Post transplant lymphoproliferative disorder

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2] Maria Fernanda Villarreal, M.D. [3]

Synonyms and keywords: PTLD;

Overview

Post-transplant lymphoproliferative disorder (also known as PTLD) is defined as a lymphoid (immune cells) and/or plasmacytic proliferations (rapid increase) due to therapeutic immunosuppression after organ transplantation especially in the patients who are undergoing solid organ or allogeneic (donor) hematopoietic stem cell transplantation. Post transplant lymphoproliferative disorder was first discovered by Denis Parsons Burkitt, an Irish physician, in 1965. According to World Health Organization (WHO) classification system, post transplant lymphoproliferative disorder may be classified into 4 subtypes: early hyperplastic lesions, polymorphic lesions, monomorphic lesions, and classic Hodgkin-type lymphomas. Patients with post-transplant lymphoproliferative disorder may develop serious complications of transplantation with infectious mononucleosis-like lesions due to Epstein-Barr virus (EBV) or polyclonal polymorphic B-cell hyperplasia. In some cases, B-cells may undergo mutations which will render them malignant, giving rise to a lymphoma. The malignant cell clone can become the dominant proliferating cell type, leading to a group of B cell lymphomas occurring in immunosuppressed patients following organ transplant. Post transplant lymphoproliferative disorder arises from germinal center or post-germinal center B cells (B-PTLD), which are normally involved the production of antibodies and durable memory B cells. Post transplant lymphoproliferative disorder is very rare, and the prevalence of post transplant lymphoproliferative disorder remains unknown. Post transplant lymphoproliferative disorder is more commonly observed among young patients. The medical treatment for post transplant lymphoproliferative disorder, includes: immunosuppression, antiviral therapy, interferon alpha therapy, CD20 antibody therapy, and chemotherapy.

Historical Perspective

• Post transplant lymphoproliferative disorder was first discovered by Denis Parsons Burkitt, an Irish physician, in 1965.
• Post transplant lymphoproliferative disorder was first introduced in 1984 by Starzl.

Classification

• Post transplant lymphoproliferative disorder may be classified according to 2008 World Health Organization (WHO) classification system, into 3 subtypes:

Category	Subtype
Early hyperplastic lesions	Infectious mononucleosis-type acute illness Polyclonal B cell proliferation No evidence of malignant transformation Plasmacytic hyperplasia
Polymorphic lesions	Evidence of malignant transformation Nuclear atypia Necrosis Lymphoid architecture distortion Found in immunocompetent patients
Monomorphic lesions	B-cell lymphomas Diffuse large B-cell lymphoma Burkitt’s/Burkitt’s-like lymphoma Plasma cell myeloma Monoclonal lymphoid proliferations T-cell lymphomas Peripheral T-cell lymphoma Gamma/delta T-cell lymphoma T-natural killer (NK) lymphoma
Other types	Hodgkin’s disease Plasmacytoma like lymphoma

Pathophysiology

• It is understood that post transplant lymphoproliferative disorder is the result of B cell proliferation induced by Epstein-Barr virus (EBV) infection.
• 90 to 95 percent of patients with post transplant lymphoproliferative disorder shows positive serologic of infection especially with Epstein-Barr virus (EBV) infection.
• Membrane proteins associated with EBV plays a major role in contribute to B cell growth and survival.
  • LMP-1-Latent membrane protein 1
  • LMP-2A-Latent membrane protein 2
  • EBNA-2 (Epstein-Barr nuclear antigen 2) and
  • EBNA-LP (Epstein-Barr nuclear antigen 2 ladder protein)

• Post transplant lymphoproliferative disorder arises from germinal center or post-germinal center B cells (B-PTLD) , which are normally involved the production of antibodies and durable memory B cells.
• The pathogenesis of post transplant lymphoproliferative disorder is also characterized by the production of interleukin-10.

• The overexpression of bcl-2 has been associated with the development of post transplant lymphoproliferative disorder.
• On gross pathology, characteristic findings of post transplant lymphoproliferative disorder, include:
  • Resemblance to large cell lymphomas
  • Palpable lymphadenopathy based on the level of involvement

• On microscopic histopathological analysis, characteristic findings of post transplant lymphoproliferative disorder, include:
  • Resemblance to large cell lymphomas
  • Large lymphoid cells with a diameter (2x a resting lymphocyte)

Causes

• The most common causes of post transplant lymphoproliferative disorder are:
  • Epstein-Barr virus
  • Immunosuppression
  • Recipient age: under 25 years
  • Ethnicity
  • History of pretransplant malignancy
  • Fewer HLA matches
  • Treatment with ATG

Differentiating Post Transplant Lymphoproliferative Disorder from Other Diseases

• Post transplant lymphoproliferative disorder must be differentiated from other diseases that cause fatigue, weight-loss, and fever, such as:
• Infectious mononucleosis
• Diffuse large B-cell lymphoma
• Lymphoblastic lymphoma
• Blastic mantle cell lymphoma (MCL)

Epidemiology and Demographics

Incidence

• The incidence of post transplant lymphoproliferative disorder is approximately 20,000 in 100,000 of all cancers especially with solid organ transplantation.
• The incidence of post transplant lymphoproliferative disorder in liver transplants is approximately 1000 to 2000 in 100,000 patients.
• The incidence of post transplant lymphoproliferative disorder in renal transplant is approximately 1000 to 3000 in 100,000 patients.
• The incidence of post transplant lymphoproliferative disorder in heart transplant is approximately 2000 to 6000 in 100,000 patients.
• The incidence of post transplant lymphoproliferative disorder in lung transplant is approximately 2000 to 9000 in 100,000 patients.
• The incidence of post transplant lymphoproliferative disorder in intestinal or multi organ transplants is approximately as high as 11,000 to 33,000 in 100,000 patients.

Prevalence

• The prevalence of post transplant lymphoproliferative disorder remains unknown.

Age

• Post transplant lymphoproliferative disorder is more commonly observed among young patients.

Gender

• Females are slightly more affected with post transplant lymphoproliferative disorder than men.

Race

• There is no racial predilection for post transplant lymphoproliferative disorder.

Risk Factors

• The most common risk factors in the development of post transplant lymphoproliferative disorder is:
  • B cell neoplasm associated with Epstein-Barr infection.
  • Cytomegalovirus (CMV).
  • Cyclosporine use.
  • Tacrolimus use.
  • Induction therapy.
  • The degree and duration of immunosuppression plays a very important role in the risk of developing PTLD.
  • EBV infection from grafted B lymphocytes.
  • Latent EBV infection leads to malignancies like:
    • HIV-associated lymphomas.
    • Endemic Burkitt’s lymphoma.
    • Hodgkin’s lymphoma.

Natural History, Complications and Prognosis

Natural History

• The majority of patients with post transplant lymphoproliferative disorder are symptomatic at the time of diagnosis.
• Early clinical features include fatigue, fever, and weight-loss.

Complications

• If left untreated, patients with post transplant lymphoproliferative disorder may progress to develop organ failure.
• The most common complication of post transplant lymphoproliferative disorder is fatal infection.

Prognosis

• Depending on the extent of the disease progression at the time of diagnosis, the prognosis may vary in post transplant lymphoproliferative disorder patients due to heterogeneity of the disease.
• Prognosis also depends on what type of PTLD the patient is presenting.

• Prognosis is generally poor, and the 5-year survival rate of patients with post transplant lymphoproliferative disorder is approximately 37- 61%.
• In post transplant lymphoproliferative disorder patients estimated average survival rates range from 25%–60%.

Diagnosis

Symptoms

• Symptoms in post transplant lymphoproliferative disorder patients are highly variable.
• Symptoms are depends on type of post transplant lymphoproliferative disorder patient present with, and the organs involved.
• Symptoms of post transplant lymphoproliferative disorder may include the following:

• Persistent fatigue
• Infectious mononucleosis–like syndrome
• Hepatosplenomegaly
• Loss of appetite
• Nausea
• Vomiting
• Unexplained weight loss
• Viral infection symptoms like headache, muscle aches etc
• Swelling of the lymph nodes:The most common presenting symptom

Physical Examination

• Patients with post transplant lymphoproliferative disorder usually appear pale and malnourished.
• Physical examination may be remarkable for:
  • Swelling in the lymph nodes in the neck or underarms.
  • Patients present with extranodal masses, especially in areas like:
    • Gastrointestinal tract(small intestine and large bowel).
    • lungs.
    • Central nervous system.
  • Fever.
  • Night sweats.
  • Unexplained weight loss.

Laboratory Findings

Laboratory findings consistent with the diagnosis of post transplant lymphoproliferative disorder include:

• According to British Committee for Standards in Haematology (BCSH) and the British Transplantation Society (BTS) Biopsy is the gold standard test for the diagnosis preferably an excisional biopsy of post transplant lymphoproliferative disorder.

• Viral load measurement:

• Marked elevation in EBV viral load.
• In post transplant lymphoproliferative disorder patients viral load can be measured by polymerase chain reaction (PCR).

• Complete blood count which shows viral load measurement:
  • Anemia.
  • Thrombocytopenia.
  • Leukopenia.
• Increased LDH.
• Increased calcium.
• Increased uric acid.
• Urine analysis for monoclonal protein.

Imaging Findings

• Fluorodeoxyglucose (FDG)-positron emission tomography (PET) may be helpful in the diagnosis of post transplant lymphoproliferative disorder which helps in the following:
  • Staging.
  • Response evaluation of malignant lymphoma.
  • Early diagnosis.
• Computed tomography (CT) or magnetic resonance imaging (MRI) may be helpful in the diagnosis of post transplant lymphoproliferative disorder in finding any abnormal nodal or extranodal masses.

Treatment

Medical Therapy

• According to following guidelines proposed post transplant lymphoproliferative disease is treated:
  • American Society of Transplantation (AST).
  • World Health Organization (WHO).
  • NCCN: National Comprehensive Cancer Network.
  • European best practice guidelines for renal transplantation.
  • British Committee for Standards in Haematology.
  • British Transplantation Society.

• Pharmacologic medical therapies for post transplant lymphoproliferative disorder highly varied based on the subtype and type of transplant.
• In post transplant lymphoproliferative disorder patients standardized therapeutic approach cannot be applied to all patients.

• The medical treatment for post transplant lymphoproliferative disorder, include the followings.

Immunosuppression

• Low-dose immunosuppressive agents protocols highly reduce the incidence of post transplant lymphoproliferative disorder.
• The mainstay of treatment for post transplant lymphoproliferative disorder is giving lose dose or reduction of the dose of immunosuppressive agents with the following:
  • rituximab.
  • Chemotherapy.
  • Radiation therapy.

Early Lesions

• Pharmacologic medical therapies for early lesions in post transplant lymphoproliferative disorder include:
  • Reduction of immunosuppression.

Polymorphic PTLD

• Pharmacologic medical therapies for polymorphic post transplant lymphoproliferative disorder include:
  • Reduction of immunosuppression with use of rituximab.

Monomorphic PTLD

• Pharmacologic medical therapies for monomorphic post transplant lymphoproliferative disorder include:
  • Rituximab with with chemotherapy and reduction of immunosuppression.

Classic Hodgkin lymphoma-like PTLD

• Pharmacologic medical therapies for classic hodgkin lymphoma like post transplant lymphoproliferative disorder include:
  • Chemotherapy with or without radiation therapy.

Rituximab

• When it comes to treatment of post transplant lymphoproliferative disorder patients rituximab play an important role which produce anti-CD20 monoclonal antibodies.
• Rituximab helps in treatment of following non-Hodgkin lymphomas:
  • Diffuse large B cell lymphoma.
  • Follicular lymphoma.
• Rituximab alone can achieve complete remission in almost 20% of the patient.
  • Preferred regimen (1): Rituximab 375 mg/m2 per week for four weeks.

Chemoimmunotherapy

• Chemoimmunotherapy medical therapy is recommended among patients with post transplant lymphoproliferative disorder.
• Along with chemoimmunotherapy, rituximab is also added if the patient tested positive for CD20.
• Preferred regimen: R-CHOP
  • Cyclophosphamide.
  • Doxorubicin.
  • Vincristine.
  • Prednisone.
• When rituximab is added to the chemoimmunotherapy regimen the complete remission rates are estimated approximately to be 65%.

Surgery

• Surgery is not recommended for patients with post transplant lymphoproliferative disorder.

Prevention

• Effective measures for the primary prevention of post transplant lymphoproliferative disorder include:
  • Tapering immunosuppressive therapy.
  • Antiviral prophylaxis with ganciclovir.
  • Pretreatment assessment: check the patient with the following:
    • Comorbidities.
    • Complete blood picture.
    • LFT's.
    • Albumin levels.
    • HIV status.
    • Hepatitis tests.
    • EBV serology tests.