Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal disorder arising after solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT). Iatrogenically impaired immune surveillance and Epstein-Barr virus (EBV) primary infection/reactivation are key factors in the pathogenesis. However, current knowledge on all aspects of PTLD is limited due to its rarity, morphologic heterogeneity, and the lack of prospective trials. Furthermore, the broad spectrum of underlying immune disorders and the type of graft represent important confounding factors. Despite these limitations, several reviews have been written aimed at offering a guide for pathologists and clinicians in diagnosing and treating PTLD. Rather than providing another classical review on PTLD, this “How I Treat” article, based on 2 case reports, focuses on specific challenges, different perspectives, and novel insights regarding the pathogenesis, diagnosis, and treatment of PTLD. These challenges include the wide variety of PTLD presentation (making treatment optimization difficult), the impact of EBV on pathogenesis and clinical behavior, and the controversial treatment of Burkitt lymphoma (BL)-PTLD.

Case 1

A 19-year-old woman with end-stage renal failure due to congenital kidney disease underwent a living-donor renal transplant in 2006. Eight years later, she was diagnosed with EBV+MYC translocation–confirmed BL-PTLD stage IVB (Figure 1) while on treatment with mycophenolate mofetil (MMF), tacrolimus, and low-dose steroids. EBV viral load was very high (5.84 log IU/mL). Due to the aggressive presentation, immune suppression was completely discontinued and immunochemotherapy with rituximab and CHOP (cyclophosphamide-doxorubicin-vincristine-prednisone) was started. Partial metabolic response was obtained after 4 cycles of chemotherapy (Figure 1). However, at the start of the sixth cycle, the patient complained of headache; clinical examination showed a peripheral facial nerve paresis. Morphologic examination of the cerebrospinal fluid confirmed the presence of a BL relapse with high EBV viral load, whereas brain magnetic resonance imaging did not reveal cerebral or cerebellar involvement. After treatment with intrathecal methotrexate, clinical symptoms disappeared, with normalization of the cerebrospinal fluid. Consolidation therapy with 4 cycles of high-dose methotrexate (3.5 g/m2) was given. A final evaluation with 18F-FDG–PET/CT, bone marrow examination, and brain magnetic resonance imaging showed complete remission. Lumbar puncture, however, showed the presence of meningeal disease, and rescue treatment with intrathecal rituximab and systemic etoposide and cytarabine was initiated, leading to an ongoing complete remission.

Figure 1

Maximum-intensity projection 18F-FDG–PET/CT images. Baseline image showed multiple supra- and infradiaphragmatic nodal lesions and extranodal lesions in breast, intestines, and bone marrow (left); 18F-FDG–PET/CT after 4 cycles of therapy showed a complete metabolic response in all nodal and extranodal lesions, with the exception of limited residual hypermetabolic lesions in the intestinal tract adjacent to the kidney transplant in the right iliac fossa (right). 18F, radionuclide fluorine 18; FDG, fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography.

Figure 1

Maximum-intensity projection 18F-FDG–PET/CT images. Baseline image showed multiple supra- and infradiaphragmatic nodal lesions and extranodal lesions in breast, intestines, and bone marrow (left); 18F-FDG–PET/CT after 4 cycles of therapy showed a complete metabolic response in all nodal and extranodal lesions, with the exception of limited residual hypermetabolic lesions in the intestinal tract adjacent to the kidney transplant in the right iliac fossa (right). 18F, radionuclide fluorine 18; FDG, fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography.

Case 2

A 36-year-old woman with end-stage renal failure due to hemolytic uremic syndrome underwent a deceased-donor renal transplant in 1981 and in 1999. Twelve years after the second transplant, she was referred to our center for investigations because of abdominal pain. 18F-FDG–PET/CT revealed a large intense hypermetabolic nonobstructive cecal and terminal ileal wall thickening, with mesenteric and retroperitoneal lymphadenopathies and diffuse omental, mesenteric, and peritoneal involvement in combination with supradiaphragmatic lymphadenopathies (stage IVA). Biopsy of the mass revealed an EBV diffuse large B-cell lymphoma (DLBCL). EBV viral load in peripheral blood was not detectable. At that moment, immune suppressive therapy consisted of MMF, tacrolimus, and low-dose steroids. Reduction of immune suppression (RIS; cessation of MMF and dose reduction of tacrolimus) in combination with rituximab was initiated. However, progressive disease was rapidly observed, and immunochemotherapy with rituximab and CHOP was started, leading to a complete remission. Three months later, the patient relapsed, necessitating treatment with intensive chemotherapy (cytarabine-cisplatin-dexamethasone), followed by high-dose chemotherapy and autologous HSCT. Three years after HSCT, there is no evidence of disease recurrence, and renal function is stable under immunosuppressive treatment with low-dose steroids and everolimus, a mammalian target of rapamycin inhibitor.

PTLD comprises a wide spectrum of lymphoid and plasmacytic proliferations occurring after SOT or allogeneic HSCT.1  This spectrum of morphologic appearances varies in terms of cellular constituents, degree of resemblance to reactive or neoplastic lesions known in immunocompetent hosts, and association with the herpesvirus EBV. Prior to diagnosing PTLD, it is important to exclude specific and nonspecific lymphoplasmacytic infiltrations associated with infection, graft rejection, graft-versus-host disease, or recurrence from a known lymphoma that developed prior to transplant.

After it is histologically proved, PTLD is categorized as precisely as possible by using the 4 categories provided by the current 2008 World Health Organization (WHO) classification (Figure 2)2 :

  1. Early-type PTLDs are nondestructive lymphoplasmacytic proliferations that are further subdivided in plasmacytic hyperplasia and infectious mononucleosis–like paracortical hyperplasia. Some authors include florid follicular hyperplasia in this category, but lymphadenopathy characterized by reactive nodular paracortical dermatopathic changes or sinus histiocytosis is generally not considered PTLD.3 

  2. Polymorphic PTLDs are the most challenging presentations because they are destructive lymphoplasmacytic proliferations that do not fulfill the strict criteria of a malignant lymphoma. In certain cases, this subtype can be problematic to differentiate from prominent infectious mononucleosis–like lesions and often show Hodgkin lymphoma (HL)-like features.4  In polymorphic cases, the infiltrate comprises a minority of transformed B-blasts in a polymorphic background of lymphocytes, histiocytes, and plasma cells. These B-blasts show a spectrum of morphologic features varying from activated immunoblasts to Hodgkin cells and to fully developed Reed-Sternberg cells. They strongly express CD20 and CD30 and generally lack CD15.

  3. Monomorphic PTLDs should be the most straightforward to diagnose because they fulfill the histopathological criteria of a lymphoma recognized in immunocompetent hosts. The majority is of B-cell phenotype (with DLBCL, BL, and plasmablastic lymphoma as most prevalent subtypes), but T-cell lymphomas (like hepatosplenic T-cell lymphoma) and even some composite lymphomas have been described.5-9  Indolent B-cell lymphomas are, at present, not considered PTLDs, even when occurring in transplant patients.

  4. Sporadically, classical HL is also diagnosed in the context of posttransplantation when typical HRS cells are present in the appropriate cellular background of plasma cells, eosinophils, and (epithelioid) histiocytes. The HRS cells show strong reactivity for CD30 and CD15, along with absent CD20 and weak PAX5 expression.10 

Figure 2

Morphologic spectrum of PTLD. (A-C) PTLD, early lesion, plasmacytic hyperplasia. (A) In a preserved underlying architecture, there is a proliferation of small reactive plasma cells (inset). Immunohistochemical staining against κ (B) and λ (C) light chains shows the polytypic character of the plasma cells. (D-F) PTLD, polymorphic. (D) Lymph node architecture is effaced by a polymorphic proliferation of B cells of variable size, shape, and degree of transformation (HRS-like cell shown in inset), which are admixed with numerous small lymphocytes, plasma cells, eosinophils, and histiocytes. (E) Immunohistochemical staining against CD20 shows membranous and often Golgi-type expression in the B blasts. (F) Epstein-Barr virus–encoded RNA in situ hybridization shows nuclear positivity not only in the HRS-like cells but also in a variety of B cells. (G-I) PTLD, monomorphic, EBV+ DLBCL. (G) Monotonous proliferation of large transformed B cells (inset) with an infiltrative growth pattern and mitotic activity. (H) Diffuse CD20 expression of the infiltrate corresponding to the B-cell phenotype. (I) Most cells are EBV+, as seen in this Epstein-Barr virus–encoded RNA in situ hybridization. Images were taken with a Leica DFC290. Bars represent 50 µm. Original magnification 630×. Hematoxylin and eosin stain. HRS, Hodgkin/Reed-Sternberg.

Figure 2

Morphologic spectrum of PTLD. (A-C) PTLD, early lesion, plasmacytic hyperplasia. (A) In a preserved underlying architecture, there is a proliferation of small reactive plasma cells (inset). Immunohistochemical staining against κ (B) and λ (C) light chains shows the polytypic character of the plasma cells. (D-F) PTLD, polymorphic. (D) Lymph node architecture is effaced by a polymorphic proliferation of B cells of variable size, shape, and degree of transformation (HRS-like cell shown in inset), which are admixed with numerous small lymphocytes, plasma cells, eosinophils, and histiocytes. (E) Immunohistochemical staining against CD20 shows membranous and often Golgi-type expression in the B blasts. (F) Epstein-Barr virus–encoded RNA in situ hybridization shows nuclear positivity not only in the HRS-like cells but also in a variety of B cells. (G-I) PTLD, monomorphic, EBV+ DLBCL. (G) Monotonous proliferation of large transformed B cells (inset) with an infiltrative growth pattern and mitotic activity. (H) Diffuse CD20 expression of the infiltrate corresponding to the B-cell phenotype. (I) Most cells are EBV+, as seen in this Epstein-Barr virus–encoded RNA in situ hybridization. Images were taken with a Leica DFC290. Bars represent 50 µm. Original magnification 630×. Hematoxylin and eosin stain. HRS, Hodgkin/Reed-Sternberg.

It should be noted that exact classification in 1 of these 4 categories will not always be possible because of overlap between several categories or because PTLDs can present as different morphologic subtypes within different locations in the body or even within a single biopsy sample. The latter finding is in concordance with the hypothesis that in some cases, there might be a progressive transition from early PTLD through polymorphic PTLD to monomorphic PTLD.11  It might therefore be useful to consider performing a new biopsy when PET imaging suggests a more malignant disease presentation than observed in the biopsy sample (especially after core needle biopsy).12  Factors causing this presumed transition are not defined, and this evolution is clearly not present in all cases, as illustrated by the observation of extremely aggressive monomorphic PTLD cases occurring <2 weeks post-HSCT.

The HL-like polymorphic PTLD subtype is among the most difficult to diagnose because there is a clear overlap with classical HL.13,14  Correlation with the clinical presentation is important, because classical HL will not primarily involve mucosa-associated lymphoid tissues, whereas HL-PTLDs generally do. Differentiating HL-like polymorphic PTLD from HL-PTLD is important, given the often aggressive presentation and poor prognosis in the former group of patients.4  However, this worse prognosis is not a constant finding, as illustrated by EBV+ mucocutaneous ulcers.15,16 

Other diagnostic challenges include cases with more extensive plasmacytic infiltrates or plasmacytoma-like lymphoproliferations and borderline cases that fall between polymorphic and monomorphic PTLD. It is generally assumed that the biological behavior will depend on the most malignant subtype, but well-defined criteria are lacking.

Clonality studies can support the diagnosis because monomorphic PTLDs typically show clonal immunoglobulin or T-cell receptor gene rearrangements in the B-cell or T-cell populations, respectively. Of interest, due to the immunosuppressed state, monomorphic B-cell PTLDs often contain (oligo)clonal reactive restricted T-cell populations that can be detected on T-cell receptor polymerase chain reaction (PCR).17  These T-cell populations, however, should not be considered composite lymphomas unless they fulfill the histopathological criteria for T-cell lymphoma. Polyclonal B- and T-cells compose early lesions, whereas clonal B-cell populations can be detected in polymorphic PTLDs, typically on a polyclonal background.

It should be noted that EBV positivity is not a prerequisite for the diagnosis of PTLD, and the number of EBV cases increased over time from 10% (1990-1995) to 48% (2008-2013).18  It is currently under debate whether EBV PTLDs are to be considered immunosuppression related or coincidental, because some molecular genetic studies suggest similar pathogenic mechanisms for EBV PTLDs and EBV lymphomas in immunocompetent hosts, but different from EBV+ PTLDs, justifying a different therapeutic approach for EBV and EBV+ PTLDs.19-25  It is therefore recommended to determine EBV association in every biopsy sample, using Epstein-Barr virus–encoded RNA in situ hybridization as the gold standard.26  In addition, immunohistochemistry for viral proteins (eg, latent membrane proteins and EBV nuclear antigens) can provide information on the latency or lytic stage of the virus (as evidenced by ZEBRA protein expression). If EBV is detected in early, polymorphic, and monomorphic PTLDs, it is characterized by a broad viral latency (type III), sometimes in the presence of some lytic reactivation.27,28  In contrast to classical HL, in which EBV is typically restricted to the fully developed HRS cells and of intermediate latency (type II), EBV is present in a wide spectrum of B-cells in the HL-like polymorphic PTLD.13,14 

Associations with other viruses, such as human herpesvirus 8 or cytomegalovirus, have been described in case reports, the former mainly coexisting with EBV and the latter being regarded as an epiphenomenon rather than a driver of the disease.29-31 

In addition to pretransplant EBV mismatch (the most important risk factor for developing PTLD) and the immune suppressive agents used to prevent rejection, the type of transplant organ also determines the risk for PTLD. Based on large transplant registries and smaller single-center retrospective analyses, the incidence of PTLD seems to be highest in haploidentical HSCT, heart/lung, and multivisceral transplants (up to 20%), followed by liver (4.5%), combination heart-lung (2.5%), pancreas (2%), kidney (1%-1.5%), and matched related and unrelated HSCT (0.5%-1%).32,33  Apart from histoincompatibility, the amount of lymphoid tissue present in the organ can partially explain the differences in PTLD development associated with different grafts. Grafts containing a substantial amount of lymphoid tissue (eg, small intestine) result in transfer of (potentially EBV-infected) donor lymphocytes, which may contribute to PTLD development.10 

In contrast to SOT, PTLD after HSCT is almost exclusively of donor origin and develops during the first 6 months after transplant. This unique feature is a consequence of the profound T cell–depleting conditioning regimen, leading to lack of EBV-specific T cells and, hence, the often impressive and rapid growth of an EBV+ clone, even within the first weeks.34  Because immune reconstitution occurs in the first 6 to 12 months and oral immune suppression can often be stopped, late PTLD is rare after HSCT. However, an interesting finding is the increased incidence of late-onset HL in patients undergoing HSCT. In this population, a standardized incidence ratio of 6.2 was observed, whereas a standardized incidence ratio after SOT is ∼3.7.35,36  The lack of association with low CD4 counts is in line with the observation of typically normal CD4 counts in HIV+ patients diagnosed with HL.37 

The incidence of PTLD has clearly increased during the last decade.18,33,38  This increase can be explained by several reasons, including the use of more potent immune suppression, the older age of both donor and recipient, the increased use of haploidentical HSCT, the increased awareness, and the prompt request for a biopsy in the case of PTLD suspicion. A notable exception seems to be the decreasing incidence in (at least pediatric) liver transplant recipients, possibly due to the use of minimal immune suppression strategies and to serial EBV monitoring.39 

Whether the type of transplant organ predisposes to a specific lymphoma subtype is currently not clear. Although the numbers are limited and based on small series or case reports, plasmablastic lymphoma seems to be observed more frequently in heart transplant recipients compared with other transplant recipients.7,40  A similar observation has been reported for primary central nervous system (CNS) lymphoma, which is predominantly seen after kidney transplant (79% in a large multicenter international analysis).41 

Accurate staging and assessment of response and end-of-treatment remission are important for optimal management of patients with lymphoma. Imaging plays a major role herein, and 18F-FDG–PET/CT has become the standard to assess pretreatment evaluation and therapy response in FDG-avid lymphomas.42,43  The superiority of 18F-FDG–PET/CT for end-of-treatment response assessment has also been extensively documented, with additional value seen mainly in patients with a radiologically unconfirmed complete response or partial response.44,45 

Because 18F-FDG–PET/CT is superior to CT alone in evaluating nodal and extranodal involvement, and due to the similarity between PTLD and non-HL[NHL]/HL, 18F-FDG–PET/CT is routinely used in the diagnostic workup of PTLD patients. Several single-center studies have demonstrated a high sensitivity and specificity for detecting both nodal and extranodal involvement.12,46,47 

To date, reports on the value of 18F-FDG–PET/CT to assess treatment response are very scarce, but several case reports have demonstrated the potential of this technique to evaluate treatment response.48-50  The recommendations for 18F-FDG–PET/CT to assess treatment response can be extrapolated to PTLD patients because of the resemblance with other FDG-avid NHLs; 18F-FGD–PET/CT is currently the standard of care at end of treatment.

There are currently no data available on the role of 18F-FDG–PET/CT for routine surveillance in PTLD patients, but similar to the recommendations for HL and FDG-avid NHL, the use of 18F-FDG–PET/CT in follow-up should be limited to patients with a clinical suspicion for recurrent disease.

Because the development of PTLD is the consequence of an imbalance between immunosuppression and immunosurveillance, different approaches can be justified for treating this disorder, including RIS, destruction of the malignant clone, and suppression of the (EBV) viral load.51  Based on several phase 2 trials, rituximab (after RIS) is now considered standard therapy for most CD20+ PTLDs, including polymorphic and monomorphic DLBCL subtypes.52-57  For CD20 monomorphic PTLDs (including plasmablastic, plasma cell myeloma/plasmacytoma-like, and T-cell lymphoma) and for primary CNS lymphomas, most clinicians agree to treat these patients according to their immune-competent counterparts. Our therapeutic approach and the main advantages and disadvantages of different treatment options are shown in Figure 3 and Table 1, respectively.

Figure 3

Proposed treatment algorithm for PTLD after SOT or HSCT. ASCT, autologous stem cell transplant; CR, complete remission; DLI, donor lymphocyte infusion; FU, follow-up; HDT, high-dose therapy; IS, immune suppression; PCNSL, primary CNS lymphoma; R-CHOP, sequential immunochemotherapy with rituximab followed by CHOP; Tx, transplant.

Figure 3

Proposed treatment algorithm for PTLD after SOT or HSCT. ASCT, autologous stem cell transplant; CR, complete remission; DLI, donor lymphocyte infusion; FU, follow-up; HDT, high-dose therapy; IS, immune suppression; PCNSL, primary CNS lymphoma; R-CHOP, sequential immunochemotherapy with rituximab followed by CHOP; Tx, transplant.

Table 1

Treatment options in PTLD

TreatmentTargetAdvantagesDisadvantages
RIS T-cell function High response rates in early lesions
Role in preemptive therapy 
Takes time, so not feasible in very aggressive presentations
Organ dependent
Risk for organ rejection
Less efficacy in HSCT 
Cytokine therapy T-cell function
B-cell mass 
Promising response rates High toxicity (not further developed) 
Donor lymphocyte infusion T-cell function
EBV 
High response rates
Rapidly available (at least in related donors) 
Only in HSCT
Unfavorable toxicity profile (graft-versus-host disease) 
Adoptive immunotherapy (EBV-specific cytotoxic T cells) T-cell function
EBV 
Promising results in refractory PTLD
Excellent toxicity profile
Rapidly developing field 
Only in EBV+ cases
Time consuming
High costs
Availability restrictions 
Surgery and radiotherapy B-cell mass Rapid symptom relief Only in limited-stage (stage I) disease
Mostly palliative 
Chemotherapy B-cell mass High response rates High treatment-related morbidity and mortality 
Rituximab B-cell mass High response rates
Favorable toxicity profile
Induces better performance state
Allows risk stratification
Role in preemptive therapy 
Only in CD20+ PTLD
Specific side effects (progressive multifocal leukoencephalopathy, hypogammaglobulinemia, hepatitis B reactivation) 
Antiviral agents EBV Promising role in combination with viral thymidine kinase–inducing agents (eg, arginine butyrate) but not further developed No efficacy in monotherapy (lack of viral thymidine kinase expression in EBV+ PTLD)
Only in EBV+ cases 
IV immunoglobulins EBV Theoretically attractive due to the presence of antibodies against EBV proteins Mostly combined with other therapies; hence, no information on real efficacy 
TreatmentTargetAdvantagesDisadvantages
RIS T-cell function High response rates in early lesions
Role in preemptive therapy 
Takes time, so not feasible in very aggressive presentations
Organ dependent
Risk for organ rejection
Less efficacy in HSCT 
Cytokine therapy T-cell function
B-cell mass 
Promising response rates High toxicity (not further developed) 
Donor lymphocyte infusion T-cell function
EBV 
High response rates
Rapidly available (at least in related donors) 
Only in HSCT
Unfavorable toxicity profile (graft-versus-host disease) 
Adoptive immunotherapy (EBV-specific cytotoxic T cells) T-cell function
EBV 
Promising results in refractory PTLD
Excellent toxicity profile
Rapidly developing field 
Only in EBV+ cases
Time consuming
High costs
Availability restrictions 
Surgery and radiotherapy B-cell mass Rapid symptom relief Only in limited-stage (stage I) disease
Mostly palliative 
Chemotherapy B-cell mass High response rates High treatment-related morbidity and mortality 
Rituximab B-cell mass High response rates
Favorable toxicity profile
Induces better performance state
Allows risk stratification
Role in preemptive therapy 
Only in CD20+ PTLD
Specific side effects (progressive multifocal leukoencephalopathy, hypogammaglobulinemia, hepatitis B reactivation) 
Antiviral agents EBV Promising role in combination with viral thymidine kinase–inducing agents (eg, arginine butyrate) but not further developed No efficacy in monotherapy (lack of viral thymidine kinase expression in EBV+ PTLD)
Only in EBV+ cases 
IV immunoglobulins EBV Theoretically attractive due to the presence of antibodies against EBV proteins Mostly combined with other therapies; hence, no information on real efficacy 

In this discussion, we mainly focus on BL-PTLD, a special subtype of monomorphic CD20+ PTLD. Guidelines on optimal treatment of BL-PTLD are lacking for several reasons. First, BL-PTLD is a very rare disorder that has been studied less intensively compared to other BL subtypes (eg, HIV associated). Second, similarly to sporadic BL, BL-PTLD affects both pediatric and adult transplant patients, hindering registration and application of uniform treatment protocols. Lastly, some BL-PTLD cases are MYC negative and characterized by the 11q-gain/loss pattern.24  Thus, the frequent lack of cytogenetic/fluorescence in situ hybridization data in published series and case reports makes distinction between true BL and BL-like cases impossible. The main questions concerning BL-PTLD are (1) does the clinical behavior of this disorder mimic other BL subtypes and, consequently, (2) does the proposed management strategy in other subtypes (ie, intensive multiagent chemotherapy, rituximab, and, in the case of HIV-associated BL, reconstitution of the immune system) also apply to patients presenting with BL-PTLD or is less-intensive treatment (rituximab and low-dose chemotherapy in combination with RIS) more desirable? Therefore, we performed a literature search and identified 6 small case series (3 pediatric and 3 adult) focusing on treatment of aggressive PTLD, including 39 patients with BL-PTLD.58-63  Twenty-five of 26 evaluable cases (those with information on MYC) had a proven MYC rearrangement. In contrast to sporadic (30%) and HIV-associated BL (25%-40%), most cases (82%) were EBV associated. Of interest, 90% of the cases were late-onset PTLDs (>1 year after transplant). In the 3 pediatric case series, treatment ranged from RIS and low-dose immunochemotherapy (rituximab-cyclophosphamide-prednisone) to RIS and intensive BL regimens, all leading to similar long-term outcome (75%-100% long-term survivors).58-60  In 2 adult case series, patients were treated with RIS, followed by short intensive chemotherapeutic regimens.61,62  Although response rates were acceptable (75%), toxicity was high, with 3 toxic deaths in 5 patients in the series described by Xicoy et al.62  In a recent case series from the German Study Group on PTLD, 5 of 8 adult patients received sequential immunochemotherapy (4 courses of rituximab followed by 4 courses of CHOP). Four of 5 patients reached complete remission, of which 1 had an early relapse. No intrathecal prophylaxis was given. The investigators concluded that sequential immunochemotherapy was a safe and effective treatment of BL-PTLD.63 

Taken together, these studies clearly indicate that no firm conclusions can be made regarding the optimal treatment of pediatric and adult patients presenting with BL-PTLD, a statement confirmed by the recent British guidelines on the management of PTLD.64  Similarly to the efforts made in HIV-related BL that have led to a promising trial with a low-intensity immunochemotherapeutic regimen, prospective trials are urgently needed because initial optimal therapy (including the need for intrathecal chemotherapy) is of extreme importance to avoid difficult-to-treat relapses often localized in the CNS, as illustrated in case 1.65  The dramatic evolution of this case has changed our institutional protocol for BL-PTLD from sequential immunochemotherapy with rituximab followed by CHOP to a more intensive regimen including CNS prophylaxis.

Despite the strong association between EBV and PTLD, 33% to 48% of PTLD cases are EBV (as in case 2).18,33,38,66  The etiology of these PTLD cases is currently unknown. A number of hypotheses, such as hit-and-run EBV infection, other infectious agents, and chronic immune triggering by the graft, have been proposed as possible pathogenic mechanisms of these EBV PTLDs.29,67-72  However, there is limited evidence supporting these theories. From a clinical viewpoint, EBV cases tend to occur later (years) compared to EBV+ PTLD (months), corresponding to the fact that positive Epstein-Barr virus–encoded RNA staining is a constant finding in early lesions and polymorphic PTLD, with both (especially the former) subtypes observed predominantly in the early posttransplant period. Gene expression profiling studies suggest EBV cases should not be considered real PTLD but rather “classical” lymphomas coincidentally occurring in a transplant recipient.23  This hypothesis is supported by a genomic study demonstrating that patients with EBV posttransplant DLBCL share several common imbalances with DLBCL in immunocompetent patients, whereas both groups significantly differentiate from EBV+ posttransplant DLBCL.25  However, the fact that some of these lymphomas respond well to RIS likely makes this hypothesis too simplified.73 

We previously suggested that the composition of the microenvironment may represent an important difference between EBV+ and EBV PTLD (Morscio et al23  and unpublished results, T.T. and D.D.), influencing lymphomagenesis. Several genes involved in immunotolerance were upregulated in EBV+ cases and potentially contribute to the early onset of EBV+ compared to EBV PTLD. Numerous studies have described how the presence or absence of particular stromal cells may impact prognosis in DLBCL patients.74,75  However, we only begin to understand the multitude of interactions that take place. In the case of EBV+ lymphomas, these studies are complicated by the fact that in most lesions, a fraction of the tumor cells is negative for EBV-encoded RNA and proteins. The reason for this is unclear, but this observation raises a number of important questions. Does the microenvironment vary in the immediate surroundings of EBV+ and EBV tumor cells? And what are the implications for EBV-targeted therapy?

Whether the prognosis of EBV cases differs from their EBV+ counterparts is currently not clear, given the controversial results in the literature. In the recently published analysis of 70 patients included in the international multicenter prospective phase 2 PTLD-1 trial, EBV association was not found to be a significant factor for overall survival or time to progression.57  Thus, there is currently no evidence that upfront treatment of EBV and EBV+ PTLD should be different; of course, this does not apply to the use of EBV-specific adoptive immunotherapy, which is restricted to EBV+ cases.

Given the important role of EBV in the pathogenesis of a substantial proportion of cases, many authors have investigated the role of viral load, determined by quantitative PCR in the diagnosis of PTLD. Although there seems to be a clear link between EBV proliferation and the development of EBV+ PTLD, especially in high-risk transplants such as pediatric liver and bowel transplant and HSCT, EBV viral load cannot replace biopsy as the gold standard for diagnosing PTLD.76,77 

Measurement of EBV viral load has, however, emerged as a useful tool to initiate preemptive treatment. This strategy, in which immune suppression is reduced and/or rituximab is administered guided by EBV viral load, has shown promising results in SOT and HSCT.78-80  Impressive results with very favorable toxicity profiles have also been obtained by prophylactic and preemptive administration of EBV-specific cytotoxic T lymphocytes (CTLs).81  Despite these results, wide applicability of this approach has been limited due to high costs, the labor-intensive procedure, and availability difficulties. However, new strategies to develop more rapid approaches for generating virus-specific T cells and the introduction of a third-party bank with HLA-typed EBV-specific CTLs might alter the therapeutic landscape of PTLD in the near future.82-85  In addition, recent studies in mice have shown that adoptive transfer of pamidronate-expanded Vγ9Vδ2 T cells and tacrolimus-resistant engineered CTLs might become potential therapies in PTLD without the need for reducing immune-suppressive therapy.86,87 

To improve the positive predictive value of EBV viral load, different approaches have been described that combine EBV PCR with measurements of diminished T-cell immunity (absolute lymphocyte count, absence of EBV-specific CD8+ T cells) or cytokine polymorphisms.88-90  Other potential candidates allowing preventive or prophylactic interventions include measurements of interleukin-6, interleukin-10, and chemokine (C-X-C motif) ligand 13.91-93  However, these approaches have not yet been validated in larger series.

Compared to DLBCL in immune-competent patients, prognosis of PTLD is poor, with observed 5-year overall survival rates ranging from 40% to 60%.33,38,66  Although most of these deaths are associated with progressive disease, up to 40% of patients will eventually die due to unrelated causes (mainly infections), emphasizing the fragility of transplant patients, even in complete remisson.33  During the last decade, several prognostic indices have been proposed by different authors, but validation of these scores in different transplant populations has shown conflicting results, mainly due to heterogeneity in design, patient population, and treatment.38,56,94-97  In most series, classical factors, including higher age, advanced disease, poor performance state, elevated lactate dehydrogenase, and CNS invasion, are also associated with poor prognosis in PTLD patients. Recently, hypoalbuminemia was also established as a very strong risk factor.38  Based on recent literature, we consider the International Prognostic Index (IPI)98  as a reliable and significant predictor of survival in patients with PTLD.33,99,100  In addition to demonstrating the prognostic role of the IPI score, a large prospective phase 2 trial evaluating the sequential use of rituximab and CHOP chemotherapy in patients with CD20+ PTLD after SOT showed that response to rituximab monotherapy predicted overall survival.57  This finding led to an amendment of the trial, introducing the concept of risk-stratified sequential treatment according to the response to rituximab. In contrast, thoracic organ transplant recipients not responding to rituximab monotherapy had a particularly poor prognosis and chemotherapy-refractory disease.100  Based on these findings, a new multicenter prospective trial (PTLD-2) has been initiated, in which risk groups are not only defined on the basis of response to rituximab monotherapy but also on the IPI and the type of transplanted organ (https://clinicaltrials.gov; NCT02042391).

The increasing number of publications on PTLD, the detailed description of this entity in the WHO 2008 classification, and the international cooperation of different clinical and research groups have all contributed to an increased knowledge on the different aspects of the disorder. However, as illustrated in Table 2, many questions and challenges remain, making further research and clinical studies mandatory in this rapidly changing field of ever-increasing transplant activities worldwide and the use of new and very potent immunosuppressive therapies.

Table 2

Perspectives and future challenges in PTLD

AspectResearch/clinical challenges/opportunities
Incidence Integrating large registries and complete multicenter/nationwide detailed information, preferentially prospective 
Risk factors Searching for tools measuring overall immunosuppressive load and association with PTLD risk and identifying new risk factors (HLA associated? Non-EBV viruses?) 
Pathogenesis Providing comprehensive overview of genomic landscape by using next-generation sequencing (both EBV+ and EBV PTLD) 
Diagnosis Refining WHO 2008 classification, including impact of EBV (negative, positive, latency type, lytic activation), stromal microenvironment, and molecular genetic findings 
Staging and response assessment Determining role of hybrid PET/magnetic resonance imaging, other tracers (eg, 18F-fluoro-3′-deoxythymidine), and immuno-PET 
Prevention Improving preemptive strategies (eg, EBV PCR, cytokine gene polymorphisms, and chemokine (C-X-C motif) ligand 13) 
Treatment Aiming for international cooperation and inclusion of patients in prospective international trials 
Prognosis Identifying new (clinical and nonclinical) prognostic factors and factors predictive for response, aiming to identify patients with poor outcome on “standard” therapy and provide an opportunity for risk-adapted treatment strategies in the future 
AspectResearch/clinical challenges/opportunities
Incidence Integrating large registries and complete multicenter/nationwide detailed information, preferentially prospective 
Risk factors Searching for tools measuring overall immunosuppressive load and association with PTLD risk and identifying new risk factors (HLA associated? Non-EBV viruses?) 
Pathogenesis Providing comprehensive overview of genomic landscape by using next-generation sequencing (both EBV+ and EBV PTLD) 
Diagnosis Refining WHO 2008 classification, including impact of EBV (negative, positive, latency type, lytic activation), stromal microenvironment, and molecular genetic findings 
Staging and response assessment Determining role of hybrid PET/magnetic resonance imaging, other tracers (eg, 18F-fluoro-3′-deoxythymidine), and immuno-PET 
Prevention Improving preemptive strategies (eg, EBV PCR, cytokine gene polymorphisms, and chemokine (C-X-C motif) ligand 13) 
Treatment Aiming for international cooperation and inclusion of patients in prospective international trials 
Prognosis Identifying new (clinical and nonclinical) prognostic factors and factors predictive for response, aiming to identify patients with poor outcome on “standard” therapy and provide an opportunity for risk-adapted treatment strategies in the future 

Diagnosis of PTLD is not always straightforward, requiring refinement of the current WHO 2008 classification. This refinement will likely be possible only by incorporating findings derived from the microenvironment and by introducing molecular genetic characteristics. Although we and others have speculated, on the basis of transcriptomic and genomic studies, that EBV+ and EBV PTLD seem to be different entities and, hence, should not be treated the same way, clinical data do not completely support this hypothesis, providing a strong rationale for well-designed clinical trials that avoid confounding factors.

RIS is considered the cornerstone of treatment in PTLD after SOT, although in most cases, additional therapy is warranted. Improved outcome observed with the use of rituximab in different B-cell NHLs has led to the introduction of this monoclonal antibody in several small (and 1 large multicenter) prospective phase 2 trials in PTLD. Results of these trials have established rituximab as the standard of care (either in monotherapy or followed by systemic chemotherapy) in most CD20+ PTLDs. Despite these improvements, survival of PTLD patients remains inferior, necessitating further international cooperation aimed at improving long-term outcome of PTLD patients. In addition, new and tolerable therapies are needed in the treatment of patients with PTLD. On the basis of in vitro observations, possible candidates include phosphatidylinositol 3-kinase inhibitors and mammalian target of rapamycin inhibitors.101,102  Whether checkpoint inhibitors can be used safely in PTLD has not yet been investigated, but a major obstacle will be the increased risk for graft rejection, which is exemplified by the fact that CTLA4-immunoglobulin (belatacept) is approved for prevention of graft rejection in kidney transplants at the expense of an increased risk for PTLD development.103  Inversely, it can be expected that CTLA4 inhibitors might be used in the treatment of PTLD, although with an increased risk for graft rejection.

The authors thank the other members of the Leuven PTLD Group (Prof Gregor Verhoef, Dr Julie Morscio, Prof Iwona Wlodarska, and Dr Marleen Renard) for their assistance in preparing the manuscript and for their critical review of the final version of the manuscript.

This work was supported by a research grant (G081411N) from Fonds Wetenschappelijk Onderzoek –Vlaanderen and by a concerted action grant (3M040406) from Catholic University Leuven (T.T.). T.T. holds a Mandate for Fundamental and Translational Research from the Stichting tegen Kanker (2014-083); D.D. holds a Mandate for Clinical Research from the University Hospitals Leuven and is a cofounder of Stefanie’s Rozen Fonds, Fonds Tom Debackere voor lymfoomonderzoek, and Fonds Jos en Mieke Vandevordt-Gaul voor de pathogenese van zeldzame lymfomen; and O.G. is a senior clinical investigator of Fonds Wetenschappelijk Onderzoek–Vlaanderen.

Contribution: D.D., T.T., and O.G. wrote the manuscript; all authors read and approved the final version of the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Daan Dierickx, Department of Hematology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium; e-mail: daan.dierickx@uzleuven.be.

1
Swerdlow
 
SH
Dharnidharka
 
VR
Green
 
M
Webber
 
SA
Pathology.
Post-transplant lymphoproliferative disorders
2010
Berlin and Heidelberg, Germany
Springer-Verlag
(pg. 
89
-
104
)
2
Swerdlow
 
SH
Webber
 
SA
Chadburn
 
A
Ferry
 
JA
Swerdlow
 
SH
Campo
 
E
Harris
 
NL
, et al. 
Post-transplant lymphoproliferative disorders.
WHO classification of Tumours of Haematopoietic and Lymphoid Tissues
2008
Lyon, France
IARC Press
(pg. 
343
-
349
)
3
Vakiani
 
E
Nandula
 
SV
Subramaniyam
 
S
, et al. 
Cytogenetic analysis of B-cell posttransplant lymphoproliferations validates the World Health Organization classification and suggests inclusion of florid follicular hyperplasia as a precursor lesion.
Hum Pathol
2007
, vol. 
38
 
2
(pg. 
315
-
325
)
4
Krishnamurthy
 
S
Hassan
 
A
Frater
 
JL
Paessler
 
ME
Kreisel
 
FH
Pathologic and clinical features of Hodgkin lymphoma--like posttransplant lymphoproliferative disease.
Int J Surg Pathol
2010
, vol. 
18
 
4
(pg. 
278
-
285
)
5
Zimmermann
 
H
Oschlies
 
I
Fink
 
S
, et al. 
Plasmablastic posttransplant lymphoma: cytogenetic aberrations and lack of Epstein-Barr virus association linked with poor outcome in the prospective German Posttransplant Lymphoproliferative Disorder Registry.
Transplantation
2012
, vol. 
93
 
5
(pg. 
543
-
550
)
6
Morscio
 
J
Dierickx
 
D
Nijs
 
J
, et al. 
Clinicopathologic comparison of plasmablastic lymphoma in HIV-positive, immunocompetent, and posttransplant patients: single-center series of 25 cases and meta-analysis of 277 reported cases.
Am J Surg Pathol
2014
, vol. 
38
 
7
(pg. 
875
-
886
)
7
Tiede
 
C
Maecker-Kolhoff
 
B
Klein
 
C
Kreipe
 
H
Hussein
 
K
Risk factors and prognosis in T-cell posttransplantation lymphoproliferative diseases: reevaluation of 163 cases.
Transplantation
2013
, vol. 
95
 
3
(pg. 
479
-
488
)
8
Herreman
 
A
Dierickx
 
D
Morscio
 
J
, et al. 
Clinicopathological characteristics of posttransplant lymphoproliferative disorders of T-cell origin: single-center series of nine cases and meta-analysis of 147 reported cases.
Leuk Lymphoma
2013
, vol. 
54
 
10
(pg. 
2190
-
2199
)
9
Morovic
 
A
Jaffe
 
ES
Raffeld
 
M
Schrager
 
JA
Metachronous EBV-associated B-cell and T-cell posttransplant lymphoproliferative disorders in a heart transplant recipient.
Am J Surg Pathol
2009
, vol. 
33
 
1
(pg. 
149
-
154
)
10
Tsao
 
L
Hsi
 
ED
The clinicopathologic spectrum of posttransplantation lymphoproliferative disorders.
Arch Pathol Lab Med
2007
, vol. 
131
 
8
(pg. 
1209
-
1218
)
11
Taoka
 
K
Nannya
 
Y
Yamamoto
 
G
, et al. 
Progressive transition of Epstein-Barr virus associated lymphoproliferative disease subtypes with the development of lung cancer.
Am J Hematol
2009
, vol. 
84
 
9
(pg. 
600
-
603
)
12
Takehana
 
CS
Twist
 
CJ
Mosci
 
C
Quon
 
A
Mittra
 
E
Iagaru
 
A
(18)F-FDG PET/CT in the management of patients with post-transplant lymphoproliferative disorder.
Nucl Med Commun
2014
, vol. 
35
 
3
(pg. 
276
-
281
)
13
Rohr
 
JC
Wagner
 
HJ
Lauten
 
M
, et al. 
Differentiation of EBV-induced post-transplant Hodgkin lymphoma from Hodgkin-like post-transplant lymphoproliferative disease.
Pediatr Transplant
2008
, vol. 
12
 
4
(pg. 
426
-
431
)
14
Pitman
 
SD
Huang
 
Q
Zuppan
 
CW
, et al. 
Hodgkin lymphoma-like posttransplant lymphoproliferative disorder (HL-like PTLD) simulates monomorphic B-cell PTLD both clinically and pathologically.
Am J Surg Pathol
2006
, vol. 
30
 
4
(pg. 
470
-
476
)
15
Dojcinov
 
SD
Venkataraman
 
G
Raffeld
 
M
Pittaluga
 
S
Jaffe
 
ES
EBV positive mucocutaneous ulcer--a study of 26 cases associated with various sources of immunosuppression.
Am J Surg Pathol
2010
, vol. 
34
 
3
(pg. 
405
-
417
)
16
Hart
 
M
Thakral
 
B
Yohe
 
S
, et al. 
EBV-positive mucocutaneous ulcer in organ transplant recipients: a localized indolent posttransplant lymphoproliferative disorder.
Am J Surg Pathol
2014
, vol. 
38
 
11
(pg. 
1522
-
1529
)
17
Nelson
 
BP
Locker
 
J
Nalesnik
 
MA
Fung
 
JJ
Swerdlow
 
SH
Clonal and morphological variation in a posttransplant lymphoproliferative disorder: evolution from clonal T-cell to clonal B-cell predominance.
Hum Pathol
1998
, vol. 
29
 
4
(pg. 
416
-
421
)
18
Luskin
 
MR
Heil
 
DS
Tan
 
KS
, et al. 
The impact of EBV status on characteristics and outcomes of posttransplantation lymphoproliferative disorders.
Am J Transplant
2015
, vol. 
15
 
10
(pg. 
2665
-
2673
)
19
Poirel
 
HA
Bernheim
 
A
Schneider
 
A
, et al. 
Characteristic pattern of chromosomal imbalances in posttransplantation lymphoproliferative disorders: correlation with histopathological subcategories and EBV status.
Transplantation
2005
, vol. 
80
 
2
(pg. 
176
-
184
)
20
Craig
 
FE
Johnson
 
LR
Harvey
 
SA
, et al. 
Gene expression profiling of Epstein-Barr virus-positive and -negative monomorphic B-cell posttransplant lymphoproliferative disorders.
Diagn Mol Pathol
2007
, vol. 
16
 
3
(pg. 
158
-
168
)
21
Vakiani
 
E
Basso
 
K
Klein
 
U
, et al. 
Genetic and phenotypic analysis of B-cell post-transplant lymphoproliferative disorders provides insights into disease biology.
Hematol Oncol
2008
, vol. 
26
 
4
(pg. 
199
-
211
)
22
Rinaldi
 
A
Capello
 
D
Scandurra
 
M
, et al. 
Single nucleotide polymorphism-arrays provide new insights in the pathogenesis of post-transplant diffuse large B-cell lymphoma.
Br J Haematol
2010
, vol. 
149
 
4
(pg. 
569
-
577
)
23
Morscio
 
J
Dierickx
 
D
Ferreiro
 
JF
, et al. 
Gene expression profiling reveals clear differences between EBV-positive and EBV-negative posttransplant lymphoproliferative disorders.
Am J Transplant
2013
, vol. 
13
 
5
(pg. 
1305
-
1316
)
24
Ferreiro
 
JF
Morscio
 
J
Dierickx
 
D
, et al. 
Post-transplant molecularly defined Burkitt lymphomas are frequently MYC-negative and characterized by the 11q-gain/loss pattern.
Haematologica
2015
, vol. 
100
 
7
(pg. 
e275
-
e279
)
25
Ferreiro
 
JF
Morscio
 
J
Dierickx
 
D
, et al. 
EBV-positive and EBV-negative posttransplant diffuse large B-cell lymphomas have distinct genomic and transcriptomic features.
Am J Transplant
 
In press
26
Stuhlmann-Laeisz
 
C
Oschlies
 
I
Klapper
 
W
Detection of EBV in reactive and neoplastic lymphoproliferations in adults-when and how?
J Hematop
2014
, vol. 
7
 
4
(pg. 
165
-
170
)
27
Hamilton-Dutoit
 
SJ
Rea
 
D
Raphael
 
M
, et al. 
Epstein-Barr virus-latent gene expression and tumor cell phenotype in acquired immunodeficiency syndrome-related non-Hodgkin’s lymphoma. Correlation of lymphoma phenotype with three distinct patterns of viral latency.
Am J Pathol
1993
, vol. 
143
 
4
(pg. 
1072
-
1085
)
28
Oertel
 
SH
Anagnostopoulos
 
I
Hummel
 
MW
Jonas
 
S
Riess
 
HB
Identification of early antigen BZLF1/ZEBRA protein of Epstein-Barr virus can predict the effectiveness of antiviral treatment in patients with post-transplant lymphoproliferative disease.
Br J Haematol
2002
, vol. 
118
 
4
(pg. 
1120
-
1123
)
29
Kapelushnik
 
J
Ariad
 
S
Benharroch
 
D
, et al. 
Post renal transplantation human herpesvirus 8-associated lymphoproliferative disorder and Kaposi’s sarcoma.
Br J Haematol
2001
, vol. 
113
 
2
(pg. 
425
-
428
)
30
Chen
 
W
Huang
 
Q
Zuppan
 
CW
, et al. 
Complete absence of KSHV/HHV-8 in posttransplant lymphoproliferative disorders: an immunohistochemical and molecular study of 52 cases.
Am J Clin Pathol
2009
, vol. 
131
 
5
(pg. 
632
-
639
)
31
Zallio
 
F
Primon
 
V
Tamiazzo
 
S
, et al. 
Epstein-Barr virus reactivation in allogeneic stem cell transplantation is highly related to cytomegalovirus reactivation.
Clin Transplant
2013
, vol. 
27
 
4
(pg. 
E491
-
E497
)
32
Opelz
 
G
Döhler
 
B
Lymphomas after solid organ transplantation: a collaborative transplant study report.
Am J Transplant
2004
, vol. 
4
 
2
(pg. 
222
-
230
)
33
Dierickx
 
D
Tousseyn
 
T
Sagaert
 
X
, et al. 
Single-center analysis of biopsy-confirmed posttransplant lymphoproliferative disorder: incidence, clinicopathological characteristics and prognostic factors.
Leuk Lymphoma
2013
, vol. 
54
 
11
(pg. 
2433
-
2440
)
34
Heslop
 
HE
How I treat EBV lymphoproliferation.
Blood
2009
, vol. 
114
 
19
(pg. 
4002
-
4008
)
35
Rowlings
 
PA
Curtis
 
RE
Passweg
 
JR
, et al. 
Increased incidence of Hodgkin’s disease after allogeneic bone marrow transplantation.
J Clin Oncol
1999
, vol. 
17
 
10
(pg. 
3122
-
3127
)
36
Grulich
 
AE
van Leeuwen
 
MT
Falster
 
MO
Vajdic
 
CM
Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis.
Lancet
2007
, vol. 
370
 
9581
(pg. 
59
-
67
)
37
Carbone
 
A
Vaccher
 
E
Gloghini
 
A
, et al. 
Diagnosis and management of lymphomas and other cancers in HIV-infected patients.
Nat Rev Clin Oncol
2014
, vol. 
11
 
4
(pg. 
223
-
238
)
38
Evens
 
AM
David
 
KA
Helenowski
 
I
, et al. 
Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era.
J Clin Oncol
2010
, vol. 
28
 
6
(pg. 
1038
-
1046
)
39
Narkewicz
 
MR
Green
 
M
Dunn
 
S
, et al. 
Studies of Pediatric Liver Transplantation Research Group
Decreasing incidence of symptomatic Epstein-Barr virus disease and posttransplant lymphoproliferative disorder in pediatric liver transplant recipients: report of the studies of pediatric liver transplantation experience.
Liver Transpl
2013
, vol. 
19
 
7
(pg. 
730
-
740
)
40
Castillo
 
JJ
Bibas
 
M
Miranda
 
RN
The biology and treatment of plasmablastic lymphoma.
Blood
2015
, vol. 
125
 
15
(pg. 
2323
-
2330
)
41
Evens
 
AM
Choquet
 
S
Kroll-Desrosiers
 
AR
, et al. 
Primary CNS posttransplant lymphoproliferative disease (PTLD): an international report of 84 cases in the modern era.
Am J Transplant
2013
, vol. 
13
 
6
(pg. 
1512
-
1522
)
42
Cheson
 
BD
Fisher
 
RI
Barrington
 
SF
, et al. 
Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Español de Médula Ósea; German High-Grade Lymphoma Study Group; German Hodgkin’s Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute
Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification.
J Clin Oncol
2014
, vol. 
32
 
27
(pg. 
3059
-
3068
)
43
Barrington
 
SF
Mikhaeel
 
NG
Kostakoglu
 
L
, et al. 
Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group.
J Clin Oncol
2014
, vol. 
32
 
27
(pg. 
3048
-
3058
)
44
Juweid
 
ME
Wiseman
 
GA
Vose
 
JM
, et al. 
Response assessment of aggressive non-Hodgkin’s lymphoma by integrated International Workshop Criteria and fluorine-18-fluorodeoxyglucose positron emission tomography.
J Clin Oncol
2005
, vol. 
23
 
21
(pg. 
4652
-
4661
)
45
Cerci
 
JJ
Trindade
 
E
Pracchia
 
LF
, et al. 
Cost effectiveness of positron emission tomography in patients with Hodgkin’s lymphoma in unconfirmed complete remission or partial remission after first-line therapy.
J Clin Oncol
2010
, vol. 
28
 
8
(pg. 
1415
-
1421
)
46
Dierickx
 
D
Tousseyn
 
T
Requilé
 
A
, et al. 
The accuracy of positron emission tomography in the detection of posttransplant lymphoproliferative disorder.
Haematologica
2013
, vol. 
98
 
5
(pg. 
771
-
775
)
47
Panagiotidis
 
E
Quigley
 
AM
Pencharz
 
D
, et al. 
(18)F-fluorodeoxyglucose positron emission tomography/computed tomography in diagnosis of post-transplant lymphoproliferative disorder.
Leuk Lymphoma
2014
, vol. 
55
 
3
(pg. 
515
-
519
)
48
von Falck
 
C
Maecker
 
B
Schirg
 
E
, et al. 
Post transplant lymphoproliferative disease in pediatric solid organ transplant patients: a possible role for [18F]-FDG-PET(/CT) in initial staging and therapy monitoring.
Eur J Radiol
2007
, vol. 
63
 
3
(pg. 
427
-
435
)
49
Bianchi
 
E
Pascual
 
M
Nicod
 
M
Delaloye
 
AB
Duchosal
 
MA
Clinical usefulness of FDG-PET/CT scan imaging in the management of posttransplant lymphoproliferative disease.
Transplantation
2008
, vol. 
85
 
5
(pg. 
707
-
712
)
50
Makis
 
W
Lisbona
 
R
Derbekyan
 
V
Hodgkin lymphoma post-transplant lymphoproliferative disorder following pediatric renal transplant: serial imaging with F-18 FDG PET/CT.
Clin Nucl Med
2010
, vol. 
35
 
9
(pg. 
704
-
705
)
51
Gottschalk
 
S
Rooney
 
CM
Heslop
 
HE
Post-transplant lymphoproliferative disorders.
Annu Rev Med
2005
, vol. 
56
 (pg. 
29
-
44
)
52
Oertel
 
SH
Verschuuren
 
E
Reinke
 
P
, et al. 
Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD).
Am J Transplant
2005
, vol. 
5
 
12
(pg. 
2901
-
2906
)
53
Blaes
 
AH
Peterson
 
BA
Bartlett
 
N
Dunn
 
DL
Morrison
 
VA
Rituximab therapy is effective for posttransplant lymphoproliferative disorders after solid organ transplantation: results of a phase II trial.
Cancer
2005
, vol. 
104
 
8
(pg. 
1661
-
1667
)
54
Choquet
 
S
Leblond
 
V
Herbrecht
 
R
, et al. 
Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study.
Blood
2006
, vol. 
107
 
8
(pg. 
3053
-
3057
)
55
González-Barca
 
E
Domingo-Domenech
 
E
Capote
 
FJ
, et al. 
GEL/TAMO (Grupo Español de Linfomas); GELCAB (Grupo para el Estudio de los Linfomas Catalano-Balear); GOTEL (Grupo Oncológico para el Tratamiento y Estudio de los Linfomas)
Prospective phase II trial of extended treatment with rituximab in patients with B-cell post-transplant lymphoproliferative disease.
Haematologica
2007
, vol. 
92
 
11
(pg. 
1489
-
1494
)
56
Choquet
 
S
Oertel
 
S
LeBlond
 
V
, et al. 
Rituximab in the management of post-transplantation lymphoproliferative disorder after solid organ transplantation: proceed with caution.
Ann Hematol
2007
, vol. 
86
 
8
(pg. 
599
-
607
)
57
Trappe
 
R
Oertel
 
S
Leblond
 
V
, et al. 
German PTLD Study Group; European PTLD Network
Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial.
Lancet Oncol
2012
, vol. 
13
 
2
(pg. 
196
-
206
)
58
Windebank
 
K
Walwyn
 
T
Kirk
 
R
, et al. 
Post cardiac transplantation lymphoproliferative disorder presenting as t(8;14) Burkitt leukaemia/lymphoma treated with low intensity chemotherapy and rituximab.
Pediatr Blood Cancer
2009
, vol. 
53
 
3
(pg. 
392
-
396
)
59
Picarsic
 
J
Jaffe
 
R
Mazariegos
 
G
, et al. 
Post-transplant Burkitt lymphoma is a more aggressive and distinct form of post-transplant lymphoproliferative disorder.
Cancer
2011
, vol. 
117
 
19
(pg. 
4540
-
4550
)
60
Gross
 
TG
Orjuela
 
MA
Perkins
 
SL
, et al. 
Low-dose chemotherapy and rituximab for posttransplant lymphoproliferative disease (PTLD): a Children’s Oncology Group Report.
Am J Transplant
2012
, vol. 
12
 
11
(pg. 
3069
-
3075
)
61
Gong
 
JZ
Stenzel
 
TT
Bennett
 
ER
, et al. 
Burkitt lymphoma arising in organ transplant recipients: a clinicopathologic study of five cases.
Am J Surg Pathol
2003
, vol. 
27
 
6
(pg. 
818
-
827
)
62
Xicoy
 
B
Ribera
 
JM
Esteve
 
J
, et al. 
Post-transplant Burkitt’s leukemia or lymphoma. Study of five cases treated with specific intensive therapy (PETHEMA ALL-3/97 trial).
Leuk Lymphoma
2003
, vol. 
44
 
9
(pg. 
1541
-
1543
)
63
Zimmermann
 
H
Reinke
 
P
Neuhaus
 
R
, et al. 
Burkitt post-transplantation lymphoma in adult solid organ transplant recipients: sequential immunochemotherapy with rituximab (R) followed by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or R-CHOP is safe and effective in an analysis of 8 patients.
Cancer
2012
, vol. 
118
 
19
(pg. 
4715
-
4724
)
64
Parker
 
A
Bowles
 
K
Bradley
 
JA
, et al. 
Haemato-oncology Task Force of the British Committee for Standards in Haematology and British Transplantation Society
Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients - BCSH and BTS Guidelines.
Br J Haematol
2010
, vol. 
149
 
5
(pg. 
693
-
705
)
65
Dunleavy
 
K
Pittaluga
 
S
Shovlin
 
M
, et al. 
Low-intensity therapy in adults with Burkitt’s lymphoma.
N Engl J Med
2013
, vol. 
369
 
20
(pg. 
1915
-
1925
)
66
Kinch
 
A
Baecklund
 
E
Backlin
 
C
, et al. 
A population-based study of 135 lymphomas after solid organ transplantation: The role of Epstein-Barr virus, hepatitis C and diffuse large B-cell lymphoma subtype in clinical presentation and survival.
Acta Oncol
2014
, vol. 
53
 
5
(pg. 
669
-
679
)
67
Shimizu
 
N
Tanabe-Tochikura
 
A
Kuroiwa
 
Y
Takada
 
K
Isolation of Epstein-Barr virus (EBV)-negative cell clones from the EBV-positive Burkitt’s lymphoma (BL) line Akata: malignant phenotypes of BL cells are dependent on EBV.
J Virol
1994
, vol. 
68
 
9
(pg. 
6069
-
6073
)
68
Jox
 
A
Rohen
 
C
Belge
 
G
, et al. 
Integration of Epstein-Barr virus in Burkitt’s lymphoma cells leads to a region of enhanced chromosome instability.
Ann Oncol
1997
, vol. 
8
 
Suppl 2
(pg. 
131
-
135
)
69
Ambinder
 
RF
Gammaherpesviruses and “Hit-and-Run” oncogenesis.
Am J Pathol
2000
, vol. 
156
 
1
(pg. 
1
-
3
)
70
Theate
 
I
Michaux
 
L
Squifflet
 
JP
Martin
 
A
Raphael
 
M
Human herpesvirus 8 and Epstein-Barr virus-related monotypic large B-cell lymphoproliferative disorder coexisting with mixed variant of Castleman’s disease in a lymph node of a renal transplant recipient.
Clin Transplant
2003
, vol. 
17
 
5
(pg. 
451
-
454
)
71
Capello
 
D
Rossi
 
D
Gaidano
 
G
Post-transplant lymphoproliferative disorders: molecular basis of disease histogenesis and pathogenesis.
Hematol Oncol
2005
, vol. 
23
 
2
(pg. 
61
-
67
)
72
Capello
 
D
Cerri
 
M
Muti
 
G
, et al. 
Molecular histogenesis of posttransplantation lymphoproliferative disorders.
Blood
2003
, vol. 
102
 
10
(pg. 
3775
-
3785
)
73
Reshef
 
R
Vardhanabhuti
 
S
Luskin
 
MR
, et al. 
Reduction of immunosuppression as initial therapy for posttransplantation lymphoproliferative disorder.
Am J Transplant
2011
, vol. 
11
 
2
(pg. 
336
-
347
)
74
Nam
 
SJ
Go
 
H
Paik
 
JH
, et al. 
An increase of M2 macrophages predicts poor prognosis in patients with diffuse large B-cell lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.
Leuk Lymphoma
2014
, vol. 
55
 
11
(pg. 
2466
-
2476
)
75
Lee
 
NR
Song
 
EK
Jang
 
KY
, et al. 
Prognostic impact of tumor infiltrating FOXP3 positive regulatory T cells in diffuse large B-cell lymphoma at diagnosis.
Leuk Lymphoma
2008
, vol. 
49
 
2
(pg. 
247
-
256
)
76
Green
 
M
Cacciarelli
 
TV
Mazariegos
 
GV
, et al. 
Serial measurement of Epstein-Barr viral load in peripheral blood in pediatric liver transplant recipients during treatment for posttransplant lymphoproliferative disease.
Transplantation
1998
, vol. 
66
 
12
(pg. 
1641
-
1644
)
77
Lee
 
TC
Savoldo
 
B
Rooney
 
CM
, et al. 
Quantitative EBV viral loads and immunosuppression alterations can decrease PTLD incidence in pediatric liver transplant recipients.
Am J Transplant
2005
, vol. 
5
 
9
(pg. 
2222
-
2228
)
78
Bakker
 
NA
Verschuuren
 
EA
Erasmus
 
ME
, et al. 
Epstein-Barr virus-DNA load monitoring late after lung transplantation: a surrogate marker of the degree of immunosuppression and a safe guide to reduce immunosuppression.
Transplantation
2007
, vol. 
83
 
4
(pg. 
433
-
438
)
79
Choquet
 
S
Varnous
 
S
Deback
 
C
Golmard
 
JL
Leblond
 
V
Adapted treatment of Epstein-Barr virus infection to prevent posttransplant lymphoproliferative disorder after heart transplantation.
Am J Transplant
2014
, vol. 
14
 
4
(pg. 
857
-
866
)
80
Omar
 
H
Hägglund
 
H
Gustafsson-Jernberg
 
A
, et al. 
Targeted monitoring of patients at high risk of post-transplant lymphoproliferative disease by quantitative Epstein-Barr virus polymerase chain reaction.
Transpl Infect Dis
2009
, vol. 
11
 
5
(pg. 
393
-
399
)
81
Merlo
 
A
Turrini
 
R
Dolcetti
 
R
, et al. 
The interplay between Epstein-Barr virus and the immune system: a rationale for adoptive cell therapy of EBV-related disorders.
Haematologica
2010
, vol. 
95
 
10
(pg. 
1769
-
1777
)
82
Icheva
 
V
Kayser
 
S
Wolff
 
D
, et al. 
Adoptive transfer of Epstein-Barr virus (EBV) nuclear antigen 1-specific t cells as treatment for EBV reactivation and lymphoproliferative disorders after allogeneic stem-cell transplantation.
J Clin Oncol
2013
, vol. 
31
 
1
(pg. 
39
-
48
)
83
Papadopoulou
 
A
Gerdemann
 
U
Katari
 
UL
, et al. 
Activity of broad-spectrum T cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT.
Sci Transl Med
2014
, vol. 
6
 
242
pg. 
242ra83
 
84
Haque
 
T
Wilkie
 
GM
Jones
 
MM
, et al. 
Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial.
Blood
2007
, vol. 
110
 
4
(pg. 
1123
-
1131
)
85
Vickers
 
MA
Wilkie
 
GM
Robinson
 
N
, et al. 
Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease.
Br J Haematol
2014
, vol. 
167
 
3
(pg. 
402
-
410
)
86
Xiang
 
Z
Liu
 
Y
Zheng
 
J
, et al. 
Targeted activation of human Vγ9Vδ2-T cells controls Epstein-Barr virus-induced B cell lymphoproliferative disease.
Cancer Cell
2014
, vol. 
26
 
4
(pg. 
565
-
576
)
87
Ricciardelli
 
I
Blundell
 
MP
Brewin
 
J
Thrasher
 
A
Pule
 
M
Amrolia
 
PJ
Towards gene therapy for EBV-associated posttransplant lymphoma with genetically modified EBV-specific cytotoxic T cells.
Blood
2014
, vol. 
124
 
16
(pg. 
2514
-
2522
)
88
Cohen
 
J
Gandhi
 
M
Naik
 
P
, et al. 
Increased incidence of EBV-related disease following paediatric stem cell transplantation with reduced-intensity conditioning.
Br J Haematol
2005
, vol. 
129
 
2
(pg. 
229
-
239
)
89
Meij
 
P
van Esser
 
JW
Niesters
 
HG
, et al. 
Impaired recovery of Epstein-Barr virus (EBV)--specific CD8+ T lymphocytes after partially T-depleted allogeneic stem cell transplantation may identify patients at very high risk for progressive EBV reactivation and lymphoproliferative disease.
Blood
2003
, vol. 
101
 
11
(pg. 
4290
-
4297
)
90
Lee
 
TC
Savoldo
 
B
Barshes
 
NR
, et al. 
Use of cytokine polymorphisms and Epstein-Barr virus viral load to predict development of post-transplant lymphoproliferative disorder in paediatric liver transplant recipients.
Clin Transplant
2006
, vol. 
20
 
3
(pg. 
389
-
393
)
91
Baiocchi
 
OC
Colleoni
 
GW
Caballero
 
OL
, et al. 
Epstein-Barr viral load, interleukin-6 and interleukin-10 levels in post-transplant lymphoproliferative disease: a nested case-control study in a renal transplant cohort.
Leuk Lymphoma
2005
, vol. 
46
 
4
(pg. 
533
-
539
)
92
Muti
 
G
Mancini
 
V
Ravelli
 
E
Morra
 
E
Significance of Epstein-Barr virus (EBV) load and interleukin-10 in post-transplant lymphoproliferative disorders.
Leuk Lymphoma
2005
, vol. 
46
 
10
(pg. 
1397
-
1407
)
93
Schiffer
 
L
Henke-Gendo
 
C
Wilsdorf
 
N
, et al. 
CXCL13 as a novel marker for diagnosis and disease monitoring in pediatric PTLD.
Am J Transplant
2012
, vol. 
12
 
6
(pg. 
1610
-
1617
)
94
Leblond
 
V
Dhedin
 
N
Mamzer Bruneel
 
MF
, et al. 
Identification of prognostic factors in 61 patients with posttransplantation lymphoproliferative disorders.
J Clin Oncol
2001
, vol. 
19
 
3
(pg. 
772
-
778
)
95
Ghobrial
 
IM
Habermann
 
TM
Maurer
 
MJ
, et al. 
Prognostic analysis for survival in adult solid organ transplant recipients with post-transplantation lymphoproliferative disorders.
J Clin Oncol
2005
, vol. 
23
 
30
(pg. 
7574
-
7582
)
96
Hourigan
 
MJ
Doecke
 
J
Mollee
 
PN
, et al. 
A new prognosticator for post-transplant lymphoproliferative disorders after renal transplantation.
Br J Haematol
2008
, vol. 
141
 
6
(pg. 
904
-
907
)
97
Caillard
 
S
Porcher
 
R
Provot
 
F
, et al. 
Post-transplantation lymphoproliferative disorder after kidney transplantation: report of a nationwide French registry and the development of a new prognostic score.
J Clin Oncol
2013
, vol. 
31
 
10
(pg. 
1302
-
1309
)
98
A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project.
N Engl J Med
1993
, vol. 
329
 
14
(pg. 
987
-
994
)
99
Dierickx
 
D
Tousseyn
 
T
Morscio
 
J
Fieuws
 
S
Verhoef
 
G
Validation of prognostic scores in post-transplantation lymphoproliferative disorders.
J Clin Oncol
2013
, vol. 
31
 
27
(pg. 
3443
-
3444
)
100
Trappe
 
RU
Choquet
 
S
Dierickx
 
D
, et al. 
German PTLD Study Group and the European PTLD Network
International prognostic index, type of transplant and response to rituximab are key parameters to tailor treatment in adults with CD20-positive B cell PTLD: clues from the PTLD-1 trial.
Am J Transplant
2015
, vol. 
15
 
4
(pg. 
1091
-
1100
)
101
Vaysberg
 
M
Balatoni
 
CE
Nepomuceno
 
RR
Krams
 
SM
Martinez
 
OM
Rapamycin inhibits proliferation of Epstein-Barr virus-positive B-cell lymphomas through modulation of cell-cycle protein expression.
Transplantation
2007
, vol. 
83
 
8
(pg. 
1114
-
1121
)
102
Furukawa
 
S
Wei
 
L
Krams
 
SM
Esquivel
 
CO
Martinez
 
OM
PI3Kδ inhibition augments the efficacy of rapamycin in suppressing proliferation of Epstein-Barr virus (EBV)+ B cell lymphomas.
Am J Transplant
2013
, vol. 
13
 
8
(pg. 
2035
-
2043
)
103
Vincenti
 
F
Larsen
 
CP
Alberu
 
J
, et al. 
Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients.
Am J Transplant
2012
, vol. 
12
 
1
(pg. 
210
-
217
)

Author notes

*

D.D., T.T., and O.G. contributed equally to this study.