Molecular Basis of Disease

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) methotrex-ate 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 neoplas-tic process that is no longer responsive to immune modulation.

Immunodeficiency-related LPD are all of either germinal center or postgerminal center cell origin, so they have undergone somatic hypermutation (SHM) of the immunoglobulin variable to joining regions. Recent studies indicate that the process of SHM often misfires, so a relatively large proportion of these lymphomas (as well as those arising outside immunodeficiency) have mutations in the regulatory region of a number of protooncogenes, including MYC, BCL6, PAX5, PIM1,and RHOH/TTF.2 Thus, in spite of aggressive therapeutic intervention and either due to the inability to reestablish normal immune function or to neoplastic transformation, these lesions may progress, leading to the patient's demise.

The morphologic diagnosis of LPD often is difficult. In some instances the lesions are clearly neoplastic, such as those arising in the setting of HIV infection; however, other lesions, such as many of the PTLD, are difficult to classify due to their polymorphic appearance. Thus, the accurate diagnosis and treatment of these immunodeficiency-related LPDs often requires not only morphologic examination but also the use of immunophenotypic and genotypic techniques.

The most frequently encountered immunodeficiency-related LPDs are those occurring in the setting of HIV infection and following organ transplantation. These lesions, because of their frequency, have been better characterized and thus are the focus of this chapter. The primary immune disorders and methotrexate-related LPDs are relatively rare and have not been as extensively studied. Other than a B-cell lineage and the documentation of a role for EBV in their development, there is not much information regarding specific molecular alterations (other than those causing the primary immunodeficiency).

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