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Post-transplant lymphoproliferative disorders (PTLDs)

Introduction

Group of conditions that involve uncontrolled proliferation of lymphoid cells as a consequence of extrinsic immunosuppression after organ or haematopoietic stem cell transplant.

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Differences between classic lymphomas and PTLDs | Greer, F. R. (1998). <em>Intrauterine Growth as Estimated From Liveborn Birth-Weight Data at 24 to 42 Weeks of Gestation</em>, by Lula O. Lubchenco et al,<em>Pediatrics</em>, 1963;32:793–800. Pediatrics, 102(Supplement 1), 237 LP – 239. Retrieved from http://pediatrics.aappublications.org/content/102/Supplement_1/237.abstract
  • PTLD typically has a more rapid onset in HSCT patients, with median time of 4–6 months after transplant
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Time from transplantation to diagnosis of PTLD of 127 patients in the German Ped-PTLD registry. Kaplan-Meyer curve (continuous line) and 95% confidence intervals (dotted curve). Note the rapid increase within the first year and another in the third year. | Mynarek, M., Schober, T., Behrends, U., & Maecker-Kolhoff, B. (2013). Posttransplant lymphoproliferative disease after pediatric solid organ transplantation. Clinical & developmental immunology, 2013, 814973. doi:10.1155/2013/814973

Classification

WHO Classification of PTLD (2008):

  • Early lesions
  • Polymorphic PTLD
  • Monomorphic PTLD
  • Classical HL-type PTLD
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Dierickx, D., & Habermann, T. M. (2018). Post-Transplantation Lymphoproliferative Disorders in Adults. New England Journal of Medicine, 378(6), 549–562. https://doi.org/10.1056/NEJMra1702693

Early lesions:

Oligo- or polyclonal proliferation of EBV-positive B cells while the underlying tissue architecture is preserved.

  • Plasmacytic hyperplasia
  • Infectious mononucleosis-like lesions

Polymorphic PTLD:

Oligo- or polyclonal B-cell proliferation, but here, the infiltrating cells destroy the original architecture of the host tissue.

  • Polyclonal
  • Monoclonal

Monomorphic PTLD:

All PTLDs fulfilling the histopathologic criteria of “classical” non-Hodgkin’s lymphoma (NHL) are diagnosed according to the classification of nontransplant associated lymphomas.

  • B cell neoplasms:
    • Diffuse large B-cell lymphoma, (DLBCL)
    • Burkitt lymphoma
    • Plasma cell myeloma
    • Plasmacytoma-like lesions
    • Others
  • T cell neoplasms:
    • Peripheral T cell lymphoma
    • Not otherwise specified (NOS)
    • Hepatosplenic lymphoma
    • Others

Classical HL-type PTLD & HL-like PTLD:

Classical Hodgkin’s disease and Hodgkin-like PTLD also belong to monomorphic PTLDs, but due to their special histological and clinical features, they represent a separate group within the WHO classification.

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Distribution of histological subtypes of pediatric PTLD reported to the German Ped-PTLD registry. | Mynarek, M., Schober, T., Behrends, U., & Maecker-Kolhoff, B. (2013). Posttransplant lymphoproliferative disease after pediatric solid organ transplantation. Clinical & developmental immunology, 2013, 814973. doi:10.1155/2013/814973

 

 

 


Aetiology

Risk factors:

  • Viral infections:
    • Associated EBV infection ((55–65%)
  • Degree of immunosuppression
  • Recipient age and race
  • Allograft type
  • Host genetic variations
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EBV load, as measured by quantitative PCR in whole blood or plasma, mirrors clinical status in transplant recipients. Nearly every human becomes infected during childhood or adolescence, at which time the viral load climbs until the infection is brought under control by the immune system. Humoral and cell-mediated immunity established during primary infection helps maintain viral quiescence for the remainder of the person’s life, with latent EBV DNA retained for life in a small subset of B lymphocytes. Healthy carriers have measurable EBV DNA in whole blood, whereas plasma rarely contains EBV DNA at levels exceeding the lower limit of detection. When a transplant patient is iatrogenically immunosuppressed to prevent graft rejection, active viral infection results in higher baseline viral loads in both whole blood and plasma. Levels often rise before clinical diagnosis of posttransplant lymphoproliferation (PTLD), allowing preemptive intervention in high-risk patients who are routinely monitored for EBV levels. Successful intervention is marked by a return to baseline. A child or a rare adult who was never infected before onset of iatrogenic immunosuppression lacks prior immunity, placing the patient at high risk for active viral infection and progression to neoplasia. | Gulley, M. L., & Tang, W. (2010). Using Epstein-Barr Viral Load Assays To Diagnose, Monitor, and Prevent Posttransplant Lymphoproliferative Disorder. Clinical Microbiology Reviews, 23(2), 350 LP – 366. https://doi.org/10.1128/CMR.00006-09

Pathophysiology

Oncogenic Epstein–Barr virus (EBV): Key pathogenic driver in many early-onset cases, through multiple mechanisms.

In immunocompetent hosts, the EBV genome is immortalized, forming an episome in latently infected B cells. Immunosuppression leads to depressed T cell function with associated lack of T cell control of B cell proliferation; this results in uncontrolled proliferation of EBV-transformed B cells, which contributes to the development of PTLD.

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From the life cycle of EBV infection to PTLD development | Dharnidharka, V. R., Webster, A. C., Martinez, O. M., Preiksaitis, J. K., Leblond, V., & Choquet, S. (2016). Post-transplant lymphoproliferative disorders. Nature Reviews Disease Primers, 2(1), 15088. https://doi.org/10.1038/nrdp.2015.88

 

 


Clinical features

  • Lymphadenopathy (often absent)

Non-specific symptoms:

Usually due to interference with the function of involved organs.

  • Extranodal involvement (common): Gastrointestinal tract (GIT), lungs, skin, bone marrow (BM), and central nervous system (CNS)
  • BM involvement (rare)

Classic B symptoms:

  • Pyrexia, sweats, and weight loss

Diagnosis

Tissue biopsy:

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Morphologic spectrum of PTLD. (A-C) PTLD, early lesion, plasmacytic hyperplasia. (A) In a preserved underlying architecture, there is a proliferation of small reactive plasma cells (inset). Immunohistochemical staining against κ (B) and λ (C) light chains shows the polytypic character of the plasma cells. (D-F) PTLD, polymorphic. (D) Lymph node architecture is effaced by a polymorphic proliferation of B cells of variable size, shape, and degree of transformation (HRS-like cell shown in inset), which are admixed with numerous small lymphocytes, plasma cells, eosinophils, and histiocytes. (E) Immunohistochemical staining against CD20 shows membranous and often Golgi-type expression in the B blasts. (F) Epstein-Barr virus–encoded RNA in situ hybridization shows nuclear positivity not only in the HRS-like cells but also in a variety of B cells. (G-I) PTLD, monomorphic, EBV+ DLBCL. (G) Monotonous proliferation of large transformed B cells (inset) with an infiltrative growth pattern and mitotic activity. (H) Diffuse CD20 expression of the infiltrate corresponding to the B-cell phenotype. (I) Most cells are EBV+, as seen in this Epstein-Barr virus–encoded RNA in situ hybridization. Images were taken with a Leica DFC290. Bars represent 50 µm. Original magnification 630×. Hematoxylin and eosin stain. HRS, Hodgkin/Reed-Sternberg. | Dierickx, D., Tousseyn, T., & Gheysens, O. (2015). How I treat posttransplant lymphoproliferative disorders. Blood, 126(20), 2274–2283. https://doi.org/10.1182/blood-2015-05-615872

Imaging:

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Maximum-intensity projection 18F-FDG–PET/CT images. Baseline image showed multiple supra- and infradiaphragmatic nodal lesions and extranodal lesions in breast, intestines, and bone marrow (left); 18F-FDG–PET/CT after 4 cycles of therapy showed a complete metabolic response in all nodal and extranodal lesions, with the exception of limited residual hypermetabolic lesions in the intestinal tract adjacent to the kidney transplant in the right iliac fossa (right). 18F, radionuclide fluorine 18; FDG, fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography. | Dierickx, D., Tousseyn, T., & Gheysens, O. (2015). How I treat posttransplant lymphoproliferative disorders. Blood, 126(20), 2274–2283. https://doi.org/10.1182/blood-2015-05-615872

Management

  • Reduction of immunosuppression (mainstay)
  • Rituximab (B cell-specific antibody against CD20) +/− combination chemotherapy
  • EBV-specific cytotoxic T cells
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Treatment algorithm of PTLD | ABVD, adriamycin/bleomycin/vinblastine/dacarbazine; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisolone; CNI, calcineurin inhibitor; CNS, central nervous system; CR, complete remission; CTx, chemotherapy; HD MTX, high-dose methotrexate; mTOR, mammalian target of rapamycin; PTCL, peripheral T-cell lymphoma; RIS, reduction of immunosuppression; RTx, radiation therapy. | Ligeti, K., Müller, L. P., Müller-Tidow, C., & Weber, T. (2017). Risk factors, diagnosis, and management of posttransplant lymphoproliferative disorder: improving patient outcomes with a multidisciplinary treatment approach. Transplant Research and Risk Management, Volume 9, 1–14. https://doi.org/10.2147/TRRM.S84744

Summary:

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Dharnidharka, V. R., Webster, A. C., Martinez, O. M., Preiksaitis, J. K., Leblond, V., & Choquet, S. (2016). Post-transplant lymphoproliferative disorders. Nature Reviews Disease Primers, 2(1), 15088. https://doi.org/10.1038/nrdp.2015.88

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