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Phenogenomic features of post-transplant PBL
vations.2,51 Almost half of the cases, including both EBV+ and EBV– cases, displayed minor foci of plasmacytic differentia- tion, concordant with the findings of other investigators.3,51 This feature was more common in PBL with chromosome 17/TP53 abnormalities. As reported for other B-cell PTLD,48 the majority (64%) of PT-PBL showed evidence of germinal center transit. Although the B-cell program is characteristi- cally downregulated in PBL,2,3 a proportion of cases express B-cell antigens.3,52,53 Partial CD20 expression was observed in 27% of PT-PBL, a frequency similar to that reported for other types of PBL (23%).53 Over half of the PT-PBL showed variable PAX5 and/or CD79a positivity. Expression of CD79a has been documented in 45% of HIV-related and 68% of PT-PBL3 and PAX5 in 23-26% of mostly HIV-related PBL.52,53 In contrast to the findings of Montes-Moreno et al., who noted more frequent CD20 and/or PAX5 expression in EBV– PBL, a larger proportion of EBV+ PT-PBL (60%) was PAX5+.53 The two EBV– PAX5+ and CD79a+ PBL had high- level MSI; otherwise, no differences in functional groups of mutations were apparent between cases expressing or lack- ing B-cell antigens. Since all patients with PTLD preceding PBL received rituximab, it is unclear whether the anti-CD20 antibody therapy was responsible for CD20 negativity of the PBL and/or promoted plasmablastic differentiation. Expression of CD56 and CD10, observed in a subset of PT- PBL, has been reported more frequently in HIV-related and PT-PBL.2,3,53 Moreover, variability in the Ki-67 proliferation indices of our PT-PBL is in line with the findings of Morscio et al. (25-100% Ki-67 labeling in PT-PBL).2
PD-L1 expression, tumor infiltration by PD1+ T cells, and upregulation of genes related to immune escape, have been observed in EBV+ PBL7,8,11 and PTLD.54 PD-L1 expression by tumor cells was observed in subsets of EBV+ and EBV– PT- PBL; the latter also harboring mutations in immune evasion- related genes (FAS and CD58). PD-1 expression by tumor cells noted in one case has been previously reported in 5% of PBL.52
Thorough clinicopathological correlation is essential for resolving the differential diagnosis of PBL, which includes other neoplasms with plasmablastic features e.g., large B-cell lymphoma arising from HHV8-associated multicentric Castleman disease, primary effusion lymphoma, and ALK+ large B-cell lymphoma. Negative staining for HHV8 and ALK excluded these possibilities. Distinguishing between PBL and plasmablastic MM , however, can be difficult and a multimodal approach is required to make a correct diagno- sis. Serum paraprotein analysis is not helpful as monoclonal proteins can be observed in some PBL patients,14 as was the case in our series. Importantly, none of the PT-PBL with bone marrow biopsies showed morphologic or immunophenotypic evidence of marrow involvement, all lacked bone (lytic) lesions on imaging as well as myeloma- related laboratory abnormalities, including hypercalcemia, and the vast majority occurred at mucosal sites, findings that
do not support a diagnosis of MM.55 Furthermore, although some of the genetic abnormalities observed in PT-PBL over- lapped with those of MM, they were detected in both EBV+ and EBV– PT-PBL and in HIV-related PBL.7,11 Furthermore, the overall complement of alterations differed from that of MM.
PT-PBL usually occur late after transplantation (median 96 months; range, 2-360 months)2,14 and are more frequent in males and in recipients of heart and kidney allografts,2,3,12,14 which was also true in our series. However, in contrast to a predominance of skin and lymph node involvement described previously,2,3 we noted a high frequency of intes- tinal disease (55%), with primary skin involvement observed in only 18% of patients. In addition to the oral cav- ity, the gastrointestinal tract is also a frequent site for HIV- related PBL.3
Age, stage, and nodal involvement influence the prognosis of PBL, which is typically poor,12 although long survival, as observed for some of our PT-PBL patients, has been reported previously.2 In contrast to Zimmermann et al., we did not observe that patients with EBV– PT-PBL or PBL harboring MYC and/or IGH rearrangements had a worse prognosis.14 We could not determine any correlation between patients’ outcome and particular functional groups of mutations or mutational burden, although most had stage IV disease. Most patients in our cohort received lymphoma-directed therapies using conventional chemotherapy and/or radio- therapy. However two patients, including one who is still alive, also received bortezomib, a proteasome inhibitor fre- quently used to treat MM, which, in combination with lym- phoma regimens, has been shown to be effective in treating PBL.3
In summary, our study is the first to investigate the genetic landscape of PT-PBL, revealing recurrent mutations in epige- netic modifiers and DNA damage response and repair, MAPK, JAK/STAT, NOTCH, and immune surveillance path- way genes. The observed genomic alterations overlap those reported for HIV-related PBL as well as subtypes of immunocompetent DLBCL and MM. Our findings reiterate the phenotypic heterogeneity of this rare type of PTLD, pro- vide novel insights into PT-PBL biology and identify path- ways amenable to targeted therapies.
Disclosures
No conflicts of interest to disclose.
Contributions
RL and GB led the project, analyzed data and wrote the manu- script, PR performed research and analyzed data, CS performed research, analyzed data and critically reviewed the manuscript, MMsupervisedmolecularanalyses,VMperformedcytogenetic analyses, SH performed molecular analyses and analyzed data, DR and FM performed research and obtained clinical data, BA and DP contributed to interpreting the data and critically reviewed the manuscript.
References
1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th edition, Volume 2. 2016.
2.Morscio J, Dierickx D, Nijs J, et al. Clinicopathologic comparison of plas- mablastic lymphoma in HIV-positive, immunocompetent, and posttransplant
patients: single-center series of 25 cases and meta-analysis of 277 reported cases. Am J Surg Pathol. 2014;38(7):875-886.
3. Castillo JJ, Bibas M, Miranda RN. The biolo- gy and treatment of plasmablastic lym- phoma. Blood. 2015;125(15):2323-2330.
4.Li YJ, Li JW, Chen KL, et al. HIV-negative plasmablasticlymphoma:reportof8cases and a comprehensive review of 394 pub- lishedcases.BloodRes.2020;55(1):49-56.
5. Chang CC, Zhou X, Taylor JJ, et al. Genomic profiling of plasmablastic lymphoma using array comparative genomic hybridization (aCGH): revealing significant overlapping genomic lesions with diffuse large B-cell lymphoma. J Hematol Oncol. 2009;2:47.
6.Sarkozy C, Kaltenbach S, Faurie P, et al. Array-CGHpredictsprognosisinplasmacell post-transplantation lymphoproliferative disorders. Genes Chromosomes Cancer.
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