Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders

INTRODUCTION — Post-transplant lymphoproliferative disorders (PTLD) are lymphoid and/or plasmacytic proliferations that occur in patients receiving chronic immunosuppression for solid organ transplantation or allogeneic hematopoietic cell transplantation (HCT). PTLDs are among the most serious complications of transplantation.

PTLD comprises a spectrum of lymphoproliferative disorders that includes morphologically benign polyclonal lymphoproliferation; florid follicular hyperplasia; polyclonal or monoclonal polymorphic B cell proliferations; and monoclonal disorders that meet criteria for B cell lymphomas, T cell lymphomas, or Hodgkin lymphoma.

PTLD following solid organ transplantation and allogeneic HCT is reviewed in this topic.

Treatment and prevention of PTLD and the development of other secondary malignancies following transplantation are discussed separately:

●(See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

●(See "Secondary cancers after hematopoietic cell transplantation".)

●(See "Malignancy after solid organ transplantation".)

PATHOGENESIS

EBV-positive disease — In most affected patients, PTLD is an Epstein-Barr virus (EBV)-positive B cell proliferation occurring in the setting of immunosuppression and decreased T cell immune surveillance [1-6]. EBV infection is common in most parts of the world, as approximately 90 to 95 percent of adults show serologic evidence of infection. Acute EBV infection leads to a polyclonal expansion of B cells harboring the virus. In immunocompetent individuals, viral antigens expressed by these B cells elicit a cytotoxic T cell response that eliminates the vast majority of the infected B cells; such a host response is often associated with the clinical syndrome of acute mononucleosis. However, a small subpopulation of the infected B cells downregulates viral antigen expression and escapes immune surveillance. These latently infected B cells persist throughout life and, if T cell immunity wanes, can give rise to lymphoproliferative disorders such as PTLD. (See "Virology of Epstein-Barr virus".)

A number of EBV-encoded proteins drive signaling events that directly contribute to B cell growth and survival. Two membrane proteins, latent membrane protein 1 (LMP-1 [7-9]) and latent membrane protein 2A (LMP-2A [10]), transmit signals that mimic certain aspects of antigen-mediated B cell activation. Mice engineered to express LMP1 in B cells develop a fatal lymphoproliferative disorder if they are depleted of T cells [11]. Two other nuclear EBV proteins, EBNA-2 and EBNA-LP, are transcriptional regulators of host genes, such as MYC, and viral transforming genes, such as LMP-1 and LMP-2A [12,13]. In concert, these and other EBV-encoded factors transform B cells into immortalized lymphoblastoid cells. Polymorphisms within cytokine genes may also contribute to host susceptibility to PTLD [14]. (See "Virology of Epstein-Barr virus".)

The EBV-infected B cells that give rise to PTLD can originate in the host (transplant recipient) or the donor. Following solid organ transplantation, host-derived PTLD is most common [15-18]. As an example, in one study utilizing a polymorphism at the D4S174 locus on chromosome 4, 10 of 11 cases originated from host cells [15]. In solid organ transplant recipients, host-derived PTLD is typically a multisystem disease, while donor-derived PTLD is more commonly limited to the allograft tissue [16,17]. In contrast, PTLD that arises after allogeneic hematopoietic cell transplantation (HCT) is much more commonly donor-derived and typically involves nodal and extranodal sites [6,19].

Solid organ transplant — The role of EBV in the pathogenesis of PTLD among solid organ transplant recipients has been suggested by the identification of EBV in the tumor and by case-control studies. As an example, a study of liver transplant recipients demonstrated EBV-encoded small nuclear RNAs (EBER) in lymphoid cells infiltrating liver biopsies taken to monitor graft rejection in most patients before overt lymphoproliferative disease was documented; this finding was generally absent in controls who did not go on to develop lymphoproliferative disease [4]. (See "Clinical manifestations and treatment of Epstein-Barr virus infection".)

Hematopoietic cell transplant (HCT) — Unlike in solid organ transplant recipients, PTLD in HCT recipients is most commonly donor-derived. In this setting, PTLD is thought to be due to the proliferation of EBV-infected B cells in the absence of normal T cell immune surveillance. If a hematopoietic stem cell donor has been infected with EBV, the donor will have a small number of transformed B cells carrying the virus (approximately one per million B cells). These B cells are "held in check" by cytotoxic T cells, resulting in an equilibrium between cell division and death of EBV-infected B cells.

Methods of treating bone marrow that remove both mature B and T cells (such as soybean lectin depletion) have a lower rate of EBV lymphoproliferative disease after transplantation [20-22]. If, however, mature T cells are depleted from a marrow graft (to reduce the risk of graft-versus-host disease [GVHD]) but B cells are not depleted, then these EBV-transformed B cells may "escape" from cytotoxic T cell surveillance, increasing the likelihood of PTLD.

A retrospective study compared rates of EBV reactivation in 85 EBV-seropositive recipients of a T cell depleted allograft (TCD-HCT) with that of 65 EBV-seropositive recipients of an unmanipulated allograft [21]. Reactivation was observed more frequently in recipients of a TCD-HCT (65 versus 31 percent), and EBV-associated PTLD occurred only in those receiving a TCD-HCT. In addition, high plasma EBV deoxyribonucleic acid (DNA) levels predicted the development of EBV-PTLD.

In addition to the risk imposed by the donor, the transplant recipient is also likely to have been infected with EBV. Ablation of the recipient's immune system prior to transplantation may remove enough cytotoxic cells to allow for proliferation of donor-transformed B cells as well, particularly in the setting of cord blood stem cell transplantation [23]. Profound deficiencies of EBV-specific T cell-mediated immunity have been documented in the early post-transplant period, the period of greatest risk for PTLD [24,25].

EBV-negative disease — EBV-negative PTLD has been documented in up to 30 percent of PTLD in some series [6,26]. The etiology of EBV-negative PTLD has not been elucidated, and gene expression profiling studies suggest that they are biologically distinct from EBV-positive disease [27]. Some may be related to EBV infections that are no longer detectable. Others may be due to unidentified viruses or other causes of chronic antigenic stimulation. As an example, post-transplantation primary effusion lymphoma may be associated with human herpes virus 8 (HHV-8) infection [28-30]. The role of HHV-8 in the pathogenesis of primary effusion lymphoma is discussed in more detail separately. (See "Primary effusion lymphoma", section on 'Pathogenesis'.)

EPIDEMIOLOGY

Incidence — PTLD is the most common malignancy complicating solid organ transplantation (excluding nonmelanoma skin cancer and in situ cervical cancer), accounting for approximately 20 percent of all cancers [31,32]. In contrast, PTLD accounts for a minority of secondary cancers following allogeneic hematopoietic cell transplantation (HCT).

The reported incidence of PTLD varies among transplant centers, likely as a result of different patient populations, allograft types, and immunosuppressive regimens. As will be described in the next section, the risk of PTLD is greatest in patients with marked immunosuppression. This probably explains part of the variability in the incidence of PTLD with different types of transplants. The cumulative incidence over five years ranges from 1 to 2 percent in HCT and liver transplants, 1 to 3 percent in renal transplants, 2 to 6 percent in heart transplants, 2 to 9 percent in lung transplants, and 11 to 33 percent in intestinal or multiorgan transplants [33-44]. More than 80 percent of PTLD occur in the first year after transplantation. (See "Malignancy after solid organ transplantation".)

Risk factors — The principal risk factors underlying the development of PTLD are the degree of T cell immunosuppression and the Epstein-Barr virus (EBV) serologic status of the recipient. Additional risk factors include time post-transplant, recipient age, and ethnicity [45,46].

Degree of immunosuppression — The degree of immunosuppression has long been considered a major determinant of the development of PTLD [6,31]. In particular, the degree of T cell immunosuppression appears to be more important than the degree of immunosuppression overall, due to the impairment of EBV-specific T cell-mediated immunity [24]. EBV-infected B cells are thought to be normally "held in check" by cytotoxic T cells. This defense mechanism is lost when T cell function is impaired, promoting the development of PTLD. (See 'EBV-positive disease' above.)

Initial studies in solid organ transplant demonstrated that the risk of developing PTLD increased with the degree of immunosuppression, particularly among pediatric patients and those exposed to certain types of induction therapy [37,38,41,47-52] or prolonged high doses of tacrolimus [50,53-55]. As examples:

●The following observations were noted in a study of over 50,000 kidney and heart transplants from centers in the Europe and North America [37]:

•The incidence of PTLD was highest in the first year after transplantation, the time of most intense immunosuppression, and fell by approximately 80 percent thereafter (figure 1). Similar observations have been made in other studies [34,42].

•The incidence of PTLD was much greater in heart transplant recipients (figure 1) in whom a greater degree of immunosuppression is required because of the more serious consequences of transplant rejection.

•Among patients who developed PTLD, renal transplant recipients were much more likely to have renal lymphoma (14.2 versus 0.7 percent in heart transplant recipients), while heart transplant recipients were more likely to develop lymphoma in the heart or especially the lungs (17.9 versus 6.8 percent in renal transplant recipients). In another report of nine lung transplant recipients with PTLD, eight had isolated intrathoracic disease [56]. These findings suggest that the microenvironment of the allograft interferes with T cell surveillance, promoting the outgrowth of B cells transformed by EBV.

●In a study of more than 41,000 recipients of a deceased donor first kidney transplant, induction therapy, including polyclonal and monoclonal antibody therapy, was associated with an increased risk of PTLD (relative risk [RR] of 1.78) [49]. With respect to tacrolimus versus cyclosporine for maintenance therapy but without induction therapy, the risk of PTLD was significantly higher among those administered tacrolimus (RR of 2.03); if induction therapy was given, there was a nonsignificant trend toward a higher risk with tacrolimus.

This hypothesis that heightened overall immunosuppression increases the risk of malignancy was challenged by the results from two clinical trials of belatacept (an anti-CTLA4 antibody) and efalizumab (an anti-lymphocyte functioning antigen-1 antibody) that demonstrated an increase in the likelihood of PTLD despite relatively low efficacy for the prevention of graft rejection [57-60]. Additional data have emerged demonstrating that the risk of PTLD varies depending on the agents used for immunosuppression. In general, agents that suppress T cell activity appear to be associated with an increased risk of PTLD. In one retrospective study of over 100,000 kidney transplant recipients, for example, the incidence ratio of PTLD, compared with the non-transplant population, was 21.5, 4.9, 29.0, 21.6, and 7.8 for those administered induction therapy with OKT3, ATG, ATGAM, Thymoglobulin, and interleukin-2 receptor antagonists, respectively [51]. ATG has also been associated with an increased risk for PTLD among allogeneic HCT recipients [33,61].

Among patients induced and maintained with OKT3, both the dose and the duration of therapy are important [47]. In one series of cardiac transplant recipients, for example, the incidence was 11 percent in those treated with OKT3 for induction and 36 percent (5 of 14) in patients who received more than 75 mg of OKT3 [41]. For these reasons, OKT3 is not currently used very often for induction therapy.

By comparison, the use of mycophenolate mofetil or alemtuzumab (an anti-CD52 antibody) may not be associated with an increased risk of PTLD. A case-control study using a matched multivariate analysis reported that the risk for PTLD was similar in kidney transplant recipients treated with triple immunosuppressive therapy with or without mycophenolate [62]. Similarly, a registry analysis of alemtuzumab showed that it was not associated with as high a rate of PTLD as other lymphocyte-depleting agents [63]. It is not clear whether the use of rituximab (an anti-CD20 antibody) in the peritransplant period significantly reduces the subsequent incidence of PTLD [64].

EBV serostatus — There is an increased risk of PTLD among EBV-negative recipients of EBV-positive donor organs. As an example, risk factors for the development of PTLD were assessed in a series of 381 consecutive adult nonrenal transplant recipients seen at the Mayo Clinic [65]. In the absence of the use of OKT3 and cytomegalovirus (CMV) seromismatch (ie, a negative recipient and a positive donor), the incidence rate of PTLD for EBV-seronegative recipients was 24 times higher than that for EBV-seropositive recipients. These patients, who had no preoperative immunity to EBV, usually acquired the infection post-transplant from the donor (approximately 85 percent of whom are EBV-positive). Similar observations have been made in other reports [42,48,66]. As an example, upon multivariate analysis in a retrospective study of 276 pediatric kidney transplant recipients, risk factors for PTLD included EBV donor positive/recipient negative status (hazard ratio [HR] 7.7, 95% CI 1.6-35.9) and age less than five years (HR 3.2, 95% CI 1.1-9.6) [48]. As previously mentioned, PTLD may be more common in children, because a higher percentage of children is EBV-seronegative prior to transplantation [48,67].

Others — Some additional risk factors for PTLD include a history of pretransplant malignancy and fewer HLA matches. In a retrospective analysis of over 25,000 patients, for example, an increased risk was associated with pretransplant malignancy (HR 3.54), fewer HLA matches (HR 1.32), younger age (HR 1.91), and treatment with ATG (HR 1.55) [68]. However, specific HLA loci mismatches may confer greater risk. In a single center study of 1013 kidney transplant recipients, one mismatch at HLA-B was associated with a hazard ratio of 1.4 and two HLA-B mismatches with a hazard ratio of 5.1 for PTLD [69]. Mismatches at HLA-A and HLA-DR were not independently associated with an increased hazard ratio.

The risk of PTLD also varies with time post-transplant. This was shown in a retrospective analysis of nearly 90,000 patients placed on the renal transplant wait list over a 10-year period, of which 357 cases of lymphoma developed in transplant recipients [46]. The highest lymphoma rate was observed during the first-year post-transplant. An increased risk was also noted in those under 25 years of age and in White populations.

A combination of risk factors markedly enhances the overall risk of PTLD. In the Mayo Clinic series, for example, therapy with OKT3 for rejection and CMV seromismatch (ie, a negative recipient and a positive donor) further increased the risk four- to sixfold above that seen in EBV-seronegative recipients [65]. The presence of all three risk factors increased the incidence rate of fatal and/or central nervous system PTLD by a factor of 654, compared with patients lacking all three factors [65].

Risk factors among HCT recipients — While many risk factors for PTLD are the same among recipients of solid organ transplant and HCT, there are a few risk factors, such as the source of stem cells, specific for HCT recipients.

The risk of PTLD was assessed in 18,014 bone marrow transplant recipients at 235 centers [33]. The cumulative incidence was 1 percent at 10 years, with 82 percent occurring in the first year and the risk being highest at one to five months post-transplant followed by a steep decline (120 versus 5 cases per 10,000 patients per year among survivors for more than one year). The major risk factors for early PTLD in this study were:

●An unrelated or HLA-mismatched related donor (RR 4.1)

●T cell depletion of donor marrow (RR 12.7), particularly if natural killer cells were also removed

●Administration of antithymocyte globulin (ATG, RR 6.4) or anti-CD3 antibodies (RR 43) for prophylaxis or treatment of acute graft-versus-host disease

●Chronic graft-versus-host disease was the major risk factor for late onset PTLD

The risk imposed by these factors was additive. The rate of PTLD increased from 8 percent in patients with two major risk factors, to 22 percent in patients with three or more risk factors.

In a similar study, PTLD occurred in 127 of 26,901 patients (0.47 percent) who underwent allogeneic HCT, with 83 percent of the cases occurring within one year following transplantation [61]. Risk factors for development of PTLD included selective T cell depletion, treatment with ATG, unrelated donor or HLA-mismatched donor accompanied by either selective T cell depletion or ATG therapy, and age ≥50 at the time of HCT. The incidences of PTLD were 0.2, 1.1, 3.6, and 8.1 percent for those with zero, one, two, or ≥3 risk factors, respectively.

The source of stem cells may affect the risk of PTLD development. To date there has been little suggestion that the use of T cell replete bone marrow versus peripheral blood progenitor cells affects the risk of second malignancies following transplantation. In contrast, the risk of PTLD may be increased among recipients of umbilical cord blood transplantations. One report using double umbilical cord blood transplantation found 18 second malignancies in 98 patients (18 percent) at a median of 134 days after transplantation [19]. Of the patients who developed a second malignancy, 16 had EBV-associated PTLD.

CLINICAL MANIFESTATIONS

Signs and symptoms — The clinical presentation of patients with PTLD is highly variable and depends at least partially upon the type of PTLD and the areas of involvement. Non-specific constitutional symptoms such as fever, weight loss, and fatigue are common. Other symptoms may be related to viral infection, lymphadenopathy, dysfunction of involved organs, or compression of surrounding structures. Viral symptoms can resemble those seen in acute infectious mononucleosis. (See "Infectious mononucleosis", section on 'Clinical manifestations' and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Clinical presentation'.)

More than half of PTLD presents with extranodal masses [70]. Involved organs include the gastrointestinal tract (stomach, intestine), lungs, skin, liver, central nervous system, and the allograft itself. More specifically, 20 to 25 percent have central nervous system disease (which is rare in the general population), and a similar proportion have infiltrative lesions in the allograft [71]. Involvement of the allograft can lead to allograft dysfunction, including renal failure, heart failure, and respiratory dysfunction [56,72-75].

The clinical manifestations and course of PTLD appear to vary with the origin of the lymphoproliferative cells [16,17]. In one report of 12 renal transplant recipients, lymphoproliferative cells arose from the transplant recipient in eight patients, while lymphoproliferative cells were from the donor in four patients [16]. Recipient-origin PTLD presented as multisystem disease at a mean of 76 months after transplantation; five of the eight patients with disease from the recipient died. In contrast, donor-origin PTLD was limited to the allograft, developed after a mean of five months after transplantation, and regressed after reduction of immunosuppression.

Epstein-Barr virus (EBV)-negative PTLD appears to differ clinically from EBV-related tumors [26,76,77]. In one study, the clinical presentation and survival of 11 transplant recipients with B cell lymphomas not due to EBV were compared with those of 21 patients with EBV-associated lymphomas [26]. Tumors not due to EBV presented much later (6.4 versus 1.5 years post-transplantation), suggesting that their incidence may increase with time. In addition, EBV-negative tumors were much more aggressive (median survival of 1 versus 37 months).

Measurement of EBV viral load — While many transplant recipients demonstrate a modestly increased EBV viral load in the peripheral blood post-transplant, the vast majority of patients with EBV-positive PTLD will demonstrate a more marked elevation in the EBV viral load. As an example, in one study, plasma from patients with PTLD had a median EBV viral load of 3225 copies/100 microL, while immunosuppressed controls without evidence of PTLD had fewer than 740 copies/100 microL [78]. This observation has led to the suggestion that PTLD may be detected early by monitoring the EBV viral load by quantitative polymerase chain reaction (PCR) of unfractionated whole blood, plasma, or peripheral blood mononuclear cells of patients at high risk of developing this complication [78-81]. While an increased EBV viral load is suggestive of PTLD, the diagnosis of PTLD is based on the histologic evaluation of a tissue biopsy. Similarly, while the absence of EBV in the peripheral blood makes PTLD less likely, it does not completely exclude the diagnosis [82,83]. (See 'Diagnosis and classification' below.)

Many transplant centers have incorporated EBV monitoring into the routine evaluation of patients at high risk for PTLD. Centers differ with regards to their definition of high-risk patients and the cutoff used to determine EBV positivity. Due to the use of different methods, EBV viral load measurements cannot be compared between institutions. The optimal primer set, the relative importance of intracellular versus free plasma EBV, and the baseline profile in an organ transplant population remain to be established [81].

Since the vast majority of EBV-positive PTLD occurs in the first year after transplantation, it is reasonable to monitor high-risk patients more frequently during the initial post-transplant period and to increase the time span between samples as the time from transplantation increases. The decision to monitor less frequently must be individualized and take into consideration many factors including the type of graft, the degree of ongoing immunosuppression, and the pattern of EBV viral loads to date. Monitoring for an uncomplicated hematopoietic cell transplantation (HCT) recipient may begin with screening on the day of transplantation, weekly monitoring for the first three months, followed by monthly monitoring for at least one year [84]. In contrast, monitoring for an uncomplicated kidney transplant recipient may begin with screening within the first week after transplant followed by monthly monitoring for the next three to six months and then every three months for the rest of the first year [85].

It may be possible to predict the development of PTLD and monitor response to treatment using PCR to detect and quantify serial changes in EBV-DNA levels in plasma or peripheral blood mononuclear cells [21,78,86-92]. Often, quantitative PCR is more useful in ruling out than in indicating the presence of PTLD. As examples:

●The ability of EBV viral load in peripheral blood monocytes to reflect the development of EBV-associated PTLD was prospectively evaluated in 85 allogeneic HCT recipients, five of whom developed EBV-associated PTLD [92]. Using an EBV viral load threshold of >300 copies/microgram DNA, the manifestation of at least one positive EBV viral load demonstrated a sensitivity, specificity, positive, and negative predictive value for the diagnosis of EBV-associated PTLD of 100, 81, 25, and 100 percent, respectively.

●In a study of 13 patients with EBV-lymphoproliferative disease following allogeneic HCT, all of the clinical responders showed decreased levels of EBV-DNA within 72 hours of initiation of treatment [86]. In contrast, all of the six non-responders showed an increase in EBV-DNA at 72 hours.

Society guidelines differ in their recommendations regarding EBV surveillance following transplant. Some recommend EBV monitoring for all transplant recipients [84,85,93,94], while others limit its use to children or adults who have received HCT [95].

Abnormal laboratory results — Similar to non-transplant patients with lymphoproliferative disorders, the following abnormal laboratory studies may be seen in patients with PTLD:

●Unexplained anemia, thrombocytopenia, or leukopenia

●Elevated level of serum lactate dehydrogenase (LDH)

●Hypercalcemia

●Hyperuricemia

●Monoclonal protein in the serum or urine

These are discussed in more detail separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Abnormal laboratory results'.)

Monitoring for the presence of a persistent monoclonal protein in the serum or urine may serve as a useful, inexpensive, and noninvasive screen for the presence, or future development, of PTLD [96-98]. In one study of 201 patients undergoing liver transplantation, a monoclonal protein was seen in five of the seven patients (71 percent) who developed PTLD and in 52 of the 194 patients (27 percent) who did not have this complication [96].

In a study of 911 consecutive patients undergoing liver transplantation, a monoclonal protein was present in 18 of the 21 patients who developed PTLD [98]. Remission, which occurred in 13 patients, was associated with disappearance of gammopathy in 10. For the diagnosis of remission of PTLD, the positive and negative predictive values of disappearance of gammopathy were 91 and 100 percent, respectively.

PATHOLOGIC FEATURES — Histologic, immunophenotypic, and genetic features of the biopsy specimen are required for diagnosis and classification of PTLDs.

PTLD categories are [6]:

●Plasmacytic hyperplasia and infectious mononucleosis-like PTLD

●Florid follicular hyperplasia

●Polymorphic PTLD

●Monomorphic PTLD

●Classic Hodgkin lymphoma-like PTLD

The pathologic features of each of these entities are described in the following sections.

Consensus statements and published guidelines have recognized limitations regarding the reliance on histologic descriptions of PTLD [85,95,99-101]. The intrinsic weaknesses in relying on histologic classification alone stem from the failure to consider the following important variables:

●Clonality (ie, polyclonal versus monoclonal)

●Genetic or cytogenetic features (eg, as DNA rearrangements, mutations)

●Presence of Epstein-Barr virus (EBV) in the specimen

●Origin of the tumor (ie, transplant recipient versus donor)

Benign polyclonal lymphoproliferation (early lesions) — Early PTLD lesions exhibit plasmacytic hyperplasia and infectious mononucleosis-like features [6]. The B lymphoid cells in these lesions are polyclonal and the architecture of the involved tissue is preserved. Histology may be consistent with reactive follicular hyperplasia. In such cases, discrete follicles of varying sizes and shapes are separated from one another by interfollicular regions rich in T cells. Tingible body (debris-laden) macrophages may be prominent. The polyclonal B cell proliferation has normal cytogenetics. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Reactive follicular hyperplasia'.)

Florid follicular hyperplasia — Florid follicular hyperplasia demonstrates polyclonal B cells and admixed T cells in which hyperplastic germinal centers are apparent and the architecture of the lymph node is preserved [6]. Florid follicular hyperplasia PTLD is variably positive for EBV. Rarely, simple cytogenetic abnormalities or very small monoclonal populations of B cells may be observed.

Polymorphic PTLD — Polymorphic PTLD demonstrates effacement of tissue architecture by a pleomorphic lymphoid infiltrate that does not fulfill the criteria for one of the B cell or T/NK cell lymphomas recognized in immunocompetent patients [6]. The infiltrate is composed of polyclonal or monoclonal cells all along the spectrum of B cell maturation and includes immunoblasts, plasma cells, and small- and intermediate-sized lymphoid cells. The tumor cells infiltrate and disrupt the underlying tissue and may undergo geographic necrosis. Immunophenotypically, the B cells may demonstrate kappa or lambda light chain class restriction, and upon genetic testing, the tumors have clonal immunoglobulin gene rearrangements. In addition, the tumor cells in polymorphic PTLD usually contain EBV, typically demonstrated with in situ hybridization for EBV-encoded small nuclear RNAs (EBERs).

Monomorphic PTLD — Monomorphic PTLD is a heterogeneous group of tumors composed of monoclonal malignant cells of B cell or T cell origin [6]. Histology demonstrates effacement of the normal tissue architecture by a lymphoid infiltrate. These tumors must fulfill the criteria for one of the B cell or T/NK cell lymphomas recognized in immunocompetent patients. Of importance, small B cell lymphoid neoplasms (eg, follicular lymphomas, small lymphocytic lymphoma) and marginal zone (MALT) lymphomas arising in the post-transplant setting are not considered PTLD. Despite the use of the term "monomorphic," cases of monomorphic PTLD may demonstrate significant variability in tumor cell size and morphology. The degree of pleomorphism is consistent with that seen in the corresponding lymphoma subtype in the immunocompetent host.

Monomorphic PTLD is further classified according to the subtype of lymphoma. The vast majority of these tumors are B cell lymphomas, most commonly diffuse large B cell lymphoma (DLBCL) and less commonly Burkitt lymphoma (BL) or a plasma cell neoplasm (eg, myeloma or extramedullary plasmacytoma) [102-105]. Lymphomas of T cell [106-111] or NK cell [108] origin are uncommon [112], but, when seen, are usually classified as peripheral T cell lymphoma, not otherwise specified (PTCL, NOS), or EBV+ T/NK cell lymphoma. Very few cases of T cell PTLD have been reported in kidney transplant recipients [110]. The diagnosis of each of these lymphoma subtypes is described briefly below and presented in more detail separately.

●Diffuse large B cell lymphoma – DLBCL is a heterogeneous group of tumors consisting of large, transformed B cells with prominent nucleoli and basophilic cytoplasm, a diffuse growth pattern and a high proliferation fraction (picture 1). Tumor cells express pan-B cell antigens. No single cytogenetic change is typical or diagnostic. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Pathology'.)

●Burkitt lymphoma – BL tumor cells are monomorphic, medium-sized cells with round nuclei, multiple nucleoli, and basophilic cytoplasm, often with prominent cytoplasmic lipid vacuoles (picture 2). There is an extremely high rate of proliferation. BL cells express surface IgM and B cell-associated antigens, as well as CD10. They lack CD5 and BCL-2. A high fraction of BL is associated with chromosomal translocations involving MYC on chromosome 8q24 and one of the three Ig loci, producing either t(8;14), t(2;8), or t(8;22). (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma", section on 'Pathology'.)

●Plasma cell neoplasm – The tumor cells of plasma cell neoplasms can resemble mature or immature plasma cells. Mature plasma cells are oval with abundant basophilic cytoplasm, a round eccentrically located nucleus, a perinuclear clearing (a hof) due to a prominent Golgi apparatus, and a "clock-face" chromatin pattern without nucleoli (picture 3). Immature plasma cells have dispersed nuclear chromatin, prominent nucleoli and a high nuclear to cytoplasmic ratio. The cytoplasm of plasma cell neoplasms contains either kappa or lambda light chains, but not both; surface immunoglobulin is absent. The tumor cells usually express CD79a, CD138, and CD38, and may express CD56. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Morphology and immunophenotype'.)

●Peripheral T cell lymphoma, not otherwise specified – PTCL, NOS are usually composed of variable mixtures of small, intermediate, and large atypical cells. The immunophenotype varies greatly from case to case, but always demonstrates expression of one or more of the pan-T antigens. Roughly one-half of cases have an aberrant immunophenotype, defined by the loss of a pan-T cell antigen that is expressed by most normal mature T cells (eg, CD5 or CD7). (See "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified", section on 'Pathology'.)

Classic Hodgkin lymphoma-like PTLD — Classic Hodgkin lymphoma-like PTLD is the least common form of PTLD. Biopsy of involved tissue should fulfill the criteria required for the diagnosis of classic HL [6]. On light microscopy, the tumor contains a minority of neoplastic cells (Reed-Sternberg cells and their variants) in an inflammatory background. The neoplastic cells typically express CD15 and CD30, variably express CD20, and do not express CD3 or CD45 (table 1).

EVALUATION

General — An accurate diagnosis of PTLD requires a high index of suspicion, since the disorder may present subtly and/or extranodally [113]. The diagnosis of PTLD should be suspected in a patient who has undergone allogeneic transplantation presenting with adenopathy, B symptoms (fever, weight loss, night sweats), unexplained hematologic or biochemical abnormalities, and/or signs or symptoms attributable to the infiltration of extralymphatic tissues. PTLD may also cause symptoms similar to those seen with organ rejection or similar to side effects from immunosuppressive medications. The initial evaluation is based on the presenting symptoms and is similar to that used in the evaluation of suspected lymphoma in the non-transplant population. This is discussed in more detail separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'History'.)

Radiologic evidence of a mass or the presence of elevated serum markers (such as increased lactate dehydrogenase [LDH] levels) is suggestive of PTLD, with positive positron emission tomography (PET) scanning (possibly indicating metabolically active areas) also favoring the diagnosis [114,115]. A rising Epstein-Barr virus (EBV) viral load also supports the diagnosis. Diagnosis and classification requires a tissue biopsy, preferably an excisional biopsy of sufficient size to ensure full characterization of the lesion [99]. Biopsy tissue should be reviewed by an expert hematopathologist and evaluated by morphology, immunophenotype, the presence or absence of EBV, cytogenetics, and antigen receptor gene rearrangement studies [95].

Central nervous system lymphoma — Primary central nervous system PTLD is uncommon and the diagnosis and treatment are difficult [116]. The diagnosis should be suspected in transplant recipients with mental status changes or new neurologic findings. Diagnostic tests include gadolinium-enhanced magnetic resonance imaging (MRI) of the head; analysis of cerebral spinal fluid (CSF) by cytology, flow cytometry, and for EBV genes by polymerase chain reaction (PCR); and assessment of circulating EBV load in plasma or white blood cells.

An MRI study with gadolinium enhancing lesions, a positive analysis of the spinal fluid for EBV by PCR, and an increased EBV load in the peripheral blood are highly suggestive of this diagnosis.

However, the diagnosis should be confirmed either by the presence of malignant lymphocytes in the CSF or by direct biopsy of the lesion [116]. Use of glucocorticoids, which may be unavoidable in the post-transplant setting, may confound such testing, as these agents are lymphocytotoxic and are known to alter proper radiologic and histopathologic evaluation. (See "Primary central nervous system lymphoma: Clinical features, diagnosis, and extent of disease evaluation", section on 'Diagnosis'.)

Cardiac lymphoma — Confirming the presence of cardiac lymphoma in heart transplant recipients is similarly difficult; the diagnosis is frequently established on postmortem examination [117]. Historically, it was first made pre-mortem in endomyocardial biopsies in which the EBV genome was demonstrated in the lymphoid infiltrates [118,119]; in the current era, the diagnostic test of choice is in situ hybridization for EBV-encoded small nuclear RNAs (EBER). (See "Cardiac tumors".)

DIAGNOSIS AND CLASSIFICATION — PTLD should be suspected in a patient who is receiving immunosuppression for a solid organ transplant or hematopoietic cell transplantation (HCT) who develops unexplained constitutional symptoms (eg, fevers, sweats, weight loss), lymphadenopathy, organ dysfunction, or compression of surrounding structures.

An adequate biopsy specimen is required for the evaluation of cellular morphology, tissue architecture, clonality, immunoglobulin gene rearrangements, and Epstein-Barr virus (EBV) status, as described above. (See 'Pathologic features' above.)

Diagnosis — Diagnosis of a neoplastic form of PTLD should have the following characteristics:

●Disruption of underlying tissue architecture by a lymphoid proliferation

●Presence of mono- or oligoclonal lymphoid cell populations, as determined by immunoglobulin light chain expression and antigen receptor gene rearrangements

There are two contemporary classification schemes for hematopoietic neoplasms:

●International Consensus Classification (ICC) – The ICC retains PTLD as a distinct subgroup within the category of Immunodeficiency-associated lymphoproliferative disorders [120]. Diagnosis and categorization are unchanged from the World Health Organization revised 4^th edition (WHO4R) [6].

●World Health Organization 5^th edition (WHO5) – WHO5 applies the same diagnostic criteria as WHO4R and ICC. However, WHO5 has categorized PTLD differently, as described below. (See 'Classification' below.)

ICC [120] and WHO5 [121] apply the same diagnostic criteria, which are unchanged from those in WHO4R [6]. (See 'Classification' below.)

Classification — The ICC, WHO5, and WHO4R have the same categories of PTLD, but WHO5 groups them differently; WHO5 groups the various categories of PTLD with other forms of immune deficiency/dysregulation (IDD).

Following are the categories of PTLD:

●Non-destructive PTLD

•Plasmacytic hyperplasia PTLD

•Infectious mononucleosis PTLD

•Florid follicular hyperplasia PTLD

●Polymorphic PTLD – Does not meet criteria for one of the B cell or T/NK cell lymphomas (see 'Polymorphic PTLD' above)

●Monomorphic PTLD – Meets criteria for a non-Hodgkin B cell or T/NK cell lymphoma (see 'Monomorphic PTLD' above)(B- and T/NK-cell types classified according to the lymphoma to which they correspond)

●Classic Hodgkin lymphoma PTLD – Meets criteria for and is classified according classic Hodgkin lymphoma (see 'Classic Hodgkin lymphoma-like PTLD' above)

In WHO5, PTLD subtypes are grouped with other forms of immune deficiency/dysregulation (IDD). As a result:

●Non-destructive PTLD (plasmacytic hyperplasia PTLD, infectious mononucleosis PTLD, florid follicular PTLD are grouped with hyperplasias)

●Polymorphic PTLD is grouped with other polymorphic lymphoproliferative disorders

●Monomorphic PTLD and classic Hodgkin lymphoma PTLD are grouped with other lymphomas

The following forms of PTLD are identified by ICC:

Small B cell lymphoid neoplasms (eg, follicular lymphomas, small lymphocytic lymphoma) and marginal zone (MALT) lymphomas arising in the post-transplant setting are not considered PTLD.

Many transplant centers incorporate EBV monitoring into the routine evaluation of patients at high risk for PTLD so that patients can be considered for pre-emptive management of PTLD at the time of viral reactivation before overt emergence of PTLD. This is discussed in more detail separately. (See "Treatment and prevention of post-transplant lymphoproliferative disorders", section on 'Preemptive treatment of viral reactivation'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of PTLD includes other disorders with a similar presentation. As described above, most patients present with unexplained fever, drenching night sweats, or weight loss (systemic B symptoms). These symptoms can also be seen in various opportunistic infections, such as disseminated mycobacterial or fungal infections. Patients with systemic symptoms should have blood cultures drawn to rule out disseminated bacterial, mycobacterial, and fungal infections; lumbar puncture as clinically indicated; and those with pulmonary symptoms should have sputum evaluated for acid fast bacilli, Pneumocystis carinii (jirovecii) pneumonia, and fungal infections. (See "Overview of infections following hematopoietic cell transplantation" and "Infection in the solid organ transplant recipient".)

Among solid organ transplant recipients, PTLD involving the allograft may have pathologic features that morphologically resemble those seen with graft rejection. Since the treatment options for rejection and PTLD are markedly different, additional studies must be performed to differentiate the two possibilities. Particularly informative studies include immunophenotyping for B and T cell antigens, including kappa and lambda light chains, polymerase chain reaction studies for antigen receptor gene rearrangements, in situ hybridization for Epstein-Barr virus (EBV)-encoded small nuclear RNAs (EBERs), and serum and urine protein electrophoresis. Imaging studies should include the graft, abdomen, pelvis, and any other clinically relevant areas. This is discussed in more detail separately. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection", section on 'Differential diagnosis'.)

SUMMARY

●Description – Post-transplant lymphoproliferative disorders (PTLD) comprise a spectrum of disorders that arise in patients receiving chronic immunosuppression for solid organ transplantation or hematopoietic cell transplantation (HCT).

PTLD comprises a spectrum of lymphoproliferative conditions that range from morphologically benign polyclonal lymphoproliferation; florid follicular hyperplasia; polyclonal or monoclonal polymorphic B cell proliferations; and monoclonal disorders that meet criteria for B cell lymphomas, T cell lymphomas, or Hodgkin lymphoma.

●Pathogenesis – PTLD is caused by immunosuppression and decreased T cell immune surveillance in transplant recipients. (See 'Pathogenesis' above.)

•EBV-positive PTLD – Most cases of PTLD are caused by Epstein-Barr virus (EBV)-positive B cell proliferation. Latent infection of B lymphocytes can persist throughout life; if T cell immunity wanes, these cells can give rise to PTLD. The tumor cells can originate with EBV-infected cells from the transplant recipient or from the transplant donor. (See 'EBV-positive disease' above.)

•EBV-negative PTLD – Up to one-third of cases are EBV-negative, but the cause of such cases is not well defined. (See 'EBV-negative disease' above.)

●Epidemiology – The incidence is approximately 1 percent in the transplant population, but this varies with the type of allograft. The incidence is lowest among HCT, renal, and liver transplants, higher among heart and lung transplants, and highest among intestinal and multiorgan transplants. (See 'Epidemiology' above.)

●Risk factors – The degree of immunosuppression and EBV serostatus of the recipient are important risk factors for PTLD. (See 'Risk factors' above.)

●Presentation – Clinical manifestations are highly variable and depend on the type of PTLD and areas of involvement. Presentation may include constitutional symptoms (eg, fever, weight loss, fatigue), lymphadenopathy, organ dysfunction, or compression of surrounding structures. Most patients present with extranodal masses (eg, gastrointestinal tract, lungs, skin, liver, central nervous system, and/or the allograft). (See 'Clinical manifestations' above.)

●Pathology – PTLD includes morphologically benign polyclonal lymphoproliferation, florid follicular hyperplasia, polyclonal or monoclonal polymorphic B cell proliferations with some features of malignant lymphoma, and monoclonal disorders (often with clonal cytogenetic abnormalities) that meet criteria for various types of lymphoma. (See 'Pathologic features' above.)

●Evaluation – Evaluation includes clinical and laboratory studies and imaging (eg, positive positron emission tomography and/or computed tomography). (See 'Evaluation' above.)

●Diagnosis and classification – PTLD should be suspected in a patient who is receiving immunosuppression for a solid organ transplant or HCT who develops unexplained constitutional symptoms, lymphadenopathy, organ dysfunction, or compression of surrounding structures.

Diagnosis and classification require pathologic confirmation with an excisional biopsy, which should be reviewed by an expert hematopathologist. (See 'Diagnosis and classification' above.)

●Differential diagnosis – Includes other disorders that cause constitutional symptoms or tumor masses in immunosuppressed patients, including viral, bacterial, and opportunistic infections (eg, disseminated mycobacterial or fungal infections) and graft rejection. (See 'Differential diagnosis' above.)