posttransplant lymphoproliferative disorder: results of a two-armprospective trial. Am J Transplant 2008;8:1016-1024.7Aucejo F, Rofaiel G, Miller C. Who is at risk for post-transplant lymphoproliferative disorders(PTLD) after liver transplantation? J Hepatol 2006;44:19-23.

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8Abe T, Ichimaru N, Kokado Y, Maeda T, Kakuta Y, Okumi M, Imamura R, Nonomura N, Isaka Y,Takahara S, Okuyama A: Post-transplant lymphoproliferative disorder following renaltransplantation: a single-center experience over 40 years. Int J Urol;17:48-54.9Uribe M, Hunter B, Alba A, Calabran L, Flores L, Soto P, Herzog C. Posttransplantlymphoproliferative disorder in pediatric liver transplantation. Transplant Proc 2009;41:2679-2681.10Fernandez MC, Bes D, De Davila M, Lopez S, Cambaceres C, Dip M, Imventarza O. Post-transplant lymphoproliferative disorder after pediatric liver transplantation: characteristics andoutcome. Pediatr Transplant 2009;13:307-310.11Gao SZ, Chaparro SV, Perlroth M, Montoya JG, Miller JL, DiMiceli S, Hastie T, Oyer PE, SchroederJ. Post-transplantation lymphoproliferative disease in heart and heart-lung transplant recipients:30-year experience at Stanford University. J Heart Lung Transplant 2003;22:505-514.12Styczynski J, Einsele H, Gil L, Ljungman P. Outcome of treatment of Epstein-Barr virus-relatedpost-transplant lymphoproliferative disorder in hematopoietic stem cell recipients: acomprehensive review of reported cases. Transpl Infect Dis 2009;11:383-392.13Buyck HC, Ball S, Junagade P, Marsh J, Chakrabarti S. Prior immunosuppressive therapy withantithymocyte globulin increases the risk of EBV-related lymphoproliferative disorder followingallo-SCT for acquired aplastic anaemia. Bone Marrow Transplant 2009;43:813-816.14Faye A, Vilmer E. Post-transplant lymphoproliferative disorder in children: incidence,prognosis, and treatment options. Paediatr Drugs 2005;7:55-65.15Shpilberg O, Wilson J, Whiteside TL, Herberman RB. Pre-transplant immunological profile andrisk factor analysis of post-transplant lymphoproliferative disease development: the results of anested matched case-control study. The University of Pittsburgh PTLD Study Group. LeukLymphoma 1999;36:109-121.16Dharnidharka VR, Ho PL, Stablein DM, Harmon WE, Tejani AH. Mycophenolate, tacrolimus andpost-transplant lymphoproliferative disorder: a report of the North American Pediatric RenalTransplant Cooperative Study. Pediatr Transplant 2002;6:396-399.17Jain A, Mazariegos G, Kashyap R, Green M, Gronsky C, Starzl TE, Fung J, Reyes J. Comparativelong-term evaluation of tacrolimus and cyclosporine in pediatric liver transplantation.Transplantation 2000;70:617-625.18Cacciarelli TV, Reyes J, Jaffe R, Mazariegos GV, Jain A, Fung JJ, Green M: Primary tacrolimus(FK506) therapy and the long-term risk of post-transplant lymphoproliferative disease inpediatric liver transplant recipients. Pediatr Transplant 2001;5:359-364.19Schubert S, Abdul-Khaliq H, Lehmkuhl HB, Yegitbasi M, Reinke P, Kebelmann-Betzig C,Hauptmann K, Gross-Wieltsch U, Hetzer R, Berger F. Diagnosis and treatment of post-transplantation lymphoproliferative disorder in pediatric heart transplant patients. PediatrTransplant 2009 Feb;13(1):54-6220Wagner HJ, Fischer L, Jabs WJ, Holbe M, Pethig K, Bucsky P. Longitudinal analysis of Epstein-Barr viral load in plasma and peripheral blood mononuclear cells of transplanted patients byreal-time polymerase chain reaction. Transplantation 2002;74:656-664.21Knight JS, Tsodikov A, Cibrik DM, Ross CW, Kaminski MS, Blayney DW. Lymphoma after solidorgan transplantation: risk, response to therapy, and survival at a transplantation center. J ClinOncol 2009;27:3354-3362.22Wu JF, Ho MC, Ni YH, Chen HL, Lu CY, Hsu HY, Lee PH, Chang MH. Timing of Epstein-Barr virusacquisition and the course of posttransplantation lymphoproliferative disorder in children.Transplantation 2009;87:758-762.

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B. Classification

The great majority of PTLDs are of the B phenotype (86%), although cases

of T-cell lineage (14%) and a small percentage of null phenotypes (1%) also

exist. PTLDs are subclassified on the basis of their phenotypic, histological, and

molecular peculiarities, as well as their clinical progression. The current system

for classification is that of the Currently used is the classification of the World

Health Organization (WHO), which is an evolution of the classification system

used by the of the American and Canadian Society of Hematopathology, which

was developed by consensus at a workshop meeting.

The initial signs of PTLD include a series of events that have reactive

processes in common and occur preferentially during the first 3 months post-

transplant. Such events include reactive follicular hyperplasia, plasma cell

hyperplasia, certain cases that have been labeled polyclonal lymphomas, and

cases of infectious mononucleosis-like disease. These events usually affect

young patients who are not infected with EBV, and they present with

preferential involvement of the adenoids, tonsils, spleen, and less commonly

the lymph nodes. Furthermore, these events are histologically characterized by

structural preservation of the affected organ, presentation of a polymorphous

lymphoid infiltrate with interspersed cells of both B and T phenotypes that are

polyclonal in most cases, molecular rearrangements of both immunoglobulins,

and EBV detectable by PCR or southern blot. Mutations of c-myc, ras, and p53

are usually not present. These are the typical cases of PTLDs described in the

literature, and are usually resolved upon reduction of immunosuppression.

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B. Figure 1Typical plasma cells (black arrow) and isolated immunoblasts (dotted red line)interspersed with normal lymphocytes (H-E, 40).

B. Figure 2The same characteristics are observed in tonsil tissue where the normalepithelium appears narrowed by plasmacytoid proliferation (H-E, 10).

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B. 1 Polymorphic Post-transplant LymphoproliferativeDisease

The polymorphic PTLD classification encompasses vague terms used

previously such as polymorphic B-cell hyperplasia and polymorphic B-cell

lymphoma. These conditions usually appear at a later point in time that varies

between 4 months and 8 years after transplant. These conditions typically

involve an extranodal location, and histologically the architecture of the

affected organ is lost. The cellular spectrum that makes up the lesions is

extremely varied, with the possible presence of plasmacytoid lymphocytes,

plasma cells, and immunoblasts being very typical. B lymphocytes usually

predominate although there are usually an important number of T lymphocytes

interspersed. In many cases, it is difficult to demonstrate restriction to light or

heavy chain immunoglobulins by histochemistry, but it is generally possible to

demonstrate monoclonality for IgH or EBV with molecular techniques. Mutations

in oncogenes such as c-myc, ras and p53 are not commonly observed. This type

of neoplasia usually regresses with the reduction of immunosuppression,

although in some cases, the disease progresses and requires a more active

intervention such as the use of monoclonal antibodies.

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B. Figure 5Lymphatic node (H-E, 10). Distortion of the lymphatic node architecture isvisible with infiltration of the surrounding adipose tissue (arrow).

B. Figure 6Polymorphic nodal infiltration including normal lymphocytes, immunoblasts,isolated plasma cells, and some mitotic forms of cells. Immunoblasts can showbizarre characteristics, mimicking ReedSternberg cells (H-E, 20).

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B. Figure 7

B. Figure 8

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B. Figure 9Polymorphic nodal infiltration including normal lymphocytes, immunoblasts,isolated plasma cells, and some mitotic forms of cells. Immunoblasts can showbizarre characteristics, mimicking ReedSternberg cells (100immersion).

B. Figure 10EBER staining.

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B. Figure 11EBER staining.

Monomorphic PTLDs include B-cell lymphomas, such as certain cases of

Burkitt lymphoma, and these PTLDs are frequently extranodal. Histologically,

these cases cannot be distinguished from those that occur in non-

immunosuppressed patients. They are typically associated with a clear loss of

tissue architecture and large zones of necrosis. Cytological appearance need

not necessarily be monomorphic, although generally they have a blastic

appearance, may be multilobular, and appear more like centroblasts or

immunoblasts.

Monomorphic PTLDs have a mature B phenotype. In these cases, it is

usually possible to demonstrate restriction for light or heavy chain surface

immunoglobulins by reaction with immunoperoxidase. In addition, molecular

techniques show most cases to be monoclonal for IgH and EBV. Mutations in

the oncogenes ras and p53 are frequently observed. These cases rarely resolve

upon the reduction of immunosuppression, and it is necessary to treat them

with chemotherapy.

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B. Figure 12Monomorphic proliferation indistinguishable from Burkitt lymphoma showingmedium-sized cells with multiple cytoplasmic basophil nucleoli and significantmitosis.

B. Figure 13CD20-positive staining.

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Approximately 10% of non-Hodgkin lymphomas observed in post-

transplant patients are T-cell lymphomas. In general, the prognosis of these

patients is poor, particularly because they commonly show no response to

treatment. The existence of classical Hodgkin lymphoma is extremely rare in

transplanted patients.

Other PTLDs that are not associated with EBV also exist. These cases

amount to approximately 814% of lymphomas that develop in post-transplant

patients, and represent a distinct clinical entity. A characteristic feature of these

PTLDs is that they occur during the later post-transplantation phase, and they

most often affect the lymph nodes. Lastly, the reduction of immunosuppression

in these patients does not influence the progression of the disease.

B. 2 Classification

B. Table 1Classification of post-transplant lymphoproliferative disorders

\\

Initial PTLD:

- Reactive plasma hyperplasia

- Infectious mononucleosis-like

Polymorphic PTLD:

- Polymorphic B-cell hyperplasia

- Polymorphic B-cell lymphoma

Monomorphic PTLD:

- Large diffuse B-cell lymphoma

- Burkitt lymphoma

- T-cell lymphoma

Others:

- Hodgkin disease

- Hodgkin-like disease

- EBV PTLD

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B. 3 Staging

In general, it is difficult to adapt staging systems for PTLDs, especially in

the polymorphic cases. The PTLD stage reflects the extent of the disease; local

vs. disseminated, and nodal vs. organ involvement. In approximately 50% of

cases, involvement of multiple organs or various nodes is found at the time of

presentation. The 2 sites that are most commonly involved are the lymph nodes

and the gastrointestinal tract. There is no formal stratification system for PTLD;

the standard classification of Ann Arbor is suggested, although no staging

system has yet been adapted for this approach.

B. References

1Jaffe ES, Harris NL, Stein H; World Health Organization. Pathology and Genetics of Tumours ofHaematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001.

C. Clinical Manifestations

The clinical presentations of PTLDs are highly varied and include

asymptomatic lymphadenopathy, similar to atypical or severe infectious

mononucleosis, and one or more nodal and/or extranodal tumors.1,2 In contrast

to that which occurs in immunocompetent individuals, PTLDs are usually

extranodal. Clinical manifestations of PTLDs include (1) a syndrome similar to

infectious mononucleosis with or without generalized lymphadenopathy, (2)

one or more extranodal tumors, and (3) fulminant disseminated presentation

with sepsis.

Mononucleosis syndrome can occur soon after transplantation, especially

in cases with primary EBV infection. This presentation is particularly common in

the pediatric population. Moreover, otolaryngological signs and symptoms are

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frequently the first manifestations of PTLDs in children. Patients can present

with symptoms that mimic tonsilar hypertrophy, pharyngitis, necrotizing

pharyngitis, lymphadenitis, sinusitis, and otitis media.3 There is a tendency for

severe forms of PTLD tend to show symptoms of area obstruction. When PTLD

occurs at a later stage after transplant, it is more anatomically circumscript and

can be associated with a more gradual clinical course. In this situation,

extranodal disease with visceral involvement is common, which is associated

with gastrointestinal; pulmonary; or, less frequently, central nervous system

(CNS) symptoms. However, the associated lymphadenopathy is not painful.

The majority of PTLD patients present with at least a dominant tumor.

The graft may also be involved with the disease;4 in such cases, the frequency

of involvement varies according to the specific graft site. In pulmonary or

intestinal transplant recipients, PTLDs demonstrate graft involvement in a

significant proportion of cases.5 In PTLDs that arise in patients receiving other

types of grafts, such as liver or kidney transplants, demonstrate graft

involvement in up to one-third of the cases. In contrast, heart transplants rarely

develop PTLDs associated with this condition.

The symptoms of PTLDs are related to the site of tumor growth.

Gastrointestinal tumors can cause abdominal pain with bleeding, and can give

rise to perforation with acute surgical abdominal symptoms.6,7 CNS tumors can

cause symptoms related to local necrosis or the effects of the tumor bulk.8

PTLDs can occur at any site, and isolated skin involvement has also been

reported.9,10 Cases arising in the pleura have occasionally been described.11

Similarly, fulminant presentation is rare, occurring in approximately 1% of

cases, but must be diagnosed early due to the high risk of mortality.12

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C. 1 Diagnosis

Diagnosis of PTLD requires knowledge of the diverse forms of

presentation of this heterogeneous syndrome, and an awareness of the high

probability of its development. The localization of organ dysfunction should

direct clinicians toward the appropriate diagnostic evaluation. For example, an

abrupt appearance of lymphadenopathy, whether isolated or systemic, means

that PTLD must be considered among the list of alternative diagnoses.

Abdominal pain, particularly in the context of intestinal bleeding, may indicate

the possibility of PTLD in the gastrointestinal tract. Persistent headache or CNS

symptoms may suggest localization of PTLD in the brain. Upper respiratory

tract infections that do not respond to antibiotic therapy and are associated

with lymphadenopathy should raise the suspicion of PTLD.

Endoscopic evaluation may lead to the discovery of nodular ulcers that

can reflect PTLD in that organ. In the case of pulmonary involvement, multiple

nodular densities can be seen with a simple chest X-ray.

Clinicians must keep in mind that PTLD may involve the graft itself.

Serological tests for EBV can be used to evaluate the presence of a recent or

remote infection.13-15 However, the diagnosis of EBV infection, whether active or

passive, is not synonymous with PTLD. For example, one study showed that

pediatric liver transplant recipients who were initially EBV-seronegative

exhibited an 80% rate of conversion to seropositivity within 3 months of

transplant. Of these patients, 85% were asymptomatic and only 15% developed

PTLD.

Of the various tests used to detect EBV, IgM against viral capsid ntigen

(VCA-IgM) is particularly useful for detection of active EBV infection. However,

the immune response in these immunocompromised patients can be

inconsistent. A quantitative PCR estimate of the number of copies of the EBV

genome in the peripheral blood has proven to be the most useful tool for

determining the type of EBV infection, and the most likely association with

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PTLD,16 Patients with PTLDs demonstrate an elevated number of circulating viral

genome copies. Normal EBV-positive patients were found to have less than

2,000 copies of the viral genome per microgram of blood cell DNA, but this

increased 10100 times in patients with PTLD. Furthermore, a regression in the

PTLD was associated with a reduced number of circulating copies, indicating

that this approach could be useful for monitoring the effect of institutional

therapy.17

Biopsy speciments obtained from the graft or transplanted organ must

be examined carefully to exclude PTLD before starting treatment for a possible

rejection of the transplanted graft, because the increased immunosuppression

is contraindicated in PTLD patients. Biopsy is the definitive diagnostic tool.

Biopsied samples should be analyzed to detect infiltration by B cells and

subjected to in situ hybridization to detect EBV.

C. Figure 1CT of abdomen. A 5-year-old patient with who received a hepatic transplant forbiliary duct atresia. Hypodense image in the right flank with necrotic images inthe interior region corresponding to Burkitt lymphoma.

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C. Figure 2CT of the abdomen. A 5-year-old patient who received a hepatic transplant forbiliary duct atresia. Hypodense image in the right flank with necrotic images inthe interior region corresponding to Burkitt lymphoma.

C. References

1Fernandez MC, Bes D, De Davila M, Lopez S, Cambaceres C, Dip M, Imventarza O. Posttransplant lymphoproliferative disorder after pediatric liver transplantation: characteristics andoutcome. Pediatr Transplant 2009;13:307-310.2Koch DG, Christiansen L, Lazarchick J, Stuart R, Willner IR, Reuben A. Posttransplantationlymphoproliferative disorder--the great mimic in liver transplantation: appraisal of theclinicopathologic spectrum and the role of Epstein Barr virus. Liver Transpl 2007;13:904-912.3Vargas H, Nazeer T, Conti D, Parnes SM. Posttransplant lymphoproliferative disorder of thenasopharynx. Am J Rhinol 2002;16:37-42.4Araya CE, Mehta MB, Gonzalez-Peralta RP, Hunger SP, Dharnidharka VR. Native kidne posttransplant lymphoproliferative disorder in a non-renal transplant patient. Pediatr Transplant2009;13:495-498.5Lee P, Minai OA, Mehta AC, DeCamp MM, Murthy S. Pulmonary nodules in lung transplantrecipients: etiology and outcome. Chest 2004;125:165-172.6Cornejo A, Bohnenblust M, Harris C, Abrahamian GA. Intestinal perforation associated withrituximab therapy for post-transplant lymphoproliferative disorder after liver transplantation.Cancer Chemother Pharmacol 2009;64:857-860.7Chia SC, Chau YP, Tan YM. Late-onset post-transplant lymphoproliferative disease presentingas massive occult gastrointestinal haemorrhage. Singapore Med J 2008;49:e117120.8Traum AZ, Rodig NM, Pilichowska ME, Somers MJ. Central nervous system lymphoproliferative

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disorder in pediatric kidney transplant recipients. Pediatr Transplant 2006;10:505-512.9Kudo K, Sonoda M, Sugimoto K, Koike M. [Cutaneous non-Hodgkin lymphoma of the legoccurring 11 years after renal transplantation]. Rinsho Ketsueki 2009;50:107-109.10Samolitis NJ, Bharadwaj JS, Weis JR, Harris RM. Post-transplant lymphoproliferative disorderlimited to the skin. J Cutan Pathol 2004;31:453-457.11Lamba M, Jabi M, Padmore R, Sengar DP, Veinot JP. Isolated pleural PTLD after cardiactransplantation. Cardiovasc Pathol 2002;11:346-350.12Gouya G, Hartmann G, Fae P, Tauber M, Holzmuller H, Benzer W, Lang A, Schuster A, Drexel H,Offner FA. A case of fulminant post-transplant lymphoproliferative disorder and septicemia. ClinTransplant 2006;20:261-264.13D'Antiga L, Del Rizzo M, Mengoli C, Cillo U, Guariso G, Zancan L: Sustained Epstein Barr virusdetection in paediatric liver transplantation. Insights into the occurrence of late PTLD. LiverTranspl 2007;13:343-348.14Geramizadeh B, Aghdai M, Azarpira N, Behabahani AB, Heidari T, Banihashemi M, Raisjalali AR,Roozbeh J, Behzadi A: Incidence of reactive antibodies against Epstein Barr in a group of renaltransplant patients. Transplant Proc 2005;37:3051-3052.15Harwood JS, Gould FK, McMaster A, Hamilton JR, Corris PA, Hasan A, Gennery AR, Dark JH:Significance of Epstein-Barr virus status and post-transplant lymphoproliferative disease inpediatric thoracic transplantation. Pediatr Transplant 1999;3:100-103.16Sato T, Fujieda M, Tanaka E, Miyamura M, Chikamoto H, Hisano M, Akioka Y, Ishiura Y, DohnoS, Maeda A, Hattori M, Wakiguchi H. Monitoring of Epstein-Barr virus load and antibody inpediatric renal transplant patients. Pediatr Int 2008;50:454-458.17Jang JY, Kim KM, Lee YJ, Lee SG, Chi HS. Quantitative Epstein-Barr virus viral load monitoring inpediatric liver transplantation. Transplant Proc 2008;40:2546-2548.

D. Treatment

The majority of centers follow a scale as to the overall treatment

approach of PTLDs, with an initial intervention influenced by the extent of the

disease and the degree of aggressiveness with which it presents in the patient.

The initial treatment always consists of a reduction of immunosuppression

whenever possible.1,2 Another measure that can be adopted as a first-line

therapy is surgical excision, when the disease is limited and the location

permits.3 Acyclovir, ganciclovir, and more recently cidofovir, are used for

prevention but their effectiveness as treatments has not been proven.4 It is

important to highlight that even though complete surgical resection can, upon

removal of all tumor manifestations, obviate the need for future treatments

such as in the case of tonsil resection, it is not adequate to attempt extensive

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resections with the same aim in other locations such as the abdomen. In these

cases, the management is similar to that for pediatric patients with non-

Hodgkin lymphoma, where the initial surgery should be limited to biopsy.

Second-line treatment modalities for PTLDs include interferon-alpha,

which currently is rarely used,5 or monoclonal antibodies; chemotherapy is

reserved for select cases.

D. 1 Immunosuppression Reduction

The most immediate measure for treating patients with PTLDs is to

reduce the level of immunosuppression. This by itself is sufficient for only

about one-third of the cases, and its efficacy varies according to the type of

PTLD and the type of transplant.2,4 One obvious disadvantage of this therapeutic

approach is the possibility of graft rejection that would later require a greater

increase in immunosuppression and possibly cause organ damage that

sometimes prevents adequte administration of chemotherapy. Reduction of

immunosuppression does not normally control lymphomas that are already

established. For this reason, other therapies, both immunological and non-

immunological have been tested to identify a cure for this disease entity.

D. 2 Systemic Antiviral Therapy

Acyclovir has been used as an inhibitor of EBV DNA replication with

marginal success in eliminating polyclonal EBV lesions of the oropharynx

(lesions that have not progressed to the proliferative phase). However, latent

infected lymphocytes are not affected by this treatment. To date, the efficiency

of this antiviral therapy for treating PTLD has not been definitively

demonstrated. The results for ganciclovir and cidofovir are similar.

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D. 3 Cytokine Therapy

Cytokine therapy is a logical extension of the therapeutic approach for

PTLDs. The intention of this strategy is to stimulate a host’s immune response

to eliminate or reject the PTLD. The cytokine that has been most commonly

used for this purpose is interferon-alpha.2 This treatment modality can be

successful when immunosuppression reduction fails to control the disease,

although the possibility of graft rejection also exists when this agent is used.

However, with the introduction of rituximab, this treatment is rarely used today.

D. 4 Radiotherapy and Chemotherapy

The role of radiation therapy and the required doses for treating PTLDs

have yet to be established, but it may be useful for the treatment of CNS

tumors6 and controlling localized PTLD processes. However, it is likely that

radiation treatment would only be useful in cases of primary cerebral lymphoma

or in those cases where a tumor may be compressing a vital structure.7

Therefore, this approach is not commonly used today.

The reported results of using conventional chemotherapy to treat PTLDs

are controversial. Clinicians must be careful in prescribing high-dose regimens

for patients with organ dysfunction.8 Cyclophosphamide alone or together with

rituximab, as well as chemotherapy regimens such as CHOP

(cyclophosphamide, adriamycin, vincristine, and prednisone), have been used in

PTLD patients.9,10 Despite the high rate of complete remission in PTLD patients

(up to 70%) after chemotherapy, the associated toxicity is significant and

includes treatment-related mortality and significant co-morbidity in this

population. The high mortality associated with standard chemotherapy

regimens in the PTLD population may be due to various factors, including

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pharmacological immunosuppression, graft dysfunction, and colonization with

hospital-acquired resistant microorganisms.

Chemotherapeutic treatment cycles are typically repeated every 2128

days or until hematological recovery. Patients who experience complete

remission after 4 cycles are treated with 2 additional cycles. These patients are

maintained without immunosuppression during treatment with this scheme and

later receive the least possible dose of immunosuppression that allows

adequate organ function. Patients with mature B-cell lymphomas must receive

prophylactic intrathecal chemotherapy.

Chemotherapy is cytotoxic for proliferative B cells, and is also useful for

treating or preventing GVHD and graft rejection. For patients with concurrent

graft rejection and PTLD, chemotherapy offers the best control for these 2

processes. However, the conventional drug doses used for treating non-

Hodgkin lymphoma patients appear to result in greater organ toxicity and

susceptibility to infection in patients with primary immunodeficiency and in

post-transplant patients.

D. 5 Cellular Therapy

Cellular therapy represents a recent innovation in the treatment of

malignant diseases related to EBV, although it is only available in specialized

treatment centers. The therapeutic use of immune effector cells against EBV

arises from the effect of graft-versus-leukemia responses in patients with bone

marrow transplant.11,12 However, this approach is not normally used in

lymphoproliferative processes after solid organ transplant.

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D. 6 Monoclonal Antibodies

Given that the majority of PTLDs are of B-lineage, the use of anti-B-cell

monoclonal antibodies appears to be an attractive approach for treating these

disorders,13,14 and is currently one of the pillars of treatment. In the first report

describing the use of monoclonal antibodies for treating PTLD, patients were

treated with both anti-CD21 and anti-CD24 antibodies, and 61% of the

patients responded to these treatments, whereas 46% of the patients achieved

long-term survival with acceptable toxicities.15 Treatment of PTLD patients with

anti-CD19 monoclonal antibodies has also shown good results.15 However,

these antibodies have not been commercialized on a large scale, and they have

beenreplaced by rituximab.

Rituximab, an anti-CD20 monoclonal antibody, has already demonstrated

its utility in treating both indolent and aggressive non-Hodgkin lymphoma, even

in pediatric patients.16 This antibody is readily available commercially, and has

recently been used in PTLD patients, with very promising results; in one study.

more than 60% of patients showed complete remission without significant

toxicity.17 Rituximab should be considered part of the necessary multimodal

strategies for treating PTLDs.

Rituximab is a chimeric monoclonal anti-CD20 IgG antibody that consists

of human constant regions ligated to murine variable domains. The murine Fab

domain of rituximab binds the CD20 antigen, a transmembrane protein situated

on the surface of mature B cells, but not on plasma cells or on hematopoietic

stem cells. The murine Fab domain confers specificity, while the human large

constant region (Fc) binds to complement proteins. Rituximab has 3 potential

mechanisms of action; apoptosis, complement activation, and antibody-

dependent cellular cytotoxicity.

Rituximab was first approved for the treatment of CD20-positive low-

grade non-Hodgkin lymphoma relapse, and later, in combination with CHOP, for

large-cell lymphomas.16 Since its initial approval, it has been widely used both

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as a single agent, and together with chemotherapy regimens for treating

various CD20-positive hematological neoplasias. Rituximab also has an

important role in the treatment of various non-malignant diseases, especially

autoimmune diseases, such as rheumatoid arthritis, Sjögren syndrome,

systemic lupus erythematosus, myasthenia gravis, autoimmune hemolytic

anemia, and idiopathic thrombocytopenia purpura.

In each of these diseases, it is assumed that B cells play a critical role in

the autoimmune process. Rituximab is generally administered weekly by slow

intravenous infusion over 4 doses. In contrast to many other chemotherapeutic

regimens, rituximab does not require dose adjustment for treatment of the

lungs, kidneys, liver, or heart. Premedication with paracetamol and

diphenhydramine is recommended before each infusion in order to prevent

reactions related to the infusion. Adverse reactions related to rituximab

treatment generally occur during the first administration. The reactions are

usually milder upon subsequent infusions. Reactions observed during the

infusion (flu-like syndrome, fever, shivering, nausea, headache, and rashes) can

be treated symptomatically. Rarely, more serious reactions can appear, such as

angioedema, hypotension, and bronchospasm, can appear around 20120

minutes after the commencement of the first infusion. At this point, rituximab

administration must be halted, but can be reinitiated at a slower infusion rate

after all symptoms have resolved. The standard dose of rituximab is 375 mg/m2

once per week for 4 consecutive weeks, although some patients require larger

doses.

Previous results have confirmed that only rituximab and chemotherapy

are highly effective in patients that fail immunosuppression reduction, even as

a second-line therapy.18,19 Both of these therapies give rise to prolonged survival

and cure in a large number of PTLD patients. The combination of rituximab and

a chemotherapy like CHOP has proven efficacious in PTLD patients, even in

those with monomorphic forms.20 Rituximab has also been used intrathecally in

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patients with primary cerebral lymphoma associated with a solid organ

transplant.21

D. References

1Mazariegos GV. Withdrawal of immunosuppression in liver transplantation: lessons learnedfrom PTLD. Pediatr Transplant 2004;8:210-213.2Swinnen LJ, LeBlanc M, Grogan TM, Gordon LI, Stiff PJ, Miller AM, Kasamon Y, Miller TP, FisherRI. Prospective study of sequential reduction in immunosuppression, interferon alpha-2B, andchemotherapy for posttransplantation lymphoproliferative disorder. Transplantation2008;86:215-222.3Buadi FK, Heyman MR, Gocke CD, Rapoport AP, Hakimian R, Bartlett ST, Sarkodee-Adoo C.Treatment and outcomes of post-transplant lymphoproliferative disease: a single institutionstudy. Am J Hematol 2007;82:208-214.4Roque J, Rios G, Humeres R, Volpi C, Herrera JM, Schultz M, Rios H, Rius M, Salgado C, Hepp J.Early posttransplant lymphoproliferative disease in pediatric liver transplant recipients.Transplant Proc 2006;38:930-931.5Setsuda J, Teruya-Feldstein J, Harris NL, Ferry JA, Sorbara L, Gupta G, Jaffe ES, Tosato G.Interleukin-18, interferon-gamma, IP-10, and Mig expression in Epstein-Barr virus-inducedinfectious mononucleosis and posttransplant lymphoproliferative disease. Am J Pathol1999;155:257-265.6Cavaliere R, Petroni G, Lopes MB, Schiff D. Primary central nervous system post-transplantationlymphoproliferative disorder: an International Primary Central Nervous System LymphomaCollaborative Group Report. Cancer;116:863-870.7Bakker NA, van Dijk JM, Slart RH, Coppes MH, van Imhoff GW, Verschuuren EA. Extraduralthoracic spinal cord compression: unusual initial presentation of post-transplantlymphoproliferative disorder. J Heart Lung Transplant 2008;27:1165-1168.8Taj MM, Messahel B, Mycroft J, Pritchard-Jones K, Baker A, Height S, Hadzic N, Pinkerton CR.Efficacy and tolerability of high-dose methotrexate in central nervous system positive orrelapsed lymphoproliferative disease following liver transplant in children. Br J Haematol2008;140:191-196.9Trappe R, Hinrichs C, Appel U, Babel N, Reinke P, Neumayer HH, Budde K, Dreyling M, DuhrsenU, Kliem V, Schuttrumpf S, Hauser IA, Mergenthaler HG, Schlattmann P, Anagnostopoulos I,Doerken B, Riess H. Treatment of PTLD with rituximab and CHOP reduces the risk of renal graftimpairment after reduction of immunosuppression. Am J Transplant 2009;9:2331-2337.10Knight JS, Tsodikov A, Cibrik DM, Ross CW, Kaminski MS, Blayney DW. Lymphoma after solidorgan transplantation: risk, response to therapy, and survival at a transplantation center. J ClinOncol 2009;27:3354-3362.11Greenfield HM, Gharib MI, Turner AJ, Guiver M, Carr T, Will AM, Wynn RF. The impact ofmonitoring Epstein-Barr virus PCR in paediatric bone marrow transplant patients: can itsuccessfully predict outcome and guide intervention? Pediatr Blood Cancer 2006;47:200-205.12Lynch BA, Vasef MA, Comito M, Gilman AL, Lee N, Ritchie J, Rumelhart S, Holida M, Goldman F.Effect of in vivo lymphocyte-depleting strategies on development of lymphoproliferative

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disorders in children post allogeneic bone marrow transplantation. Bone Marrow Transplant2003;32:527-533.13Oertel SH, Verschuuren E, Reinke P, Zeidler K, Papp-Vary M, Babel N, Trappe RU, Jonas S,Hummel M, Anagnostopoulos I, Dorken B, Riess HB. Effect of anti-CD 20 antibody rituximab inpatients with post-transplant lymphoproliferative disorder (PTLD). Am J Transplant2005;5:2901-2906.14Svoboda J, Kotloff R, Tsai DE. Management of patients with post-transplant lymphoproliferativedisorder: the role of rituximab. Transpl Int 2006;19:259-269.15Swinnen LJ. Diagnosis and treatment of transplant-related lymphoma. Ann Oncol 2000;11Suppl 1:45-48.16Reiter A, Klapper W. Recent advances in the understanding and management of diffuse large Bcell lymphoma in children. Br J Haematol 2008.17Zilz ND, Olson LJ, McGregor CG. Treatment of post-transplant lymphoproliferative disorderwith monoclonal CD20 antibody (rituximab) after heart transplantation. J Heart LungTransplant 2001;20:770-772.18Trappe RU, Choquet S, Reinke P, Dreyling M, Mergenthaler HG, Jager U, Kebelmann-Betzing C,Jonas S, Lehmkuhl H, Anagnostopoulos I, Leblond V, Hetzer R, Dorken B, Riess H, Oertel S.Salvage therapy for relapsed posttransplant lymphoproliferative disorders (PTLD) with a secondprogression of PTLD after Upfront chemotherapy: the role of single-agent rituximab.Transplantation 2007;84:1708-1712.19Hayashida M, Ogita K, Matsuura T, Takahashi Y, Nishimoto Y, Ohga S, Hara T, Soejima Y,Taketomi A, Maehara Y, Kohashi K, Tsuneyoshi M, Taguchi T. Successful prolonged rituximabtreatment for post-transplant lymphoproliferative disorder following living donor livertransplantation in a child. Pediatr Transplant 2007;11:671-675.20Lee JJ, Lam MS, Rosenberg A. Role of chemotherapy and rituximab for treatment ofposttransplant lymphoproliferative disorder in solid organ transplantation. Ann Pharmacother2007;41:1648-1659.21van de Glind G, de Graaf S, Klein C, Cornelissen M, Maecker B, Loeffen J. Intrathecal rituximabtreatment for pediatric post-transplant lymphoproliferative disorder of the central nervoussystem. Pediatr Blood Cancer 2008;50:886-888.

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