Phenogenomic heterogeneity of post-transplant plasmablastic lymphomas

Abstract

Plasmablastic lymphoma (PBL) is a rare and clinically aggressive neoplasm that typically occurs in immunocompromised individuals, including those with HIV infection and solid organ allograft recipients. Most prior studies have focused on delineating the clinicopathologic features and genetic attributes of HIV-related PBLs, where MYC deregulation and EBV infection, and more recently, mutations in JAK/STAT, MAP kinase, and NOTCH pathway genes have been implicated in disease pathogenesis. The phenotypic spectrum of post-transplant (PT)-PBLs is not well characterized and data on underlying genetic alterations are limited. Hence, we performed comprehensive histopathologic and immunophenotypic evaluation and targeted sequencing of 18 samples from 11 patients (8 males, 3 females, age range 12-76 years) with PT-PBL; 8 de novo and 3 preceded by other types of PTLDs. PT-PBLs displayed morphologic and immunophenotypic heterogeneity and some features overlapped those of plasmablastic myeloma. Six (55%) cases were EBV+ and 5 (45%) showed MYC rearrangement by fluorescence in situ hybridization. Recurrent mutations in epigenetic regulators (KMT2/MLL family, TET2) and DNA damage repair and response (TP53, mismatch repair genes, FANCA, ATRX), MAP kinase (KRAS, NRAS, HRAS, BRAF), JAK/STAT (STAT3, STAT6, SOCS1), NOTCH (NOTCH1, NOTCH3, SPEN), and immune surveillance (FAS, CD58) pathway genes were observed, with EBV+ and EBV- cases exhibiting similarities and differences in their mutational profiles. Clinical outcomes also varied, with survival ranging from 0-15.9 years postdiagnosis. Besides uncovering the biological heterogeneity of PT-PBL, our study highlights similarities and distinctions between PT-PBLs and PBLs occurring in other settings and reveals potentially targetable oncogenic pathways in disease subsets.

EBV‐positive diffuse large B‐cell lymphoma, not otherwise specified: 2022 update on diagnosis, risk‐stratification, and management

“…33 PBL is an aggressive B-cell lymphoma usually arising in an immunosuppressive setting, such as HIV infection, but also occurs in an immunocompetent setting. [34][35][36] It usually affects adult males who present with extranodal disease and advanced stage of disease. 35,37 The histopathological presentation is characterized by a diffuse infiltrate of large, atypical cells with round to oval central or peripheral nuclei, single nucleoli, and abundant amphophilic cytoplasm, resembling an immunoblast or a plasmablast.…”

“…PBL is an aggressive B‐cell lymphoma usually arising in an immunosuppressive setting, such as HIV infection, but also occurs in an immunocompetent setting 34–36 . It usually affects adult males who present with extranodal disease and advanced stage of disease 35,37 .…”

KRAS and RAS-MAPK Pathway Deregulation in Mature B Cell Lymphoproliferative Disorders

“…In regard to the association with prognosis, Frontzek et al reported a trend toward unfavorable outcomes in PBL patients with NRAS aberrations [52]. Recurrent RAS/RAF aberrations (55% of mutation incidence) were also identified in post-transplant PBLs, a rare type of post-transplant lymphoproliferative disorder accounting for 5-14% of PBL cases [133]. The ctivation of RAS-MAPK signaling emerges as a pathogenetic mechanism in plasma cell dyscrasias, [49] and the therapeutic potential of RAS/RAF/MEK/ERK inhibition should be addressed in PBL [52].…”

Recent Advances in Adult Post-Transplant Lymphoproliferative Disorder

“…Recurrent mutations in epigenetic modifiers, such as the KMT2/MLL family of histone H3 methyltransferases were among the most frequent alterations. Treatment was variable, mainly including rituximab and/or chemotherapy (sometimes with addition of bortezomib) with or without radiation; however, given the heterogeneity, no conclusions can be made [ 142 ]. Another case series of eight patients combined IST reduction with systemic chemotherapy; however, five patients died from early progression.…”