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.

Figure 1.

Morphologic spectrum of post-transplant plasmablastic lymphomas. Representative hematoxylin and eosin (H&E)-stained sections of post-transplant plasmablastic lymphomas - from (A) case 4, showing a monotonous infiltrate of plasmablasts, with insets highlighting areas of plasmablastic morphology (top) and focal areas of plasmacytic differentiation (bottom), (B) case 5, showing numerous tingible body macrophages that impart a “starry sky” appearance, and (C) case 7, showing pleomorphic morphology, with insets displaying areas of plasmablastic morphology (top) and anaplastic-appearing multinucleated cells (bottom).

Figure 2.

Immunophenotypic features of post-transplant plasmablastic lymphomas. (A) Hematoxylin and eosin (H&E)-stained section of tissue from case 2 showing plasmablasts, which are (B) partially positive for CD138 and (C) diffusely positive for MUM1 and display variable (D) PAX5 and (E) CD56 expression and evidence of (F) EBV infection by in situ hybridization for EBER. (G) H&E-stained section of case 9 showing plasmablasts, which are (H) partially positive for CD79a, (I) diffusely positive for MUM1 and display (J) aberrant CD10 expression, (K) P53 overexpression, and (L) moderate (30%) MYC expression.