{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T03:27:04Z","timestamp":1794367624874,"version":"4.9.0"},"reference-count":53,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"8","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are immunomodulatory molecules overexpressed in lymphomas and are promising immunotherapy targets for hematologic malignancies. However, studies of PD-1\/PD-L1 overexpression and their clinical significance in aggressive pediatric non-Hodgkin lymphomas (NHL) are limited. We assessed PD-1\/PD-L1 overexpression using immunohistochemistry in 68 aggressive pediatric NHL: ALK-positive anaplastic large cell lymphoma (ALK+ ALCL, n=8), Burkitt lymphoma (BL, n=27), and large B-cell lymphoma (LBCL) de novo LBCL, n=22 and diffuse LBCL arising as monomorphic post-transplant lymphoproliferative disorder [PTLD-DLBCL], n=11. In LBCL, correlations between PD-L1 overexpression and Epstein-Barr virus (EBV) status, cell of origin, stage, nodal status, overall survival (OS), and event-free survival (EFS) were examined. The genetic mechanisms of PD-L1 overexpression were investigated using targeted next-generation sequencing (NGS) and cytogenetic data. All ALK+ ALCL samples, 50.0% of de novo LBCL (11\/22), 72.7% of PTLD-DLBCL (8\/11), and no BL overexpressed PD-L1. Overexpressed PD-L1 correlated with EBV positivity (P=0.033) in LBCL and lower EFS in de novo LBCL (P=0.017). NGS of select LBCL revealed distinct somatic mutations and an ultra-hypermutated PTLD-DLBCL. Most cases with 9p24.1 copy gains overexpressed PD-L1 although some cases had no discernible genetic drivers of PD-L1 overexpression. Overexpressed PD-L1 is common in pediatric LBCL, associated with EBV positivity and 9p24.1 gains, and may have prognostic significance in de novo LBCL. Furthermore, diverse molecular mechanisms for PD-L1 overexpression in aggressive pediatric NHL can occur. Thus, additional studies exploring the therapeutic and prognostic significance and molecular mechanisms of PD-L1 overexpression in aggressive pediatric NHL are warranted.<\/jats:p>","DOI":"10.3324\/haematol.2021.280342","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T02:15:41Z","timestamp":1643249741000},"page":"1880-1890","source":"Crossref","is-referenced-by-count":18,"title":["Programmed cell death ligand 1 expression in aggressive pediatric non-Hodgkin lymphomas: frequency, genetic mechanisms, and clinical significance"],"prefix":"10.3324","volume":"107","author":[{"given":"Kevin E.","family":"Fisher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizmery S.","family":"Ferguson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy M.","family":"Coffey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian Y.","family":"Merritt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan L.","family":"Curry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea N.","family":"Marcogliese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela M.","family":"Major","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kala Y.","family":"Kamdar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dolores H.","family":"Lopez-Terrada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Choladda V.","family":"Curry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2022,1,27]]},"reference":[{"key":"38589","doi-asserted-by":"crossref","unstructured":"Weber J. 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PD-L1 expression is associated with ALK positivity and STAT3 activation, but not outcome in patients with systemic anaplastic large cell lymphoma. Mod Pathol. 2020; 33(3):324-333.","DOI":"10.1038\/s41379-019-0336-3"},{"key":"38601","doi-asserted-by":"crossref","unstructured":"Kinch A, Sundstr\u00f6m C, Baecklund E, Backlin C, Molin D, Enblad G. Expression of PD-1, PD-L1, and PD-L2 in posttransplant lymphoproliferative disorder after solid organ transplantation. Leuk Lymphoma. 2019; 60(2):376-384.","DOI":"10.1080\/10428194.2018.1480767"},{"key":"38602","doi-asserted-by":"crossref","unstructured":"Chan TA, Yarchoan M, Jaffee E. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol. 2019; 30(1):44-56.","DOI":"10.1093\/annonc\/mdy495"},{"key":"38603","doi-asserted-by":"crossref","unstructured":"Rizvi NA, Hellmann MD, Snyder A. Cancer immunology. 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J Clin Oncol. 2016; 34(23):2690-2697.","DOI":"10.1200\/JCO.2016.66.4482"},{"key":"38607","doi-asserted-by":"crossref","unstructured":"Kataoka K, Shiraishi Y, Takeda Y. Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers. Nature. 2016; 534(7607):402-406.","DOI":"10.1038\/nature18294"},{"key":"38608","doi-asserted-by":"crossref","unstructured":"Chen BJ, Chapuy B, Ouyang J. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 2013; 19(13):3462-3473.","DOI":"10.1158\/1078-0432.CCR-13-0855"},{"key":"38609","doi-asserted-by":"crossref","unstructured":"Green MR, Rodig S, Juszczynski P. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012; 18(6):1611-1618.","DOI":"10.1158\/1078-0432.CCR-11-1942"},{"key":"38610","doi-asserted-by":"crossref","unstructured":"Atsaves V, Tsesmetzis N, Chioureas D. PD-L1 is commonly expressed and transcriptionally regulated by STAT3 and MYC in ALK-negative anaplastic large-cell lymphoma. Leukemia. 2017; 31(7):1633-1637.","DOI":"10.1038\/leu.2017.103"},{"key":"38611","doi-asserted-by":"crossref","unstructured":"Davis KL, Fox E, Merchant MS. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2020; 21(4):541-550.","DOI":"10.1016\/S1470-2045(20)30023-1"},{"key":"38612","doi-asserted-by":"crossref","unstructured":"Geoerger B, Kang HJ, Yalon-Oren M. Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2020; 21(1):121-133.","DOI":"10.1016\/S1470-2045(19)30671-0"},{"key":"38613","doi-asserted-by":"crossref","unstructured":"Hamanishi J, Mandai M, Matsumura N, Abiko K, Baba T, Konishi I. PD-1\/PD-L1 blockade in cancer treatment: perspectives and issues. Int J Clin Oncol. 2016; 21(3):462-473.","DOI":"10.1007\/s10147-016-0959-z"},{"key":"38614","doi-asserted-by":"crossref","unstructured":"Davis KL, Agarwal AM, Verma AR. Checkpoint inhibition in pediatric hematologic malignancies. Pediatr Hematol Oncol. 2017; 34(6-7):379-394.","DOI":"10.1080\/08880018.2017.1383542"},{"key":"38615","doi-asserted-by":"crossref","unstructured":"Luchtel RA, Dasari S, Oishi N. Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements. Blood. 2018; 132(13):1386-1398.","DOI":"10.1182\/blood-2018-03-838524"},{"key":"38616","doi-asserted-by":"crossref","unstructured":"Teng MW, Ngiow SF, Ribas A, Smyth MJ. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res. 2015; 75(11):2139-2145.","DOI":"10.1158\/0008-5472.CAN-15-0255"},{"key":"38617","doi-asserted-by":"crossref","unstructured":"Kiyasu J, Miyoshi H, Hirata A. Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood. 2015; 126(19):2193-2201.","DOI":"10.1182\/blood-2015-02-629600"},{"key":"38618","doi-asserted-by":"crossref","unstructured":"Kwon D, Kim S, Kim PJ. Clinicopathological analysis of programmed cell death 1 and programmed cell death ligand 1 expression in the tumour microenvironments of diffuse large B cell lymphomas. Histopathology. 2016; 68(7):1079-1089.","DOI":"10.1111\/his.12882"},{"key":"38619","doi-asserted-by":"crossref","unstructured":"Xing W, Dresser K, Zhang R. PD-L1 expression in EBV-negative diffuse large B-cell lymphoma: clinicopathologic features and prognostic implications. Oncotarget. 2016; 7(37):59976-59986.","DOI":"10.18632\/oncotarget.11045"},{"key":"38620","doi-asserted-by":"crossref","unstructured":"Swerdlow SH, Campo E, Pileri SA. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016; 127(20):2375-2390.","DOI":"10.1182\/blood-2016-01-643569"},{"key":"38621","doi-asserted-by":"crossref","unstructured":"Angelo Rosolen A, Perkins SK, Pinkerton CR. Revised International Pediatric Non-Hodgkin Lymphoma Staging System. J Clin Oncol. 2015; 33(18):2112-2118.","DOI":"10.1200\/JCO.2014.59.7203"},{"key":"38622","doi-asserted-by":"crossref","unstructured":"Schiefer AI, Salzer E, F\u00fcreder A. PD-L1 and PD1 expression in post-transplantation lymphoproliferative disease (PTLD) of childhood and adolescence: an inter- and intra-individual descriptive study covering the whole spectrum of PTLD categories. Cancer Med. 2019; 8(10):4656-4668.","DOI":"10.1002\/cam4.2394"},{"key":"38623","doi-asserted-by":"crossref","unstructured":"Hans CP, Weisenburger DD, Greiner TC. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004; 103(1):275-282.","DOI":"10.1182\/blood-2003-05-1545"},{"key":"38624","doi-asserted-by":"crossref","unstructured":"Zhou T, Bloomquist MS, Ferguson LS. Pediatric myeloid sarcoma: a single institution clinicopathologic and molecular analysis. Pediatr Hematol Oncol. 2020; 37(1):76-89.","DOI":"10.1080\/08880018.2019.1683107"},{"key":"38625","doi-asserted-by":"crossref","unstructured":"Li MM, Datto M, Duncavage EJ. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017; 19(1):4-23.","DOI":"10.1016\/j.jmoldx.2016.10.002"},{"key":"38626","doi-asserted-by":"crossref","unstructured":"Giulino-Roth L, Wang K, MacDonald TY. Targeted genomic sequencing of pediatric Burkitt lymphoma identifies recurrent alterations in antiapoptotic and chromatin-remodeling genes. Blood. 2012; 120(26):5181-5184.","DOI":"10.1182\/blood-2012-06-437624"},{"key":"38627","doi-asserted-by":"crossref","unstructured":"Shlien A, Campbell BB, de Borja R. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. 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Blood. 2015; 126(7):863-872.","DOI":"10.1182\/blood-2015-02-630632"},{"key":"38631","doi-asserted-by":"crossref","unstructured":"McCord R, Bolen CR, Koeppen H. PD-L1 and tumor-associated macrophages in de novo DLBCL. Blood Adv. 2019; 3(4):531-540.","DOI":"10.1182\/bloodadvances.2018020602"},{"key":"38632","doi-asserted-by":"crossref","unstructured":"Garcia-Lacarte M, Grijalba SC, Melchor J, Arnaiz-Lech\u00e9 A, Roa S. The PD-1\/PD-L1 checkpoint in normal germinal centers and diffuse large B-cell lymphomas. Cancers (Basel). 2021; 13(18):4683.","DOI":"10.3390\/cancers13184683"},{"key":"38633","doi-asserted-by":"crossref","unstructured":"Li X, Zhang W. Expression of PD-L1 in EBV-associated malignancies. Int Immunopharmacol. 2021; 95:107553.","DOI":"10.1016\/j.intimp.2021.107553"},{"key":"38634","doi-asserted-by":"crossref","unstructured":"Chong LC, Twa DD, Mottok A. Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas. 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Int J Cancer. 2019; 144(9):2303-2312.","DOI":"10.1002\/ijc.32002"},{"key":"38638","doi-asserted-by":"crossref","unstructured":"Yarchoan M, Albacker LA, Hopkins AC. PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers. JCI Insight. 2019; 4(6):e126908.","DOI":"10.1172\/jci.insight.126908"},{"key":"38639","doi-asserted-by":"crossref","unstructured":"Reddy A, Zhang J, Davis NS. Genetic and functional drivers of diffuse large B cell lymphoma. Cell. 2017; 171(2):481-494.","DOI":"10.1016\/j.cell.2017.09.027"},{"key":"38640","doi-asserted-by":"crossref","unstructured":"Kotlov N, Bagaev A, Revuelta MV. Clinical and biological subtypes of B-cell lymphoma revealed by microenvironmental signatures. Cancer Discov. 2021; 11(6):1468-1489.","DOI":"10.1158\/2159-8290.CD-20-0839"},{"key":"38641","doi-asserted-by":"crossref","unstructured":"Wright GW, Huang DW, Phelan JD. A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications. 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