Recent insights in the pathogenesis of post-transplantation lymphoproliferative disorders.
Post-transplant lymphoproliferative disorder (PTLD) is an aggressive complication of solid organ and hematopoietic stem cell transplantation that arises in up to 20% of transplant recipients. Infection or reactivation of the Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, in combination with chronic immunosuppression are considered as the main predisposing factors, however insight in PTLD biology is fragmentary. The study of PTLD is complicated by its morphological heterogeneity and the lack of prospective trials, which also impede treatment optimization. Furthermore, the broad spectrum of underlying disorders and the graft type represent important confounding factors. PTLD encompasses different malignant subtypes that resemble histologically similar lymphomas in the general population. Post-transplant diffuse large B-cell lymphoma (PT-DLBCL), Burkitt lymphoma (PT-BL) and plasmablastic lymphoma (PT-PBL) occur most frequently. However, in many studies various EBV(+) and EBV(-) PTLD subtypes are pooled, complicating the interpretation of the results. In this review, studies of the gene expression pattern, the microenvironment and the genetic profile of PT-DLBCL, PT-BL and PT-PBL are summarized to better understand the mechanisms underlying post-transplantation lymphomagenesis. Based on the available findings we propose stratification of PTLD according to the histological subtype and the EBV status to facilitate the interpretation of future studies and the establishment of clinical trials.
Julie Morscio, Department for Imaging and Pathology, Translational Cell and Tissue Research, 3000 Leuven, Belgium.
Julie
J
Morscio
Julie Morscio, Department for Imaging and Pathology, Translational Cell and Tissue Research, 3000 Leuven, Belgium.
Thomas
T
Tousseyn
Burkitt lymphoma; Diffuse large B-cell lymphoma; Epstein-Barr virus; Immunodeficiency; Plasmablastic lymphoma; Post-transplant lymphoproliferative disorder
J Virol. 1994 Sep;68(9):6069-73
8057484
Blood. 2004 Jan 1;103(1):275-82
14504078
Genes Chromosomes Cancer. 2006 Mar;45(3):313-8
16283619
F1000Prime Rep. 2014 Mar 03;6:13
24669294
Am J Surg Pathol. 2003 Jun;27(6):818-27
12766587
Nat Immunol. 2010 Oct;11(10):889-96
20856220
Eur J Immunol. 2012 Feb;42(2):541-50
22105417
J Allergy Clin Immunol. 2005 Aug;116(2):251-61; quiz 262
16083776
Int J Cancer. 2007 Sep 15;121(6):1274-81
17520680
Biomark Res. 2015 Nov 04;3:28
26543559
Clin Cancer Res. 2012 Jul 15;18(14):3762-71
22645050
Blood. 2015 Apr 9;125(15):2323-30
25636338
Br J Cancer. 2015 Jul 28;113(3):500-9
26068398
Clin Transplant. 2003 Oct;17(5):451-4
14703929
Adv Cancer Res. 2010;107:119-36
20399962
J Med Virol. 2014 Oct;86(10):1788-95
24615673
Clin Transplant. 2013 Jul-Aug;27(4):E491-7
23781897
Blood. 2003 Nov 15;102(10):3775-85
12907442
Blood. 1997 Feb 15;89(4):1413-20
9028965
Int J Cancer. 2007 Apr 1;120(7):1387-95
17211884
Mod Pathol. 2005 Jun;18(6):806-15
15578069
Transplantation. 2005 Jul 27;80(2):176-84
16041261
PLoS Pathog. 2006 Mar;2(3):e23
16557291
Mod Pathol. 2014 Dec;27(12 ):1599-611
24762547
Exp Clin Transplant. 2014 Mar;12 Suppl 1:136-8
24635811
Hum Pathol. 2012 Dec;43(12):2274-81
22795355
J Pathol. 2008 Dec;216(4):440-50
18802929
Am J Clin Pathol. 2015 Nov;144(5):817-22
26486748
J Virol. 2013 Aug;87(16):9041-52
23760235
Curr Opin Immunol. 2016 Apr;39:59-67
26799208
Br J Haematol. 2010 May;149(4):569-77
20230398
Nat Med. 2002 Oct;8(10):1098-104
12219084
MBio. 2015 Oct 20;6(5):e01574-15
26489865
Hematol Oncol. 2005 Jun;23(2):61-7
16216037
Am J Transplant. 2016 Feb;16(2):414-25
26780579
Inflamm Bowel Dis. 2007 Jun;13(6):703-9
17230494
Blood. 2015 May 14;125(20):e14-22
25827832
Lancet. 2003 Jan 18;361(9353):217-23
12547545
Curr Opin Virol. 2015 Oct;14:138-44
26453799
Blood. 2013 Jul 18;122(3):424-33
23652804
Clin Cancer Res. 2012 Mar 15;18(6):1611-8
22271878
Medicine (Baltimore). 2015 Jan;94(4):e470
25634193
Int J Cancer. 1996 Oct 9;68(2):251-8
8900437
Leuk Lymphoma. 2009 Dec;50(12):2005-12
19860626
Histopathology. 2007 Dec;51(6):774-7
17944927
N Engl J Med. 2015 Jan 22;372(4):311-9
25482239
Blood. 2012 Oct 18;120(16):3280-7
22948049
Pediatr Transplant. 2009 Aug;13(5):628-31
19067927
Nat Immunol. 2007 Aug;8(8):825-34
17589510
Ann Surg. 1968 Sep;168(3):416-35
4175449
Blood. 2011 Apr 21;117(16):4315-22
21300977
Cell. 2011 Sep 16;146(6):904-17
21889194
Int J Cancer. 2003 May 1;104(5):624-30
12594818
Eur J Immunol. 2003 Jun;33(6):1593-602
12778477
Acta Oncol. 2014 May;53(5):669-79
24164103
Leuk Lymphoma. 2015 Jun 18;:1-4
25976108
Nat Rev Dis Primers. 2016 Jan 28;2:15088
27189056
Blood. 2014 Feb 20;123(8):1187-98
24398325
Br J Haematol. 2004 Nov;127(3):362-4
15491294
Trends Microbiol. 2016 Aug;24(8):649-64
27068530
Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):5002-7
15047891
J Virol. 2005 Nov;79(22):13993-4003
16254335
Diagn Mol Pathol. 2007 Sep;16(3):158-68
17721324
Br J Haematol. 2002 Dec;119(3):622-8
12437635
Am J Transplant. 2013 May;13(5):1305-16
23489474
N Engl J Med. 2000 Aug 17;343(7):481-92
10944566
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13520-5
18765795
Clin Cancer Res. 2013 Jul 1;19(13):3462-73
23674495
J Clin Oncol. 2013 Jan 10;31(2):256-62
23045593
Genes Chromosomes Cancer. 2015 Jun;54(6):383-96
25832818
Am J Surg Pathol. 2000 Mar;24(3):375-85
10716151
Nature. 2000 Feb 3;403(6769):503-11
10676951
Am J Clin Pathol. 2009 May;131(5):632-9
19369621
Oral Oncol. 2011 Sep;47(9):883-7
21783402
Cancer. 2011 Oct 1;117(19):4540-50
21446044
Nat Rev Microbiol. 2008 Dec;6(12):913-24
19008891
J Clin Oncol. 1998 Jun;16(6):2052-9
9626203
Transpl Int. 2011 Sep;24(9):892-903
21668529
J Virol. 2005 Jan;79(2):1296-307
15613356
Am J Surg Pathol. 2014 Jul;38(7):875-86
24832164
Blood. 2011 Mar 31;117(13):3596-608
21245480
Haematologica. 2016 Aug;101(8):976-84
27175027
J Hematol Oncol. 2009 Nov 12;2:47
19909553
Blood. 2015 Nov 12;126(20):2274-83
26384356
Lancet. 1964 Mar 28;1(7335):702-3
14107961
J Virol. 2011 Jan;85(1):165-77
20980506
PLoS Pathog. 2013;9(5):e1003341
23671415
Adv Cancer Res. 2007;97:81-109
17419942
Am J Transplant. 2015 Oct;15(10):2665-73
25988622
Blood. 2014 Nov 27;124(23):3431-40
25267198
J Virol. 2012 Oct;86(20):11096-106
22855490
Cancer Genet. 2016 Mar;209(3):117-8
26776268
Leukemia. 2015 Nov;29(11):2270-3
25921246
Cancer Sci. 2014 May;105(5):537-44
24581222
Hematol Oncol. 2008 Dec;26(4):199-211
18457340
Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13255-60
11687624
Semin Cancer Biol. 2015 Dec;35 Suppl:S185-98
25818339
Blood. 2005 Aug 1;106(3):1031-6
15840698