What is Post-Transplant Lymphoproliferative Disorder (PTLD)?

What is Post-Transplant Lymphoproliferative Disorder (PTLD)?

Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases characterized by uncontrolled neoplastic proliferation of lymphoid or plasmacytic cells that occurs following hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT), predominantly driven by Epstein-Barr virus (EBV) infection in the setting of immunosuppression. 1

Pathophysiology and EBV Association

PTLD results from the oncogenic potential of EBV, which transforms and immortalizes B-lymphocytes, leading to uncontrolled proliferation of these cells in immunodeficient transplant recipients 1. The key distinction between transplant types is critical:

• Post-HSCT PTLD: Almost exclusively EBV-related (>90% of cases), though rare non-EBV cases exist 1
• Post-SOT PTLD: Approximately 80-90% are EBV-associated, with a minority being EBV-negative 1

The mechanism involves EBV's ability to transform B-lymphocytes while immunosuppressive therapy impairs the immune system's ability to control this viral-driven proliferation 1, 2.

Clinical Significance and Mortality

PTLD represents one of the most severe complications of transplantation with historically devastating outcomes. Before 2000, attributable mortality reached 84.6% after HSCT 1. Despite advances including EBV PCR monitoring, pre-emptive therapy, and rituximab treatment, mortality remains approximately 33% of diagnosed patients 1. In SOT recipients, mortality can reach 50% 3.

Risk Factors

The highest-risk population includes 1:

• EBV-seronegative recipients receiving organs from EBV-seropositive donors (D+/R-) - this represents the greatest risk profile
• Recipients of allogeneic HSCT, particularly those receiving T-cell depleted grafts 4
• Patients receiving anti-T-cell therapies (e.g., OKT3, anti-thymocyte globulin) 1
• Pediatric transplant recipients (up to 15% incidence vs. 2% in adults) 1
• Patients on more potent immunosuppressive regimens 1

WHO Classification

PTLD encompasses four distinct morphological categories 1:

1. Polyclonal early lesions
2. Polymorphic PTLD
3. Monomorphic PTLD (B-cell or T/NK-cell subtypes)
4. Classical Hodgkin lymphoma-type PTLD

A rare variant, plasmacytic PTLD (approximately 4% of cases), presents as monoclonal plasma cell proliferation resembling multiple myeloma, characterized by CD138 positivity and CD20 negativity 5.

Diagnostic Criteria

Probable PTLD 1

Requires significant lymphadenopathy, hepatosplenomegaly, or other end-organ manifestations (without tissue biopsy but excluding other documented causes) plus significant EBV DNA-emia.

Proven PTLD 1

Requires detection of EBV nucleic acids or EBV-encoded proteins in tissue specimen plus symptoms and/or signs from the affected organ.

Critical diagnostic principle: Detection of EBV nucleic acid in blood alone is NOT sufficient for PTLD diagnosis 1.

Histological Diagnosis

Diagnosis requires at least two of the following features 1:

1. Disruption of underlying cellular architecture by lymphoproliferative process
2. Presence of monoclonal or oligoclonal cell populations (revealed by cellular and/or viral markers)
3. Evidence of EBV infection in many cells (DNA, RNA, or protein)

The gold standard histological method is EBV-encoded RNA detection by in situ hybridization (EBER-ISH), which provides high sensitivity and specificity 1. Immunohistochemistry for viral proteins has good specificity but lower sensitivity 1. PCR detection of EBV DNA from histological extracts is inappropriate due to very high sensitivity but low positive predictive value 1.

Clinical Presentation

Common manifestations include 1, 5:

• Constitutional symptoms: fever, night sweats, malaise, weight loss
• Lymphadenopathy (though PTLD can occur without it) 1
• Extranodal involvement, particularly in plasmacytic variant with subcutaneous solid tumors 5
• Hepatosplenomegaly 1

Timing of Occurrence

PTLD typically develops within the first year post-transplant in most adult recipients, with peak incidence at 3-5 years for certain subtypes like cutaneous manifestations 1. However, cases can occur at any time post-transplantation, with some plasmacytic variants presenting as late as 24 years post-transplant 5.

Screening and Monitoring

All transplant recipients and donors should undergo EBV serology testing pre-transplantation 1, 4. High-risk patients (EBV-seronegative recipients, those receiving T-cell depleted grafts, or with graft-versus-host disease) require prospective EBV DNA-emia monitoring by quantitative PCR 4. EBV-seronegative recipients should have EBV viral load measured at least monthly during the first year 1.