Genetic and phenotypic analysis of B‐cell post‐transplant lymphoproliferative disorders provides insights into disease biology

Abstract

B-cell post-transplant lymphoproliferative disorders (PTLD) are classified as early lesions, polymorphic lymphomas (P-PTLD) and monomorphic lymphomas (M-PTLD). These morphologic categories are thought to reflect a biologic continuum, although supporting genetic data are lacking. To gain better insights into PTLD pathogenesis, we characterized the phenotypes, immunoglobulin (Ig) gene alterations and non-Ig gene (BCL6, RhoH/TTF, c-MYC, PAX5, CIITA, BCL7A, PIM1) mutations of 21 PTLD, including an IM-like lesion, 8 P-PTLD and 12 M-PTLD. Gene expression profile analysis was also performed in 12 cases. All PTLD with clonal Ig rearrangements showed evidence of germinal centre (GC) transit based on the analysis of Ig and BCL6 gene mutations, and 74% had a non-GC phenotype (BCL6 +/- MUM1+). Although surface Ig abnormalities were seen in 6/19 (32%) PTLD, only three showed 'crippling' Ig mutations indicating other etiologies for loss of the B-cell receptor. Aberrant somatic hypermutation (ASHM) was almost exclusively observed in M-PTLD (8/12 vs. 1/8 P-PTLD) and all three recurrent cases analysed showed additional mutations in genes targeted by ASHM. Gene expression analysis showed distinct clustering of PTLD compared to B-cell non-Hodgkin lymphomas (B-NHL) without segregation of P-PTLD from non-GC M-PTLD or EBV+ from EBV- PTLD. The gene expression pattern of PTLD appeared more related to that of memory and activated B-cells. Together, our results suggest that PTLD represent a distinct type of B-NHL deriving from an antigen experienced B-cell, whose evolution is associated with accrual of genetic lesions.

Post‐transplant Burkitt lymphoma is a more aggressive and distinct form of post‐transplant lymphoproliferative disorder

“…5,[9][10][11][12][13][14][15][16][17] This expression of EBV is much higher than that reported for both sporadic and immunodeficiencyassociated BL, primarily HIV-associated BL. [6][7][8] The interplay of active EBV infection in the immunosuppressed state with the development of BL-PTLD is noteworthy.…”

“…5 BL is an aggressive, mature B-cell lymphoma, composed of a monomorphic population of small to intermediate-sized, noncleaved, lymphoid cells with high mitotic and proliferation rates and a characteristic ''starrysky'' appearance imparted by the scattered tingible body macrophages engulfing apoptotic debris of the tumor. Ancillary studies with immunophenotyping and cytogenetic analysis confirm the diagnosis, separating it from a diffuse large B-cell lymphoma (DLBCL).…”

Determinación de la clonalidad en tejidos humanos

“…A diferencia de las demás pruebas que evalúan cambios patológicos del ADN, el principio de las pruebas para la evaluación de la clonalidad linfoide es un proceso fisiológico, de manera que el significado de los clones, en caso de encontrarse, se debe determinar en un contexto adecuado (24). Además de utilizarse en oncología, el estudio de los rearreglos es útil en casos de trasplante y enfermedades autoinmunes (17,25).…”

p52 Activation in Monomorphic B-Cell Posttransplant Lymphoproliferative Disorder/Diffuse Large B-Cell Lymphoma without BAFF-R Expression

“…7 DLBCL/ PTLD specimens generally demonstrated an activated pattern (Tables 2 and 3): of 21 cases, 19 expressed the NGC phenotype, and 2 could not be characterized because of nondetection of the four markers. 28 Of 30 DLBCL/IC cases, 12 expressed the GC pattern, and 18 expressed the NGC pattern (Table 3).…”