Transplantation Posttransplantation Lymphoproliferative Disorders


Article Author:
Hrishikesh Samant


Article Editor:
Jiten Kothadia


Editors In Chief:
Jessica Snowden
Asif Noor
H Davies


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
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John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
7/1/2019 10:18:46 AM

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 higher the 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 attention is crucial to the clinician for early diagnosis and prompt treatment.[1][2][3][4][5]

Etiology

PTLD is a proliferative B-cell disorder that is associated with 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 regimen, 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 recipient. There are higher rates of PTLD observed in the patients receiving heart, lung, small bowel transplant, or combined heart-lung transplant. The reason for these differences is partly due to an increased need for excessive immunosuppression medication 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 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 such as PTLD it causes B-cell activation and continuous proliferation.

Histopathology

Only 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 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 growth. Patients who are high-risk (D+/R-) 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 the involved area.
  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]

Treatment / Management

Treatment strategies for PTLD are different from the management of lymphoproliferative disorders in immunocompetent patients. The mainstay of the management strategy includes reduction of immunosuppression, surgical excision of the localized lesion, radiation therapy, rituximab monotherapy, immunochemotherapy, chemotherapy, stem-cell transplantation, and immunotherapy.[9][10][11]

Reduction of Immunosuppression

The initial management of PTLD is to reduce immunosuppression to restore cellular immunity without compromising allograft function. Reduction of the immunosuppression strategy should include at least 50% reduction calcineurin inhibitors (cyclosporine or tacrolimus) and discontinuation of antimetabolic agents such as azathioprine or mycophenolate mofetil (MMF).

Rituximab

Rituximab is a monoclonal anti-CD20 antibody is a standard of care in patients that do not respond adequately to reduced Immunosuppression. Rituximab can be administered as a single agent after reduction of immunosuppression medications or in combination with chemotherapy (concurrently or sequentially). In the PTLD-1 study, the complete treatment response the rate was around 25%  after standard induction plus four courses of rituximab every 21 days. The primary side effects of rituximab include infusion reactions and increased risk of infections due to neutropenia. Also increased risk of hepatitis B reactivation in patients with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc) should be kept in mind. 

Chemoimmunotherapy

Chemotherapy is indicated in patients who have not had an adequate response to reduced immunosuppression and rituximab. It is usually administered in combination with rituximab for patients with CD20+ PTLD.  R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is commonly used in chemotherapy regimen for most patients with PTLD.

Radiation Therapy

Radiation therapy is used for the patients with localized disease and those with central nervous system (CNS) involvement either alone or in combination.

Adoptive Immunotherapy

This uses EBV-specific cytotoxic T lymphocytes (EBV-CTLs) or donor lymphocyte infusion (DLI) to induce a robust EBV-specific cellular immune response in patients with EBV-associated PTLD.  However, the adoptive immunotherapy is associated with high risk of developing acute and chronic graft-versus-host disease (GVHD).

Differential Diagnosis

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

Prognosis

With the introduction of rituximab, a monoclonal anti-CD20 antibody and lymphoma-specific treatment regimens have improved overall prognosis for patients with PTLD. In a clinical trial, the sequential treatment with rituximab followed by CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy in the patients with PTLD showed the median overall survival of 6.6 years in 70% of the patients. Different prognostic scores have been published for PTLD but lacks validity given small sample size, heterogeneous patient population and treatment protocol used. The International Prognostic Index (IPI) is the commonly used prognostic index that 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.

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 is with a multidisciplinary team that consists of an oncologist, radiation specialist, hemaologist, surgeon, nurse practitioner and primary care provider. The latter two monitor cancer patients following therapy and should be aware of PTLD.

Treatment strategies for PTLD are different from the management of lymphoproliferative disorders in immunocompetent patients. The mainstay of the management strategy includes reduction of immunosuppression, 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.[12]


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Transplantation Posttransplantation Lymphoproliferative Disorders - Questions

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Transplantation Posttransplantation Lymphoproliferative Disorders - References

References

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Dharnidharka VR, Comprehensive review of post-organ transplant hematologic cancers. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2018 Mar;     [PubMed]
Elserwy NA,Lotfy EE,Fouda MA,Mahmoud MI,Donia AF,Mashaly ME,Abbas MH,Abuelmagd MM,Abouelenein RK,Ismail MI,Bakr MA, Postrenal transplant malignancy: Incidence, risk factors, and prognosis. Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia. 2017 May-Jun;     [PubMed]
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