Introduction

Post-transplant lymphoproliferative disorder (PTLD) is a well-known, life-threatening complication after organ transplantation, predominantly following solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). The majority of the cases of PTLD are associated with Epstein-Barr virus (EBV), and it occurs within the first posttransplant year. In the transplant setting, it is essential to consider the timeline following surgery and initiation of immunosuppression when considering infectious complications. High-dose immunosuppression is associated with a higher risk of PTLD. The clinical presentation of PTLD can be highly variable ranging from localized to disseminated disease, and it can imitate benign conditions. Consequently, a high degree of clinical suspicion is critical for early diagnosis and prompt treatment.[1][2][3][4][5]

Etiology

PTLD is a proliferative B-cell disorder that is associated with the Epstein-Barr virus (EBV). It can be acquired either as a result of primary infection (frequently), from the donor or environmental exposure. EBV-negative PTLD occurs in approximately 23% of patients. Solid organ transplant recipients are more commonly affected when compared to recipients of a hematopoietic stem cell transplant.

Epidemiology

The incidence of PTLD is variable, and it depends mainly on the type of organ transplant received, and immunosuppression used. The reported incidence of PTLD is between 2% to 20%, with a greater number of cases in patients who receive a solid organ transplant compared to allogeneic stem cell transplant recipients. The most important risk factors for PTLD include transplantation status (donor EBV-seropositive/recipient EBV-seronegative), ongoing immunosuppressive therapy, duration of immunosuppression, and status of EBV infection. Most described cases of PTLD arise in the setting of Epstein-Barr Virus (EBV) seropositivity and reactivation from latent B-cells, as a consequence of immune-suppression. Primary EBV infection occurs when an EBV-seronegative recipient gets an allograft from an EBV-seropositive donor (D+/R-), is known as the most significant risk factor for developing PTLD. Thus, higher rates of PTLD have been reported in pediatric than adult transplant recipients. A higher rate of PTLD is observed in the patients receiving heart, lung, small bowel transplant, or combined heart-lung transplant. The reason for these differences is partly due to the need for a higher dose of immunosuppression medications to prevent allografts' rejection.

Pathophysiology

The majority of cases of PTLD are caused by EBV that is a herpes virus infecting up to 95% of the adult population. Primary infection with EBV in immunocompetent adult patients usually results in self-limiting illness without significant complications. However, once EBV infection occurs, either the virus remains latent in B-cell lymphocytes by the transformation of the cell expressing partial EBV genome, or it results in viral replication and B-cell lysis. In the immunocompetent patient, B-cell proliferation is controlled by cytotoxic T-cells while in an immunocompromised patient unchecked B-cell activation and continuous proliferation leads to PTLD.

Histopathology

Only a histopathologic analysis of the tumor can determine the definite diagnosis of PTLD. The diagnosis is based on  the World Health Organization (WHO) classification and includes the following 4 main categories:

1. Monomorphic PTLD
2. Polymorphic PTLD
3. Early lesions
4. Classic Hodgkin lymphoma

History and Physical

Clinical manifestations are heterogeneous, non-specific, and highly variable. PTLD can present as a localized or disseminated disease. Malaise, fatigue, fever, and a mononucleosis-like picture are some presenting features of PTLD. B-symptoms of fever, night sweats, and weight loss, as well as lymphadenopathy, are also frequent manifestations. PTLD develops rapidly and may cause compressive symptoms near the tumor site. Patients who are high-risk (EBV IgG Donor+/Recipient-) are generally noted to be at risk for developing PTLD of the transplanted graft causing a decline in organ function. It may be the only presenting symptom. The high index of suspicion for PTLD is necessary given highly variable presentation also rising EBV PCR in post-transplant recipient raises the possibility of PTLD.

Evaluation

Besides a detailed history and physical examination of patients whom PTLD is considered, the investigations include:

1. Complete blood cell count (CBC) to evaluate unexplained anemia, thrombocytopenia or leukopenia
2. Comprehensive chemistry panel
3. Lactate dehydrogenase (LDH) to evaluate for tumor lysis syndrome. 
4. Urine analysis for Monoclonal protein, hyperuricemia
5. EBV Status of recipient and donor
6. Epstein-Barr virus (EBV) testes: EBV IgM, EBV IgG, EBV viral load (PCR). Also, serial EBV quantitative PCR measurement (that is rising) is more important and valuable than single positive EBV quantitative PCR. Negative EBV PCR does not exclude the possibility of PTLD.
7. Radiological studies include computed tomography (CT), magnetic resonance imaging (MRI), and positive positron emission tomography (PET) scanning to evaluate spread.
8. Lumbar puncture with cerebral spinal fluid (CSF) analysis (EBV PCR in CSF fluid) in patients with PTLD with CNS involvement

Histopathologic examination of the tumor can only determine the definitive diagnosis.[6][7][8]

Differential Diagnosis

Given the highly variable presentation of PTLD differential diagnosis should broadly be considered depending upon the patient's clinical presentation. Rejection of allograft organ (in the case of graft involvement), opportunistic infections, and common infectious etiology should be considered in the differential diagnosis.

Prognosis

With the introduction of rituximab, a monoclonal anti-CD20 antibody, and lymphoma-specific treatment regimens the overall prognosis for patients with PTLD has improved. In an international multicenter, open-label trial, sequential treatment with rituximab followed by CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, 53 of 59 patients had a complete or partial response, of which 40 patients had a complete response.[12] Different prognostic scores have been published for PTLD but lack validity given small sample size, heterogeneous patient population, and treatment protocol used. The International Prognostic Index (IPI) is the commonly used prognostic index derived from five variables: age, stage, lactate dehydrogenase level, performance status, and the number of extranodal sites. Retransplantation after treatment of  PTLD is possible but is advised to wait at least one year after treatment for PTLD.[13]

Pearls and Other Issues

PTLD is one of the severe complications of transplantation. The better understanding of the pathophysiology of PTLD, improvements in immunosuppressive strategies for solid organ transplantation, advances in the diagnosis and treatment of PTLD have led to improved clinical outcomes and overall prognosis for patients with PTLD.

Enhancing Healthcare Team Outcomes

The diagnosis and management of PTLD require a multi-professional team of oncologists, radiation specialists, hematologists, surgeons, nurse practitioners, and primary care providers. 

Treatment strategies for PTLD are different from the management of lymphoproliferative disorders in immunocompetent patients. The mainstay of the management strategy includes a reduction in immunosuppression followed by surgical excision of the localized lesion, radiation therapy, rituximab monotherapy, immunochemotherapy, chemotherapy, stem-cell transplantation, and immunotherapy.

The better understanding of the pathophysiology of PTLD, improvements in immunosuppressive strategies for solid organ transplantation, advances in the diagnosis and treatment of PTLD have led to improved clinical outcomes and overall prognosis for patients with PTLD.[14]