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Pulmonary Pathology Online

Pathology of Post-Transplant Lymphoproliferative Disease

 Dr Sampurna Roy MD


Post-transplant lymphoproliferative  disease (PTLD) constitutes a spectrum of lymphoproliferation ,which follows immunosuppression for solid organ and bone marrow transplantation.


It is often associated with Epstein-Barr Virus infection.


(Visit:  Epstein-Barr Virus Related Malignant Tumours )


Similar lesions may occur in congenital immunodeficiency.


Specific risk factors :

(1) type of transplant, 

(2) young age,

(3) number of rejection episodes,

(4) multi-agent immunosuppression,

(5) use of T-cytolytic therapy and

(6) pre-transplant EBV seronegativity.


Incidence:  Incidence in solid organ transplantation is 1-2%, ranging from less than 1% in renal recipients to 9% for lung and heart-lung recipients to 17% for intestinal recipients.

Time of occurence: The majority of cases occur in the first two years following transplantation  and are associated with  active or latent EBV infection.

Source  of infection: The source of EBV in most cases is primary or reactivated infection in the recipient.

Cause of proliferation of cells:  Uncontrolled proliferation of EBV-immortalised B-cells results due to loss of cytotoxic T-cell control because of immunosuppression for the prevention and treatment of acute allograft rejection.

Disease regression may occur once undertaking immunosuppression is reduced or reversed, although the graft may be compromised PTLD may also develop several years after transplantation, when it often lacks EBV and tends to behave more aggressively.

Pathological Features:

Disease may be nodal or extra-nodal, and may involve the graft, notably the lung. The non-transplanted lung may be involved by PTLD in recipients of other solid organs.

The spectrum of morphological appearances ranges from plasma cell hyperplasia and infectious mononucleosis-like changes to appearances identical with B-cell lymphomas.

These are classified into three major morphological groups -"early", polymorphic and monomorphic - and the majority are of B-cell origin.

It has been suggested that monomorphic monoclonal lesions with clonal EBV expression tend to have a worse prognosis than polymorphous polyclonal lesions with non-clonal EBV expression.

Hodgkin’s disease-like PTLD and EBV-negative non-Hodgkin’s lymphomas, often with rearranged oncogenes such as c-myc, have also been described.

Diagnosis of PTLD:

The morphological diagnosis of PTLD is made on evaluation of cell morphology and immuno-phenotype, immunoglobulin clonality  and detection of tissue EBV DNA or RNA.

Immunoglobulin clonality should be determined using PCR for heavy chain rearrangement.

Detection  for EBV should be done using in-situ hybidization for EBV RNA (EBERs) on paraffin sections, or immunohistochemistry for EBV nuclear antigen 1 – 6 (EBNA) on cryostat sections.

The histopathological report should include a full description of the findings and a diagnosis using the WHO classification. Final interpretation must always be "in the clinical setting of immunosuppression ".

Synchronous and metasynchronous lesions must be fully investigated as variations in clonality and morphology may occur both within an individual lesion and between simultaneous or subsequent lesions in individual patients.

PTLD may involve the transplanted or native lung, either in isolation or as part of disseminated disease.

It may be asynptomatic or associated with cough, fever and malaise.

Chest X-ray and CT scan may show diffuse infiltrates or incidental single or multiple nodules.

Tissue may be obtained by transthoracic needle biopsy or, rarely, by thoracoscopic wedge biopsy.

Difficulties encountered in diagnosis (especially on core biopsies):

(1) from the small size of the sample ,

(2) the risk of crush artefact and

(3) the tendency for pulmonary PTLD to show extensive necrosis because of angioinvasion.

Differential diagnosis of PTLD:  Infections such as Cytomegalovirus   or  Pneumocystis carinii , inflammation related to previous biopsy sites, other pulmonary lymphoproliferative disorders, and in the transplanted lung, acute allograft rejection, and rarely, graft-versus-host disease.

Microscopic features:   The microscopic features of pulmonary PTLD is variable and bears more resemblance to pulmonary PTLD is variable and bears some resemblance to LYG in that it is usually angioinvasive, and also shows extensive necrosis.

Infiltration of septal and pleural lymphatics, terminal bronchioles and visceral pleura may also be seen.

Early lesions may be rich in mature plasma cells or show changes suggestive of infectious mononucleosis.

Polymorphous infiltrates may include plasma cells and lymphoplasmacytoid cells (resembling the spectrum of appearances in lymphoplasmacytoid lymphomas).

Monomorphous infiltrates may include transformed blasts, centroblasts, show a high proliferation index and resemble large B-cell lymphomas.

Single cell necrosis is common.

There is a background population of interstitial histiocytes and T lymphocytes, often cuffing the tumour.

"Early" lesions tend to be polyclonal and monomorphous lesions monoclonal, whilst polymorphous lesions may be either.

Almost all B - cell lesions contain EBV either as EBERs or as EBNAs.

Rarely, EBV-negative lesions resembling resembling T-cell lymphomas or anaplastic large cell lymphomas are seen.


Regression of pulmonary PTLD occurring early after transplantation is rapid and usually complete after reduction of immunosuppression and treatment with antiviral agents.

Disease relapse or progression may require treatment with radio- or chemotherapy, with variable results.

Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of transplantation for which new therapies are being explored, including cytotoxic T-cell infusion and anti-CD20 antibody.


Further reading:

Impact of Epstein-Barr virus in monomorphic B-cell posttransplant lymphoproliferative disorders: a histogenetic study.

Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder following lung transplantation is more commonly of host origin.

Tumor origin and CD20 expression in posttransplant lymphoproliferative disorder occurring in solid organ transplant recipients: implications for immune-based therapy.

Posttransplant lymphoproliferative disorders in lung transplant patients: the Cleveland Clinic experience.

Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity?

Post-transplant lymphoproliferative disorders: a morphologic, phenotypic and genotypic spectrum of disease. 



Dr Sampurna Roy  MD

Consultant  Histopathologist (Kolkata - India)






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