EBV-Negative Monomorphic B-Cell Posttransplant Lymphoproliferative Disorder with Marked Morphologic Pleomorphism and Pathogenic Mutations in ASXL1, BCOR, CDKN2A, NF1, and TP53

Abstract

Posttransplant lymphoproliferative disorders (PTLDs) are a diverse group of lymphoid or plasmacytic proliferations frequently driven by Epstein-Barr virus (EBV). EBV-negative PTLDs appear to represent a distinct entity. This report describes an unusual case of a 33-year-old woman that developed a monomorphic EBV-negative PTLD consistent with diffuse large B-cell lymphoma (DLBCL) 13 years after heart-lung transplant. Histological examination revealed marked pleomorphism of the malignant cells including nodular areas reminiscent of classical Hodgkin lymphoma (cHL) with abundant large, bizarre Hodgkin-like cells. By immunostaining, the malignant cells were immunoreactive for CD45, CD20, CD79a, PAX5, BCL6, MUM1, and p53 and negative for CD15, CD30, latent membrane protein 1 (LMP1), and EBV-encoded RNA (EBER). Flow cytometry demonstrated lambda light chain restricted CD5 and CD10 negative B-cells. Fluorescence in situ hybridization studies (FISH) were negative for cMYC, BCL2, and BCL6 rearrangements but showed deletion of TP53 and monosomy of chromosome 17. Next-generation sequencing studies (NGS) revealed numerous genetic alterations including 6 pathogenic mutations in ASXL1, BCOR, CDKN2A, NF1, and TP53(x2) genes and 30 variants of unknown significance (VOUS) in ABL1, ASXL1, ATM, BCOR, BCORL1, BRNIP3, CDH2, CDKN2A, DNMT3A, ETV6, EZH2, FBXW7, KIT, NF1, RUNX1, SETPB1, SF1, SMC1A, STAG2, TET2, TP53, and U2AF2.

Identification of Hub Genes and Key Pathways Associated with Two Subtypes of Diffuse Large B-Cell Lymphoma Based on Gene Expression Profiling via Integrated Bioinformatics

“…Although the translocations or deletions of ETV6 gene are reported in a variety of hematologic neoplasms, including acute myeloid and lymphoblastic leukemia, myelodysplastic syndrome, and myeloproliferative disorders, it is rarely reported in DLBCL [ 34 , 35 ]. A mutational analysis of primary central nervous system lymphoma also revealed that ETV6 might be an underlying target for this kind of lymphoma treatment [ 36 ]. In recent study [ 37 ], ETV6 and other 149 genes are identified as driver genes of DLBCL.…”

Distinctive Clinicopathologic Features of Monomorphic B-cell Post-transplant Lymphoproliferative Disorders in Children

“…Extensive molecular studies were performed on a monomorphic EBV-negative PTLD case that developed 13 years after a combined heart-lung transplant and revealed genetic alterations including 6 pathogenic mutations ( ASXL1 , BCOR , CDKN2A , NF1 , and TP53 x2) and 30 variants of unknown significance. 4 A study of 32 cases of monomorphic PTLD from two institutions also found that PTLDs diagnosed in the small bowel/mesentery were statistically more likely to be EBV-negative by EBER in situ hybridization, and they more frequently contained a pathogenic TP53 mutation than PTLDs diagnosed at other locations. All the EBV-negative cases subjected to testing (9 of 9, mostly adults) carried TP53 mutations, while only 2 of 15 EBV-positive cases showed mutated TP53.…”

“…Earlyonset PTLDs are typically EBV-driven lymphoproliferations, whereas late onset patients typically have monoclonal lymphoid malignancies that can lack EBV association. 4 The median time to developing PTLD is on average only 16 months for EBV-positive cases, whereas EBV-negative cases often develop PTLD much later (median time of 102 months after transplant). 5 In recent years, we also gained more knowledge about the pathologic characteristics of different forms of monomorphic B-cell PTLDs, and these differences may reflect the variations in pathogenesis of EBV-negative and positive cases.…”

“…Early-onset PTLDs are typically EBV-driven lymphoproliferations, whereas late onset patients typically have monoclonal lymphoid malignancies that can lack EBV association. 4 The median time to developing PTLD is on average only 16 months for EBV-positive cases, whereas EBV-negative cases often develop PTLD much later (median time of 102 months after transplant). 5…”

High ETV6 Levels Support Aggressive B Lymphoma Cell Survival and Predict Poor Outcome in Diffuse Large B-Cell Lymphoma Patients

“…What was rather unexpected were also findings regarding ETV6, which is an ETS family transcriptional factor with a crucial role in hematopoiesis and embryonic development [ 50 ]. While ETV6 is frequently rearranged or fused with other genes in human myeloid and lymphoid leukemias [ 51 , 52 ], it is only rarely altered in B-cell lymphoma [ 53 , 54 ]. Recently, however, whole-exome sequencing studies have found a significant fraction of DLBCL samples (mainly of the ABC-subtype) harboring ETV6 mutations/alterations [ 35 , 55 ].…”