What is the best next step in management for a 65-year-old kidney transplant patient (2 years status post-transplant) presenting with malaise, unquantified fevers, and cervical lymphadenopathy?

Management of Cervical Lymphadenopathy in a Kidney Transplant Recipient

The best next step is to perform an excisional lymph node biopsy to evaluate for post-transplant lymphoproliferative disorder (PTLD), as this presentation of malaise, fevers, and cervical lymphadenopathy in a solid organ transplant recipient 2 years post-transplant is highly concerning for PTLD, which requires tissue diagnosis for definitive management. 1

Immediate Diagnostic Workup

Tissue Diagnosis is Essential

• Excisional lymph node biopsy is the gold standard for diagnosing PTLD in transplant recipients presenting with lymphadenopathy 1
• The biopsy should include histological examination with EBER in situ hybridization (ISH) and immunohistochemistry for viral antigens to detect EBV-associated PTLD 1
• PTLD can occur in the absence of obvious lymphadenopathy, but when present, biopsy of the enlarged node provides definitive diagnosis 1

Concurrent Laboratory and Imaging Studies

• Obtain EBV PCR from peripheral blood, as 80-90% of PTLD cases are associated with EBV infection 1
• Perform contrast CT of chest, abdomen, and pelvis for staging per WHO recommendations 1
• Measure serum lactate dehydrogenase for prognostic purposes 1
• Complete blood count to assess for cytopenias that may accompany PTLD 1

Critical Differential Diagnoses to Exclude

Infectious Etiologies Must Be Ruled Out

• Blood cultures are mandatory before attributing symptoms solely to PTLD, as immunosuppressed transplant recipients are at high risk for opportunistic infections 1
• CMV enteritis or systemic CMV infection can present with fever, malaise, and lymphadenopathy; obtain CMV PCR or antigenemia assay 1
• Endemic fungal infections (histoplasmosis, coccidioidomycosis) should be considered if there is relevant travel history, as these can mimic PTLD with lymphadenopathy and constitutional symptoms 2, 3, 4
• Disseminated fungal infections may require fungal complement fixation panels and urine antigen testing, though urine antigens can be falsely negative 3

Other Malignancies

• Non-EBV-associated lymphomas occur in transplant recipients and require tissue diagnosis 1
• The 2-year post-transplant timeframe is within the peak risk period for PTLD (most common in first year but can occur later) 1

Management Algorithm Based on Biopsy Results

If PTLD is Confirmed

• Reduction of immunosuppression is the first-line therapy and should be individualized based on allograft function and disease severity 1
• Coordinate immunosuppression reduction with the transplant center to balance PTLD treatment against rejection risk 1
• Symptomatic improvement may occur within 1-2 weeks of reducing immunosuppression, with clinical response by 4 weeks 1
• Monitor renal allograft function closely during immunosuppression reduction 1
• Patients with aggressive disease or those unable to tolerate immunosuppression reduction may require additional therapies (rituximab, chemotherapy) 1

If Infection is Identified

• Initiate pathogen-specific antimicrobial therapy immediately 1
• For CMV: ganciclovir and/or CMV-specific hyperimmune globulin 1
• For fungal infections: liposomal amphotericin B (3-5 mg/kg daily) or appropriate azole therapy based on organism 2, 3, 4
• Consider temporary reduction in immunosuppression for severe infections, coordinated with transplant team 1

Common Pitfalls to Avoid

• Do not delay tissue biopsy while pursuing extensive serologic or imaging workup alone, as definitive diagnosis requires histopathology 1
• Do not assume all fever and lymphadenopathy in transplant recipients is infectious—PTLD is a critical differential that requires different management 1
• Do not reduce immunosuppression empirically before establishing a diagnosis, as this could precipitate rejection if the etiology is infectious rather than PTLD 1
• Do not rely solely on EBV PCR for diagnosis, as viral load helps with monitoring but tissue diagnosis is required for definitive PTLD diagnosis 1
• Avoid attributing symptoms to benign causes like polymyalgia rheumatica without first excluding PTLD and infection, even though these can rarely occur in immunosuppressed patients 5

Monitoring During Workup

• Assess renal allograft function (creatinine, urine output) to ensure stable graft function 1
• Monitor for signs of graft rejection (rising creatinine, decreased urine output) if immunosuppression adjustments are made 1
• Serial inflammatory markers (ESR, CRP) can help track disease activity but are nonspecific 5