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R.J. Leeman-Neill et al.
(55%). The frequency of TP53 mutations in PT-PBL (27%) was comparable to that reported in monomorphic PTLD (DLBCL) (36-44%) and, as in the latter, mutations, were more common in EBV– cases.21,30 A lower frequency of TP53 mutations has been observed in HIV-related PBL (9%).7 Of interest, TP53 mutations are present in up to 23% of immunocompetent DLBCL; however, a high proportion of DLBCL with plasmablastic/plasmacytoid features (85%) harbor TP53 deletions.24-26,31 TP53 mutations are uncommon in MM at diagnosis,22,23,28 but can be detected at disease pro- gression, concomitant with TP53 deletions, and are associat- ed with poor prognosis.23,32 MSI, resulting from mutations in DNA MMR genes, was identified in two EBV– PBL that showed a high mutation burden. MMR defects and MSI are unusual in B-cell non-Hodgkin lymphomas of immunocom- petent individuals, but not infrequent in MM33 and immun- odeficiency-associated B cell neoplasms, including PTLD.34
Gain-of-function mutations in MAPK pathway genes also appear to be more frequent in PT-PBL (55%) compared to HIV-related PBL (28%).7 Moreover, concurrent mutations of multiple MAPK pathway members, noted in several PT-PBL, could reflect the presence of multiple subclones, as described in MM.35 Different members of the MAPK pathway are mutated in diverse hematologic and lymphoid malignancies. However, KRAS and NRAS mutations, which are common in MM,23 are infrequent in immunocompetent DLBCL. Knowles et al. reported an NRAS mutation in a post-trans- plantplasmacytoidimmunoblasticlymphoma,whichcould have represented a PBL.36 Well-known, activating BRAF K601E and codon 469 mutations were observed in our study. The latter and the canonical V600E mutation have also been documented in PBL arising in other settings.7,11 Intriguingly, the BRAF V600E mutation was recently report- ed in an immunomodulatory therapy-associated EBV+ anaplastic large cell lymphoma.37 Further studies are required to determine whether this mutation is a recurrent, lineage- independent, phenomenon in immune dysregulation-relat- ed lymphomas.
Recurrent mutations in members of the NOTCH signaling pathway, which controls B-cell fate determination,38 were observed in 45% of PT-PBL, mostly in EBV– cases (80% vs. 17% in EBV+ cases); it is unclear whether EBNA2 activates NOTCH signaling in a proportion of EBV+ PBL.39 Gain- and loss-of-function alterations in NOTCH pathway genes have been described in a variety of hemato-lymphoid neoplasms, including 24% of HIV-related PBL and some immunocom- petent PBL.7,1 The pathogenesis of immunocompotent DLBCL of the N1 molecular subclass, which harbor NOTCH1 mutations and display a plasmacytic phenotype,26 is considered to be distinct from DLBCL of the BN2/Cluster 1 molecular subclass that have mutations in NOTCH2 and/or the NOTCH regulator, SPEN.24,26 However, we observed mutations in both, NOTCH1 and NOTCH2, as well as SPEN, at times concurrently, in PT-PBL. Deregulated activity of the NOTCH signaling pathway has also been implicated in the pathogenesis of MM, facilitating plasma cell growth and migration, but via different (non-mutation- al) mechanisms.40
JAK/STAT signaling, due to constitutive activation conse- quent to mutations, downstream effects of cytokine signal- ing, or EBV infection, contributes to the pathogenesis of sev- eral types of lymphoid neoplasms.41 Recurrent alterations in constituents of the JAK/STAT pathway, as observed in 36% ofourcasesandahigherproportion(62%)ofHIV-related PBL, are known or predicted to enhance signaling. The
STAT3 D661Y mutation, also detected in 8% of HIV-related PBL7 and STAT6 E372K mutations, occur in the SH2 and DNA binding domains, respectively, resulting in nuclear localization and activation of the transcription factors.42,43 Recurrent STAT3 mutations were noted exclusively in EBV+ HIV-related PBL,11 but mutations in several JAK/STAT path- way members, including STAT3, were observed in both EBV+ and EBV– PT-PBL. Multiple concomitant mutations in SOCS1, a negative regulator of JAK family proteins, present in one PT-PBL, have not been functionally characterized, but are predicted to inactivate SOCS1.44 Abrogation of SOCS1 and SOCS3 function by epigenetic silencing or mutations has been described in other immunodeficiency-associated non-Hodgkin lymphomas, including monomorphic PTLD (DLBCL) and polymorphic PTLD.45
Mutations in immune surveillance-associated genes also occurred in PT-PBL. FAS, a member of the tumor necrosis factor receptor superfamily and an important mediator of T- cell cytotoxicity, was recurrently mutated in our series. FAS mutations have not been previously reported in PTLD or PBL, but have been documented in MM.46 They are also common in immunocompetent DLBCL, particularly in Cluster 1, which frequently also harbor NOTCH pathway mutations,24 and, as in our series, are almost exclusively seen in EBV– cases.29 In addition to FAS mutation, one PBL had a frameshift mutation in CD58, another immune surveillance- related protein required for activation of natural killer cells, which is commonly mutated in immunocompetent DLBCL.47
Prior studies have reported variants in PRDM1, an inducer of terminal B-cell differentiation and regulator of MYC, in 20-50% of PBL.11,17 However, many of the variants were not expected to be deleterious.11,17 PRDM1 variants were detect- ed in 4% of HIV-related PBL.7 None of the PT-PBL in our cohort had pathogenic PRDM1 mutations and only a single VUS (Q586H) was observed.
Similar to our findings in PT-PBL, differences in the fre- quency or spectrum of genomic abnormalities between EBV+ and EBV– tumors have also been delineated in other types of B-cell PTLD.21,48-50 A lower mutation burden has been noted in EBV+ compared to EBV– monomorphic PTLD (DLBCL); this has been ascribed to the inherent oncogenic activity of the virus and, hence, a reduced requirement for proto-oncogene or tumor suppressor gene alterations.
EBV+ cases constituted 55% of our PT-PBL, a frequency not significantly different from previous studies of PT-PBL (67-79%) and intermediate between that reported for HIV- related PBL (75-90%) and immunocompetent PBL (33- 50%).2-4,7,12 Data regarding the EBV latency program in PBL have been conflicting. Ambrosio et al. reported a non-canon- ical EBV latency program i.e., partial expression of proteins characteristic of type II latency with simultaneous expres- sion of lytic phase proteins in HIV+ and HIV– cases.10 Similarly, gene expression studies of HIV-related PBL have shown a much higher expression of the EBV lytic genes (BALF4 and BALF5) than canonical latency program genes, in most cases.7 Castillo et al., however, described latency I or III in most HIV-related EBV+ PBL, latency I in immunocom- petent PBL, and predominantly latency III in PT-PBL.3 The vast majority of the EBV+ cases in our study displayed a latency II profile, similar to the observations of Morscio et al.,2 but different from those of Zimmerman et al., who reported mostly latency 0/I in PT-PBL.14
In our series, PBL exhibited morphologic and immunophenotypic heterogeneity, in line with prior obser-
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haematologica | 2022; 107(1)