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Clinical Presentation and Diagnosis

Rates of EBV+ PTLD after SOT and HCT

SOT

The highest rate of EBV+ PTLD in the SOT setting occurs in the first year after transplant1,2
A second peak occurs 7 to 10 years after transplant2

After SOT median time to PTLD onset 4-5.3 years1

4-5.3
Years(1)

due to taking lifelong immunosuppressives1
 



 

HCT

EBV+ PTLD usually occurs within 12 months1

Only 4% of PTLD cases develop after 12 months1

After HCT median time to PTLD onset 2-4 months3

2-4
Months(3)

Cases occurring >5 years after HCT are extremely rare due to discontinued use of immunosuppressives1

Rate of EBV+ PTLD after HCT

In a multicenter, retrospective study of 127 patients with PTLD after allogeneic HCT, incidence rates for PTLD peaked at 2 to 3 months after transplant, and then declined sharply with increasing time since transplantation3

Time to PTLD Diagnosis after SOT, by Organ Transplanted

A single-center, retrospective study found that heart transplantation had a numerically longer time from transplant to PTLD diagnosis versus other SOTs4

 

 

Median time to diagnosis of PTLD by organ type*:

  • Liver: 0.49 years (n=4; 95% CI: 0–3.5)
  • Multi-organ: 2.4 years (n=3; 95% CI: 0.21–4.6)
  • Kidney: 4 years (n=21; 95% CI: 1.4–6.6)
  • Heart: 9.1 years (n=38, 95% CI: 6.2–12.0)
     

Adapted from Lau E, et al. Cancers (Basel). 2021. https://creativecommons.org/licenses/by/4.0/. 

*Out of 66 patients identified with a histologically-confirmed diagnosis of PTLD, 50 were EBV+, 10 were unknown, and 6 were EBV-negative. 

Key risk factors for EBV+ PTLD after SOT and HCT

SOT2,6

Early PTLD risk factors (<12 months after transplant)

  • Primary EBV infection derived from the donor
  • Younger age (children)
  • Type of organ transplanted : Incidence of EBV+ PTLD in recipients based on organ type2,7 
     
diagramme_key-factor-risks-ebv-ptld
  • Treatment with anti-lymphocyte antibodies

Late PTLD risk factors (>12 months after transplant)

  • Duration of immunosuppressive treatment
  • Type of organ transplanted
  • Older age (adults)

HCT5,6

Pre-transplant risk factors

  • Degree of T-cell reduction and impairment
  • EBV sero-mismatch
  • Stem cell source (i.e., cord blood transplantation)
  • HLA mismatch

Post-transplant risk factors

  • Severe acute/chronic GvHD
  • High/rising EBV viral load (DNAemia)
  • Treatment with mesenchymal stem cells
Clinical Presentation & Diagnosis

Symptoms and presenting features

The symptoms of EBV+ PTLD vary as the patient progresses from asymptomatic EBV infection to fulminant PTLD and may include1–7,10:

  • Malaise and lethargy
  • Fever or night sweats
  • Sore throat
  • Enlargement or swelling of the lymph nodes
  • Weight loss
  • Chronic sinus congestion
  • Abdominal pain
  • Nausea and vomiting
  • Anorexia
  • Gastrointestinal symptoms (e.g., bleeding, bowel perforation)
  • End-organ disease (e.g., hepatitis)

As EBV+ PTLD progresses, it can involve any organ, such as the gastrointestinal tract, bone marrow, liver, spleen, lung, kidney, and CNS1,10

In patients with EBV+ PTLD, fever and lymphadenopathy are associated with rapidly progressive multi-organ failure and death5

Monitoring recommendations

In addition to vigilant monitoring for symptoms, surveillance following transplant should include testing for EBV viral load (DNAemia) to inform a pre-emptive treatment strategy against PTLD6,7

Consider assessing EBV viral load for SOT and HCT patients at increased risk of PTLD:2,6

  • SOT recipients
    • EBV-seronegative recipients receiving seropositive donor organs and EBV seronegative paediatric patients
    • EBV-seropositive children <1 year of age and intestinal transplant recipients
       
  • Recipients of high-risk allogeneic HCT

Recommendations for monitoring EBV viral load

 

Testing Method

Sample Type

Timing

SOT2,8

qPCR

Whole blood, plasma, lymphocytes

Suggested weekly to biweekly over the high-risk period (first-year)

HCT5

qPCR

Whole blood, plasma, serum

Begin within the first month
Continue for at least 4 months post-HCT, 1x/week

Diagnostic and evaluation recommendations for EBV+ PTLD

For patients in whom progression to EBV+ PTLD is suspected:

The gold standard to confirm PTLD diagnosis is histological examination and immunophenotyping of tumor tissue, preferably through excisional biopsy or resection of suspected sites of disease; if not possible, core needle biopsy is an alternative5,7,12

Additional diagnostic confirmation can involve non-invasive methods, including quantification of EBV viral load (DNA-emia) and PET-CT/CT imaging5,7,12,13 and can be considered for patients unable to undergo tissue biopsy5

Diagnostic workup Includes:5,12,13

  • Physical exam and evaluation of performance status
  • History of immunosuppressive regimen
  • PET-CT/CT imaging
  • Tissue biopsy with ISH/IHC staining for viral antigens and/or flow cytometry
  • EBV viral load (DNAemia) and serology assessment
  • Laboratory assessments: complete blood count with differential and metabolic panel (e.g., liver enzymes, renal function)
  • Bone marrow evaluation in select cases
  • Endoscopy in cases of gastro-intestinal symptoms
  • Echocardiography where appropriate
  • Fertility-preserving treatment for eligible patients

Staging of EBV+ PTLD

Classification of PTLD according to WHO-HAEM5

The 2022 revision of the World Health Organization (WHO) Classification of Haematolymphoid Tumours (WHO-HAEM5) incorporated significant changes to the categorisation of lymphoproliferative disorders associated with immunodeficiencies to introduce an overarching framework14

Relationship between PTLDs as defined in WHO-HAEM4 and WHO-HAEM514
Click to show new classification:

WHO-HAEM4

WHO-HAEM5

Non-destructive PTLD

Hyperplasias—histologic subtypes are:

  • Follicular hyperplasia
  • Mononucleosis-like hyperplasia
  • Plasma cell hyperplasia
  • KSH/HHV8 MCD

    EBV+ in most cases 15

 Polymorphic PTLD

Polymorphic LPDs

The majority is EBV+; onset can be early or late after transplant13

Monomorphic PTLD

Lymphoma

The majority of early-onset disease is EBV+ while late-onset monomorphic DLBCL-like subtype is often EBV−15

CHL-PTLD

(Classic Hodgkin) Lymphoma

CHL-PTLD is an uncommon subtype16 and the majority is EBV+15,16

Nomenclature in the immune deficiency/dysregulation setting according to WHO-HAEM5

WHO-HAEM5 has additionally introduced a standardised nomenclature to encompass the various settings of immune dysfunction14

Three-part nomenclature for lymphoid proliferations and lymphomas14

Histological diagnosis Viral association Immune deficiency/dysregulation setting
  • Hyperplasia (specify type)
  • Polymorphic lymphoproliferative disorder
  • Mucocutaneous ulcer
  • Lymphoma (classify as for immunocompetent patients)
  • EBV +/–
  • KSHV/HHV8 +/–
  • Inborn error of immunity (type)
  • HIV infection
  • Post-transplant (organ/stem cells)
  • Autoimmune disease
  • Iatrogenic/therapy-related (specify)
  • Immune senescence

Adapted from Alaggio R, et al., et al. Leukemia. 2022. https://creativecommons.org/licenses/by/4.0/. Table title abridged.

References

  1. Fujimoto A, Suzuki R. Cancers (Basel). 2020;12(2):328.
  2. Allen UD, Preiksaitis JK. Clin Transplant. 2019;33(9):e13652.
  3. Landgren O, et al. Blood. 2009;113(20):4992-5001.
  4. Lau E. Cancers (Basel). 2021;13(4):899.
  5. Styczynski J, et al. Haematologica. 2016;101(7):803–811.
  6. Yamada M, et al. J Pediatric Infect Dis Soc. 2024;13(Suppl 1):S31–S38.
  7. Nijland ML, et al. Transplant Direct. 2015;2(1):e48.
  8. Clerico M, et al. J Clin Med. 2022;11(24):7542.
  9. Lindsay J, et al. Curr Opin Infect Dis. 2021;34(6):635–645.
  10. Dierickx D, Habermann TM. N Engl J Med. 2018;378(6):549–562.
  11. Sureda A, et al. The EBMT Handbook: Haematopoietic Stem Cell Transplantation and Cellular Therapies. 8th edition. Cham (CH): Springer; 2024.
  12. Shah N, et al. Br J Haematol. 2021;193(4):727–740.
  13. Samant H, et al. Posttransplant Lymphoproliferative Disorders. StatPearls Publishing; 2023. 
  14. Alaggio R, et al. Leukemia. 2022;36(7):1720–1748.
  15. Atallah-Yunes SA, et al. Br J Haematol. 2023;201(3):383–395.
  16. Rosenberg AS, et al. Am J Hematol. 2016; 91(6): 560–565.

Abbreviations

  • CHL  Classic Hodgkin Lymphoma
  • CNS  central nervous system
  • CT  computed tomography
  • DLBCL  diffuse large B-cell lymphoma
  • EBV(+)  Epstein–Barr virus (positive)
  • FDG  18F-fluorodeoxyglucose
  • GvHD graft-versus-host disease
  • HCT  haematopoietic cell transplantation
  • HHV8  human herpesvirus-8
  • HLA  human leukocyte antigen
  • IHC  immunohistochemistry
  • ISH  in situ hybridisation
  • KSH(V)  Kaposi sarcoma-associated herpesvirus
  • LPDs   lymphoproliferative disorders
  • MCD   multicentric Castleman disease
  • PET  positron emission tomography
  • PTLD  post-transplant lymphoproliferative disorder
  • qPCR  quantitative real-time polymerase chain reaction
  • SOT  solid organ transplant
  • WHO  World Health Organization
  • WHO-HAEM  World Health Organization Classification of Haematolymphoid Tumours