What is the appropriate initial work‑up for a solid‑organ transplant recipient in whom post‑transplant lymphoproliferative disorder is suspected?

Work-up for Post-Transplant Lymphoproliferative Disorder (PTLD)

When PTLD is suspected in a solid organ transplant recipient, obtain tissue biopsy of the enlarged lymph node or mass for definitive diagnosis, combined with contrast CT imaging of chest/abdomen/pelvis, serum LDH, and EBV PCR. 1

Clinical Presentation to Recognize

PTLD commonly presents with fever, night sweats, malaise, weight loss, and constitutional symptoms—but can occur without obvious lymphadenopathy. 1 This is a critical pitfall: the absence of palpable nodes does not exclude PTLD, so maintain high clinical suspicion in any transplant recipient with unexplained systemic symptoms. 1

• Most cases (80-90%) are associated with EBV infection, occurring in approximately 2% of adult solid organ transplant recipients and up to 15% of pediatric recipients. 1
• Peak incidence is within the first year post-transplant, though a second peak occurs >1 year post-transplant and is typically EBV-negative. 1, 2

Essential Diagnostic Work-up

Physical Examination Focus

Examine specifically for fever, tonsillitis, lymphadenopathy (cervical, axillary, inguinal), and hepatosplenomegaly. 1 Do not rely on a general physical exam—these are the key findings that drive further investigation.

Tissue Diagnosis (Mandatory)

Biopsy of enlarged lymph nodes or identified mass is required for definitive diagnosis. 1 The tissue must be analyzed with:

• EBER in situ hybridization (EBER-ISH)—this is the gold standard with high sensitivity and specificity. 1
• Immunohistochemistry for viral proteins (e.g., LMP1, EBNA1) has high specificity but lower sensitivity. 1
• Flow cytometry to assess for monoclonal or oligoclonal cell populations. 1

Critical pitfall: EBV DNA detection by PCR of tissue extracts has very high sensitivity but low positive predictive value and should NOT be used alone for diagnosis. 1

Imaging Studies

Obtain contrast-enhanced CT of chest, abdomen, and pelvis for staging. 1 This is the WHO-recommended staging approach.

• PET-CT is preferred over CT alone, particularly for extranodal disease, as PTLD is FDG-avid. 1
• Stage according to Ann Arbor classification or Lugano classification (for PET-CT). 1

Laboratory Testing

Order the following blood tests:

• EBV PCR (quantitative viral load in whole blood, plasma, or serum)—helpful for both diagnosis and monitoring treatment response. 1
• Serum lactate dehydrogenase (LDH)—for prognosis only, not diagnostic. 1
• Complete blood count, comprehensive metabolic panel, and assessment of allograft function. 1

Important distinction: Detection of EBV nucleic acid in blood alone is NOT sufficient for diagnosing PTLD—tissue confirmation is mandatory. 1

Endoscopy When Indicated

Perform endoscopy if gastrointestinal symptoms are present. 1 PTLD can involve the GI tract, and direct visualization with biopsy may be necessary.

Diagnostic Criteria

PTLD diagnosis requires at least two of the following histological features: 1

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

Proven vs. Probable PTLD

• Proven PTLD: Detection of EBV nucleic acids or proteins in tissue specimen + symptoms/signs from affected organ. 1
• Probable PTLD: Significant lymphadenopathy, hepatosplenomegaly, or end-organ manifestations (without biopsy) + significant EBV DNA-emia, in absence of other documented cause. 1

WHO Classification to Report

The pathologist should classify PTLD into one of four categories: 1

• Polyclonal early lesions
• Polymorphic PTLD
• Monomorphic PTLD (B-cell or T/NK-cell)
• Classical Hodgkin lymphoma-type PTLD

CD20-positive B-cell PTLD accounts for approximately 75% of cases. 3 This distinction is critical because it determines eligibility for rituximab therapy.

Clinical Staging

Document whether disease is: 1

• Nodal vs. extranodal
• Limited (unifocal) vs. advanced (multifocal)
• Stage I-IV by Ann Arbor or Lugano classification

Coordination with Transplant Center

Immediately contact the transplant center when PTLD is suspected—do not attempt to reduce immunosuppression independently. 1, 4 Reduction of immunosuppression is the first-line treatment but must be individualized based on allograft type, severity of disease, and rejection risk. 1, 4

• Monitor for symptomatic improvement as early as 1-2 weeks, with clinical response expected within 4 weeks if reduction of immunosuppression will be effective. 1, 4
• Allograft function must be monitored closely during this period. 4