Post-transplant lymphoproliferative disorders: molecular basis of disease histogenesis and pathogenesis

Abstract

Post-transplant lymphoproliferative disorders (PTLD) represent a serious complication of solid organ and allogeneic bone marrow transplantation. PTLD generally display B-cell lineage derivation, involvement of extranodal sites, aggressive histology and clinical behaviour, and frequent association with EBV infection. The occurrence of IgV mutations in the overwhelming majority of PTLD documents that malignant transformation targets germinal centre (GC) B-cells and their descendants both in EBV-positive and EBV-negative cases. Analysis of phenotypic markers of B-cell histogenesis, namely BCL6, MUM-1 and CD138, allows further distinction of PTLD histogenetic categories. PTLD expressing the BCL6(+)/MUM1(+/-)/CD138(-) profile reflect B-cells actively experiencing the GC reaction and comprise diffuse large B-cell lymphoma (DLBCL) centroblastic and Burkitt lymphoma. PTLD expressing the BCL6(-)/MUM1(+)/CD138(-) phenotype putatively derive from B-cells that have concluded the GC reaction and comprise the majority of polymorphic PTLD and a fraction of DLBCL. A third group of PTLD is reminiscent of post-GC and pre- terminally differentiated B-cells that show the BCL6(-)/MUM1(+)/CD138(+) phenotype and are morphologically represented by either polymorphic PTLD or DLBCL immunoblastic. The molecular pathogenesis of PTLD involves infection by oncogenic viruses, namely Epstein-Barr virus, as well as genetic or epigenetic alterations of several cellular genes. At variance with lymphoma arising in immunocompetent hosts, whose genome is relatively stable, a fraction of PTLD are characterized by microsatellite instability as a consequence of defects in the DNA mismatch repair mechanism. Apart from microsatellite instability, molecular alterations of cellular genes recognized in PTLD include alterations of c-MYC, BCL-6, p53, DNA hypermethylation, and aberrant somatic hypermutation of proto-oncogenes.

EBV-Positive and EBV-Negative Posttransplant Diffuse Large B Cell Lymphomas Have Distinct Genomic and Transcriptomic Features

“…Given this, as well as other evidences that EBV þ and EBV À PT-DLBCL are distinct entities (35,36), thorough revision and possible reclassification of PT-DLBCL should be considered. In addition, the high level of genomic and transcriptomic similarities between EBV À PT-DLBCL and IC-DLBCL documented in our present and previous studies (5) provides strong evidence that EBV À PT-DLBCL is not driven by a virus other than EBV, as debated (37). With the current treatment protocols, EBV þ and EBV À monomorphic PTLD seem to have an equally bad prognosis (38); however, the biological differences associated with the EBV status offer an opportunity for differential therapy.…”

Epstein-Barr virus–associated lymphoproliferative disorders

“…Because approximately 50% of PTLD cases are derived from GC B cells lacking a functional BCR because of certain crippling mutations, and because these cells manage to escape apoptosis despite lacking antigen affinity, it is believed that EBV aids in rescuing these cells from an imminent programmed cell death [52,53]. As in Hodgkin cases, LMP1 and LMP2A may replace survival signals induced by activated BCR and CD40 receptors and also activate the NF-κB signaling pathway, inducing proliferation of neoplastic cells.…”

Malignancy After Solid Organ Transplantation: An Overview

“…The molecular pathogenesis of PTLD is most likely a result of the combined effects of immunosuppressive agents and infection by oncogenic viruses such as the EBV [37]. In an uncompromised host, EBV-infected cells are killed by EBV-specific cytotoxic T lymphocytes (CTLs).…”

“…Subsequently, constant lymphocytic stimulation in the setting of a foreign allograft, either in the presence or absence of EBV, may be important in the development of mutations and eventual malignancy [22]. In addition to EBV, the presence of genetic or epigenetic mutations can also lead to the development of PTLD: molecular alterations of BCL-6, c-MYC, and p53, DNA hypermethylation, and aberrant somatic hypermutation have been implicated in PTLD [37].…”

“…Early, polymorphic lymphomas are usually EBV positive and respond well to immunosuppression reduction [31,37]. Late-onset, monomorphic disease is usually EBV negative, unresponsive to immunosuppression reduction, and associated with a worse prognosis [31,38].…”