Lymphoproliferations of Immunodeficiency

  • Ethel Cesarman
  • Amy Chadburn


Immunodeficient patients are at an increased risk for developing lymphoproliferative disorders (LPD), including lymphomas. The World Health Organization (WHO) classification recognizes four clinical settings associated with the development of immunodeficiency-related LPDs: (1) primary immune disorders, (2) HIV infection, (3) iatrogenic immunosuppression following solid organ or allogeneic bone marrow transplantation (posttransplant lymphoproliferative disorder [PTLD]), and (4) methotrexate therapy, usually for an autoimmune disorder.1 These lesions are highly heterogeneous, largely due to the various underlying causes of the different immunodeficiencies; however, they share several features (see Table 34-1). In most instances, the LPD are related to Epstein-Barr virus (EBV or HHV-4) infection, and thus, in situations where immunocompetence can be reestablished, these EBV-driven proliferations may regress. However, the development of secondary genetic structural alterations in oncogenes and tumor suppressor genes, not all of which have been defined, results in transformation to a neoplastic process that is no longer responsive to immune modulation.


Primary Effusion Lymphoma BCL6 Mutation IGLL Gene Burkitt Lymphoma Terminal Repeat Region 
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  1. 1.
    Jaffe ES, Harris NL, Stein H, Vardiman JW. Pathology and Genetics of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001.Google Scholar
  2. 2.
    Gaidano G, Pasqualucci L, Capello D, et al. Aberrant somatic hypermutation in multiple subtypes of AIDS-associated non-Hodgkin lymphoma. Blood. 2003;102:1833–1841.PubMedCrossRefGoogle Scholar
  3. 3.
    Gaidano G, Carbone A, Dalla-Favera R. Genetic basis of acquired immunodeficiency syndrome-related lymphomagenesis. J Natl Cancer Inst Monogr. 1998;23:95–100.PubMedGoogle Scholar
  4. 4.
    Carbone A. Emerging pathways in the development of AIDS-related lymphomas. Lancet Oncol. 2003;4:22–29.PubMedCrossRefGoogle Scholar
  5. 5.
    Knowles DM. Neoplastic Hematopathology. 2nd ed. Baltimore: Williams and Wilkins; 2001.Google Scholar
  6. 6.
    Raphael M, Borisch B, Jaffe ES. Lymphomas associated with infection by the human immune deficiency virus (HIV). In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization Classification of Tumors, Tumors of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001:260–263.Google Scholar
  7. 7.
    Nalesnik MA, Jaffe R, Starzl TE, et al. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression. Am J Pathol. 1988;133:173–192.PubMedGoogle Scholar
  8. 8.
    Knowles DM, Cesarman E, Chadburn A, et al. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Blood. 1995;85:552–565.PubMedGoogle Scholar
  9. 9.
    Cesarman E, Chadburn A, Liu YF, Migliazza A, Dalla-Favera R, Knowles DM. BCL-6 gene mutations in posttransplantation lymphoproliferative disorders predict response to therapy and clinical outcome. Blood. 1998;92:2294–2302.PubMedGoogle Scholar
  10. 10.
    Shapiro RS, McClain K, Frizzera G, et al. Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Blood. 1988;71:1234–1243.PubMedGoogle Scholar
  11. 11.
    Chadburn A, Hyjek E, Frizzera G, et al. Post-transplantation lymphoproliferative disorders (PT-LPDs) in bone marrow and solid organ transplant recipients differ. Blood. 2000;96(suppl 1):505a.Google Scholar
  12. 12.
    Abed N, Casper JT, Camitta BM, et al. Evaluation of histogenesis of B-lymphocytes in pediatric EBV-related post-transplant lymphoproliferative disorders. Bone Marrow Transplant. 2004;33:321–327.PubMedCrossRefGoogle Scholar
  13. 13.
    Chadburn A, Hyjek E, Pan L, et al. Bcl-6 gene mutations in bone marrow transplantation (BMT). Mod Pathol. 2001;14:167A.Google Scholar
  14. 14.
    Chadburn A, Chen JM, Hsu DT, et al. The morphologic and molecular genetic categories of posttransplantation lymphoproliferative disorders are clinically relevant. Cancer. 1998;82:1978–1987.PubMedCrossRefGoogle Scholar
  15. 15.
    Leblond V, Davi F, Charlotte F, et al. Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol. 1998;16:2052–2059.PubMedGoogle Scholar
  16. 16.
    Choquet S, Mamzer BM, Hermine O, et al. Identification of prognostic factors in post-transplant lymphoproliferative disorders. Recent Results Cancer Res. 2002;159:67–80.PubMedGoogle Scholar
  17. 17.
    Hoshino Y, Kimura H, Kuzushima K, et al. Early intervention in posttransplant lymphoproliferative disorders based on Epstein-Barr viral load. Bone Marrow Transplant. 2000;26:199–201.PubMedCrossRefGoogle Scholar
  18. 18.
    Niesters HG, van Esser J, Fries E, Wolthers KC, Cornelissen J, Osterhaus AD. Development of a real-time quantitative assay for detection of Epstein-Barr virus. J Clin Microbiol. 2000;38:712–715.PubMedGoogle Scholar
  19. 19.
    Fan H, Gulley ML. Epstein-Barr viral load measurement as a marker of EBV-related disease. Mol Diagn. 2001;6:279–289.PubMedCrossRefGoogle Scholar
  20. 20.
    Gulley ML. Molecular diagnosis of Epstein-Barr virus-related diseases. J Mol Diagn. 2001;3:1–10.PubMedGoogle Scholar
  21. 21.
    van Esser JW, Niesters HG, Thijsen SF, et al. Molecular quantification of viral load in plasma allows for fast and accurate prediction of response to therapy of Epstein-Barr virus-associated lymphoproliferative disease after allogeneic stem cell transplantation. Br J Haematol. 2001;113:814–821.PubMedCrossRefGoogle Scholar
  22. 22.
    Clave E, Agbalika F, Bajzik V, et al. Epstein-Barr virus (EBV) reactivation in allogeneic stem-cell transplantation: relationship between viral load, EBV-specific T-cell reconstitution and rituximab therapy. Transplantation. 2004;77:76–84.PubMedCrossRefGoogle Scholar
  23. 23.
    Gartner BC, Schafer H, Marggraff K, et al. Evaluation of use of Epstein-Barr viral load in patients after allogeneic stem cell transplantation to diagnose and monitor posttransplant lymphoproliferative disease. J Clin Microbiol. 2002;40:351–358.PubMedCrossRefGoogle Scholar
  24. 24.
    Raab-Traub N, Flynn K. The structure of the termini of the Epstein-Barr virus as a marker of clonal cellular proliferation. Cell. 1986;47:883–889.PubMedCrossRefGoogle Scholar
  25. 25.
    Leung E, Shenton BK, Jackson G, Gould FK, Yap C, Talbot D. Use of real-time PCR to measure Epstein-Barr virus genomes in whole blood. J. Immunol. Methods. 2002;270:259–267.PubMedGoogle Scholar
  26. 26.
    Brooks L, Yao QY, Rickinson AB, Young LS. Epstein-Barr virus latent gene transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and LMP2 transcripts. J Virol. 1992;66:2689–2697.PubMedGoogle Scholar
  27. 27.
    Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science. 1994;266:1865–1869.PubMedCrossRefGoogle Scholar
  28. 28.
    Pan L, Milligan L, Michaeli J, Cesarman E, Knowles DM. Polymerase chain reaction detection of Kaposi’s sarcoma-associated herpesvirus-optimized protocols and their application to myeloma. J Mol Diagn. 2001;3:32–38.PubMedGoogle Scholar
  29. 29.
    Cesarman E. Epstein-Barr virus (EBV) and lymphomagenesis. Front Biosci. 2002;7:e58–e65.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Ethel Cesarman
    • 1
  • Amy Chadburn
    • 2
    • 3
    • 4
  1. 1.Department of PathologyWeill Medical College of Cornell UniversityNew YorkUSA
  2. 2.Department of Pathology and Laboratory MedicineUSA
  3. 3.Immunopathology LaboratoryNew York
  4. 4.Presbyterian Hospital/Weill Medical College of Cornell UniversityNew YorkUSA

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