Clinicopathologic Spectrum of Pediatric Posttransplant Lymphoproliferative Diseases Following Solid Organ Transplant

Page 1: Introduction and Overview of PTLD

• Posttransplant Lymphoproliferative Disorder (PTLD)

  • Significant complication in pediatric solid organ transplant (SOT) patients.

  • Primarily EBV-driven CD20+ B-cell proliferations.

  • Treatment includes reduction of immunosuppression and anti-CD20 therapy.

  • Low incidence of PTLD leads to scarce prospective studies.

• Objectives of the Review

  • Analysis of clinical features, pathogenesis, and classification of pediatric PTLD.

• Data Sources

  • Personal experiences and published works from PubMed.

• Key Conclusions

  • PTLD encompasses a broad spectrum of disorders from nonmalignant lymphoproliferations to lymphomas.

  • Majority of pediatric PTLDs are EBV positive.

  • Need for further research into biology, risk factors for aggressive disease, and treatment strategies.

Epidemiology

• History and Incidence

  • PTLD first reported in 1968.

  • 5-year cumulative incidence in pediatric SOT (2005-2014): 2% to 15.8%.

  • Highest incidence in lung, intestine, and multiorgan transplants.

Risk Factors

• Contributing Factors

  • EBV status, type of transplanted organ, and immunosuppressive regimen.

  • Kidney transplants have lower PTLD risk compared to heart and lung transplants.

  • Age and race also contribute, with higher incidence in young White males.

  • EBV serostatus of both donor and recipient is crucial.

  • Surveillance of EBV via PCR is routine; higher EBV DNA levels correlate with PTLD risk.

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Page 2: Pathogenesis of PTLD

• Primary Mechanisms

  • Combination of impaired immunity and EBV infection leads to PTLD.

  • Over 90% of pediatric PTLD cases are EBV positive.

• Viral Profile

  • EBV is a gamma herpesvirus with tropism for B cells; can establish lifelong infection.

  • Distinct latency phases in infected B cells.

• Latency Phases

  • Latency 0: EBV genome persists without protein expression.

  • Latency I: EBNA1 expressed.

  • Latency II: LMP1 & LMP2 expressed, linked to malignancies in immunocompetent hosts.

  • Latency III: All EBNA and LMP proteins expressed; often seen in PTLD.

• Post-SOT Implications

  • Post-transplant immunosuppression impairs CTL response, increasing risk for B-cell lymphoproliferation.

  • EBV-negative PTLD usually occurs later, is frequently monomorphic, and exhibits different pathogenesis.

Page 3: Classification of PTLD

• Current Classifications

  • WHO 2017 classification recognizes PTLD as an immunodeficiency-associated disorder.

  • Distinct categories: Nondestructive PTLD (ND-PTLD) and Polymorphic PTLD.

• Nondestructive PTLD

  • Common in children; affects adenoids, tonsils, lymph nodes, and GI tract.

  • Histopathologic subtypes include plasmacytic hyperplasia, infectious mononucleosis-like, florid follicular hyperplasia.

• Histopathologic Characteristics

  • EBV positivity in ND-PTLD without disruption of tissue architecture.

  • Recurrent mutations found such as NOTCH1, CREBBP, indicating clonal cytogenetic abnormalities.

• Polymorphic PTLD Characteristics

  • Architectural destruction, extensive infiltrate with varied cell types, often with necrosis.

  • Difficulty in differentiating from monomorphic PTLD.