Post-transplant Lymphoproliferative Disorder, Monomorphic



Post-transplant Lymphoproliferative Disorder, Monomorphic


Pei Lin, MD

L. Jeffrey Medeiros, MD





Key Facts


Terminology



  • Monomorphic PTLDs fulfill criteria for lymphomas as observed in immunocompetent patients


Etiology/Pathogenesis



  • Epstein-Barr virus (EBV) infection plays important role in pathogenesis


  • ˜ 80% of all PTLDs are EBV(+); usually type A


  • Risk factors for developing PTLDs



    • EBV seronegativity before transplant; young age


    • Degree of overall immunosuppression


    • Types of immunosuppression or organs transplanted


Clinical Issues



  • Lymphadenopathy &/or extranodal sites


  • EBV(+) PTLDs usually occur < 5 years after transplant


  • EBV(-) PTLDs develop later (median: 50 months)


  • 3-step approach is taken for treating PTLD patients



    • Reduction of immunosuppression


    • Single agent rituximab (anti-CD20 antibody)


    • Cytotoxic chemotherapy


Microscopic Pathology



  • ˜ 80% monomorphic PTLDs are of B-cell origin



    • Diffuse large B-cell lymphoma is most common


  • ˜ 15% are NK/T-cell


  • ˜ 5% plasma cell neoplasms and Hodgkin lymphoma


Ancillary Tests



  • Karyotypic aberrations are detectable in most cases


  • Monomorphic B-cell PTLD: Monoclonal Ig rearrangements


  • NK/T-cell PTLDs: Monoclonal TCR rearrangements







Monomorphic post-transplant lymphoproliferative disorder (PTLD), consistent with diffuse large B-cell lymphoma, involving brain shows atypical lymphoid infiltrate image and necrosis image.






Monomorphic PTLD, consistent with diffuse large B-cell lymphoma, involving brain. Numerous large atypical lymphoid cells image are present in a background of reactive T cells.


TERMINOLOGY


Abbreviations



  • Post-transplant lymphoproliferative disorder (PTLD)


Synonyms



  • Post-transplantation lymphoproliferative disease (PTLD)


Definitions



  • PTLDs are plasmacytic or lymphoid proliferations that occur as a result of immunosuppressive therapy following solid organ or bone marrow transplantation


  • Monomorphic PTLDs fulfill criteria for lymphomas as observed in immunocompetent patients



    • All cells appear to be transformed but lesions are not completely monotonous



      • Plasmacytoid/plasmacytic differentiation &/or pleomorphism of neoplastic cells are common


ETIOLOGY/PATHOGENESIS


Infectious Agents



  • Epstein-Barr virus (EBV) infection plays important role in pathogenesis



    • ˜ 80% of all PTLDs are EBV(+); usually type A


    • Prior to onset of PTLDs



      • Serum EBV antibody titers and EBV DNA levels in blood increase


      • Numbers of EBV(+) cytotoxic T cells decrease prior to onset of PTLD


    • Therapy with EBV-specific T cells effective in subset of patients


    • EBV genomes are monoclonal shown by EBV terminal repeat analysis



      • Virus is present prior to monoclonal expansion


  • EBV can transform germinal center B cells



    • Extends lifespan of B cells


    • Increases likelihood of additional genetic abnormalities that confer growth advantage


    • EBV latent membrane protein (LMP)1 and LMP2A proteins activate B-cell receptor and intracellular signaling pathways


Decreased Host Immunosurveillance Resulting from Therapeutic Immunosuppression



  • Underlying immune deficiency can be involved (e.g., cystic fibrosis, hepatitis C infection)


  • Cumulative amount of immunosuppression



    • Cyclosporin A, antithymocyte globin (ATG) or OKT3 monoclonal antibodies


  • Type of organ transplanted



    • Multiorgan > lung > liver > heart > pancreas > kidney > bone marrow and stem cell transplantation


    • Kidney transplant patients are more susceptible to NK/T-cell lymphoma and EBV(-)


    • Stem cell transplant patients are more susceptible to Hodgkin lymphoma



      • T-cell depletion in donor allograft increases risk


Cell of Origin



  • B-cell PTLDs arise from germinal center (GC) or post-GC B-cells


  • Cell of origin of T-cell PTLDs is unknown


  • 90% of PTLD in recipients of solid organ transplants are of host origin


  • Most PTLD in recipients of bone marrow/stem cell transplant are of donor origin


Risk Factors for PTLDs in General



  • EBV seronegativity before transplant


  • Degree of overall immunosuppression



    • Higher risk if multiple regimens are used or if patients receive multiple transplants


  • Type of immunosuppression



    • Higher risk with




      • Tacrolimus


      • Monoclonal antibody OKT3


      • Antithymocyte globulin


  • Type of organs transplanted



    • Highest risk in patients receiving intestinal or multi-organ transplants


    • Lowest risk in patients who receive kidney allograft


    • Likely attributable, in part, to immunosuppressive regimens used


  • Age



    • Children who receive allografts have higher frequency of PTLD


    • Likely related to higher frequency of EBV seronegativity at time of transplant


  • Patients who receive bone marrow/stem cell transplants have additional risk factors



    • HLA-mismatched allograft


    • Allograft that has been T cell depleted


    • Immunosuppressive therapy for graft vs. host disease


CLINICAL ISSUES


Epidemiology



  • Incidence



    • PTLD occurs in < 2-3% of all patients who receive organ allografts



      • Kidney: 1-3% of transplant patients


      • Liver: 1-3% of transplant patients


      • Heart: 1-6% of transplant patients


      • Heart-lung: 2-6% of transplant patients


      • Lung: 4-10% of transplant patients


      • Small intestine: ˜ 20% of transplant patients


    • Younger patients have higher incidence


  • Age



    • Predicted by age of population undergoing transplant


  • Gender



    • Predicted, in part, by underlying diseases of population undergoing transplant


Presentation



  • Highly variable; depends on



    • Organ(s) involved by PTLD


    • Histology of PTLD


    • Status of EBV infection


  • EBV(+) PTLDs usually occur within 5 years of transplant



    • Commonly arise within 1st year after transplant


  • EBV(-) cases occur a median of 50 months after transplantation


  • Constitutional symptoms are common


  • Lymphadenopathy; can be localized or systemic


  • Extranodal sites are commonly involved (up to 75% of cases)



    • Often involve gastrointestinal (GI) tract or brain


    • PTLD commonly involves allograft, but can be generalized



      • Associated with allograft failure


    • Most NK/T-cell PTLDs involve extranodal sites



      • Skin, blood, bone marrow, spleen, lung, GI tract


  • Bone marrow transplant recipients can develop generalized PTLD that mimics graft vs. host disease



    • ± pancytopenia


  • Classical Hodgkin lymphoma type of PTLD is more common in patients with kidney or bone marrow/stem cell transplants


Natural History

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Post-transplant Lymphoproliferative Disorder, Monomorphic

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