title: Molecular characterization of post-transplant lymphoproliferative disorders of donor origin occurring in liver transplant recipients.
abstract: Post-transplant lymphoproliferative disorders (PTLDs) represent a frequent complication of solid organ transplantation. Although most PTLDs arise from recipient lymphoid cells, a considerable fraction of cases may arise from donor B-cells. In an attempt to clarify the histogenesis and pathogenesis of PTLDs derived from donor B-cells, monoclonal PTLDs occurring in liver transplant recipients were chosen as a model to compare donor (D-PTLDs) versus recipient PTLDs (R-PTLDs). The tumour panel included nine D-PTLDs and six R-PTLDs. D-PTLDs were early-onset, EBV-infected lymphoproliferations classified as polymorphic PTLD (P-PTLD; n = 7) or diffuse large B-cell lymphoma (DLBCL; n = 2) with tumour localization confined to the hepatic hilum. All R-PTLDs were late-onset DLBCLs and showed extrahepatic localization. A BCL-6(-)/MUM1(+)/CD138(+/-) phenotype, consistent with a post-germinal centre (GC) stage of pre-terminal B-cell differentiation, was observed in all D-PTLDs and in 2/6 R-PTLDs, whereas a BCL6(+)/MUM1(-)/CD138(-) profile, reminiscent of GC B-cells, was detected in 4/6 R-PTLDs. The presence of somatic IGHV hypermutation was observed in 6/9 D-PTLDs and in 4/6 R-PTLDs, suggesting derivation from antigen-experienced B-cells. IGHV4-39 was the IGHV gene most frequently encountered, being rearranged in 3/9 D-PTLDs. Among IGHV-mutated PTLDs, a mutational profile suggesting antigen stimulation and/or selection was observed in 4/6 D-s and in 2/4 R-PTLDs. The presence of ongoing IGHV mutations was detected in 2/4 D-PTLDs. Aberrant SHM was detected in 10/15 (66.7%) PTLDs, including 6/9 D-PTLDs and 4/6 R-PTLDs. Our findings suggest that (i) D-PTLDs show a clinical presentation distinct from R-PTLDs; (ii) immunophenotypic and genetic features of D-PTLDs are consistent with mature, GC-experienced B-cells; (iii) transformed donor-derived B-cells may experience antigen-driven stimulation and selection, and may acquire genetic lesions during neoplastic expansion in the recipient environment; and (iv) EBV infection and expression of viral oncoproteins may be relevant in the pathogenesis of D-PTLDs.
authors.affiliation: Division of Hematology, Department of Clinical and Experimental Medicine & BRMA, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy. capello@med.unipmn.it
authors.forename: Daniela
authors.initials: D
authors.lastname: Capello
authors.forename: Silvia
authors.initials: S
authors.lastname: Rasi
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Oreste
authors.forename: Silvio
authors.initials: S
authors.lastname: Veronese
authors.forename: Michaela
authors.initials: M
authors.lastname: Cerri
authors.forename: Erika
authors.initials: E
authors.lastname: Ravelli
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Ernesto
authors.initials: E
authors.lastname: Minola
authors.forename: Anna
authors.initials: A
authors.lastname: Colosimo
authors.forename: Marcello
authors.initials: M
authors.lastname: Gambacorta
authors.forename: Giuliana
authors.initials: G
authors.lastname: Muti
authors.forename: Enrica
authors.initials: E
authors.lastname: Morra
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
mesh_terms: D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D005260:Female; D015321:Gene Rearrangement; D018858:Germinal Center; D004854:Herpesvirus 4, Human; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics; D016130:Immunophenotyping; D016031:Liver Transplantation / Q000009:adverse effects*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011183:Postoperative Complications / Q000276:immunology / Q000821:virology*; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D007135:Immunoglobulin Variable Region