Nodal cytotoxic peripheral T-cell lymphoma occurs frequently in the clinical setting of immunodysregulation and is associated with recurrent epigenetic alterations.
Journal
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
ISSN: 1530-0285
Titre abrégé: Mod Pathol
Pays: United States
ID NLM: 8806605
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
04
10
2021
accepted:
26
01
2022
pubmed:
19
3
2022
medline:
28
7
2022
entrez:
18
3
2022
Statut:
ppublish
Résumé
Nodal peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) with cytotoxic phenotype is overall rare, with most reports coming from Asia. Given its elusive pathobiology, we undertook a clinicopathological and molecular study of 54 Western patients diagnosed with PTCL, NOS expressing cytotoxic molecules, within a lymph node. More commonly males (M/F-2,6/1) with median age of 60 years were affected. Besides lymphadenopathy, 87% of patients had ≥1 involved extranodal site. High-stage disease (III-IV), International Prognostic Index >2, B symptoms, LDH level, and cytopenia(s) were observed in 92, 63, 67, 78, and 66% of cases, respectively. Ten patients had a history of B-cell malignancies, one each of myeloid neoplasm, breast or prostate cancer, and 4 others had underlying immune disorders. Most patients (70%) died, mostly of disease, with a median overall survival of 12.7 months. Immunophenotypically, the neoplastic lymphocytes were T-cell receptor (TCR) αβ + (47%), TCR-silent (44%) or TCRγδ+ (10%), commonly CD8 + (45%) or CD4-CD8- (32%). All except one had an activated cytotoxic profile, and 95% were subclassified into PTCL-TBX21 subtype based on CXCR3, TBX21, and GATA3 expression pattern. Seven patients (13%) disclosed EBER + tumor cells. Targeted DNA deep-sequencing (33 cases) and multiplex ligation-dependent reverse transcription-polymerase chain reaction assay (43 cases) identified frequent mutations in epigenetic modifiers (73%), including TET2 (61%) and DNMT3A (39%), recurrent alterations affecting the TCR (36%) and JAK/STAT (24%) signaling pathways and TP53 mutations (18%). Fusion transcripts involving VAV1 were identified in 6/43 patients (14%). Patients with nodal cytotoxic PTCL, NOS have an aggressive behavior and frequently present in a background of impaired immunity, although the association with Epstein-Barr virus is rare. The recurrent alterations in genes involved in DNA methylation together with genes related to cytokine or TCR signaling, suggest that co-operation of epigenetic modulation with cell-signaling pathways plays a critical role in the pathogeny of these lymphomas.
Identifiants
pubmed: 35301414
doi: 10.1038/s41379-022-01022-w
pii: S0893-3952(22)00106-5
doi:
Substances chimiques
Receptors, Antigen, T-Cell, alpha-beta
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1126-1136Informations de copyright
© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.
Références
WHO classif 2016 TJ. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th Edition, Volume 2.
Laurent, C. et al. Impact of Expert Pathologic Review of Lymphoma Diagnosis: Study of Patients From the French Lymphopath Network. J. Clin. Oncol. 35, 2008–2017 (2017).
pubmed: 28459613
doi: 10.1200/JCO.2016.71.2083
Weisenburger, D. D. et al. Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project. Blood 117, 3402–3408 (2011).
pubmed: 21270441
doi: 10.1182/blood-2010-09-310342
Trapani, J. A. & Smyth, M. J. Functional significance of the perforin/granzyme cell death pathway. Nat. Rev. Immunol. 2, 735–747 (2002).
pubmed: 12360212
doi: 10.1038/nri911
Sánchez-Jiménez, C. & Izquierdo, J. M. T-cell intracellular antigens in health and disease. Cell Cycle 14, 2033–2043 (2015).
pubmed: 26036275
pmcid: 4614917
doi: 10.1080/15384101.2015.1053668
Kanavaros, P., Boulland, M. L., Petit, B., Arnulf, B. & Gaulard, P. Expression of cytotoxic proteins in peripheral T-cell and natural killer-cell (NK) lymphomas: association with extranodal site, NK or Tgammadelta phenotype, anaplastic morphology and CD30 expression. Leuk. Lymphoma. 38, 317–326 (2000).
pubmed: 10830738
doi: 10.3109/10428190009087022
Swerdlow, S. H. et al. Cytotoxic T-cell and NK-cell lymphomas: current questions and controversies. Am. J. Surg. Pathol. 38, e60–e71 (2014).
pubmed: 25025449
pmcid: 6329302
doi: 10.1097/PAS.0000000000000295
Asano, N. et al. Linkage of expression of chemokine receptors (CXCR3 and CCR4) and cytotoxic molecules in peripheral T cell lymphoma, not otherwise specified and ALK-negative anaplastic large cell lymphoma. Int. J. Hematol. 91, 426–435 (2010).
pubmed: 20217288
doi: 10.1007/s12185-010-0513-0
Asano, N. et al. Clinicopathologic and prognostic significance of cytotoxic molecule expression in nodal peripheral T-cell lymphoma, unspecified. Am. J. Surg. Pathol. 29, 1284–1293 (2005).
pubmed: 16160469
doi: 10.1097/01.pas.0000173238.17331.6b
Heavican, T. B. et al. Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma. Blood 133, 1664–1676 (2019).
pubmed: 30782609
pmcid: 6460420
doi: 10.1182/blood-2018-09-872549
Iqbal, J. et al. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood 123, 2915–2923 (2014).
pubmed: 24632715
pmcid: 4014836
doi: 10.1182/blood-2013-11-536359
Iqbal, J. et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood 115, 1026–1036 (2010).
pubmed: 19965671
pmcid: 2817630
doi: 10.1182/blood-2009-06-227579
Kato, S. et al. T-cell receptor (TCR) phenotype of nodal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (CTL): a clinicopathologic study of 39 cases. Am. J. Surg. Pathol. 39, 462–471 (2015).
pubmed: 25634749
doi: 10.1097/PAS.0000000000000323
Kato, S. et al. Nodal cytotoxic molecule (CM)-positive Epstein-Barr virus (EBV)-associated peripheral T cell lymphoma (PTCL): a clinicopathological study of 26 cases. Histopathology 61, 186–199 (2012).
pubmed: 22690710
doi: 10.1111/j.1365-2559.2012.04199.x
Ng, S.-B. et al. Epstein-Barr virus-associated primary nodal T/NK-cell lymphoma shows a distinct molecular signature and copy number changes. Haematologica 103, 278–287 (2018).
pubmed: 29097495
pmcid: 5792272
doi: 10.3324/haematol.2017.180430
Yamashita, D. et al. Reappraisal of nodal Epstein-Barr Virus-negative cytotoxic T-cell lymphoma: Identification of indolent CD5+ diseases. Cancer Sci. 109, 2599–2610 (2018).
pubmed: 29845715
pmcid: 6113510
doi: 10.1111/cas.13652
Amador, C. et al. Reproducing the molecular subclassification of peripheral T-cell lymphoma-NOS by immunohistochemistry. Blood 134, 2159–2170 (2019).
pubmed: 31562134
pmcid: 6908831
doi: 10.1182/blood.2019000779
Theodorou, I. et al. VJ rearrangements of the TCR gamma locus in peripheral T-cell lymphomas: analysis by polymerase chain reaction and denaturing gradient gel electrophoresis. J. Pathol. 178, 303–310 (1996).
pubmed: 8778336
doi: 10.1002/(SICI)1096-9896(199603)178:3<303::AID-PATH475>3.0.CO;2-I
Trimech, M. et al. Angioimmunoblastic T-Cell Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Novel Form of Composite Lymphoma Potentially Mimicking Richter Syndrome. Am. J. Surg. Pathol. 45, 773–786 (2021).
pubmed: 33739791
doi: 10.1097/PAS.0000000000001646
van Dongen, J. J. M. et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 17, 2257–2317 (2003).
pubmed: 14671650
doi: 10.1038/sj.leu.2403202
Kopanos, C. et al. VarSome: the human genomic variant search engine. Bioinformatics 35, 1978–1980 (2019).
pubmed: 30376034
doi: 10.1093/bioinformatics/bty897
Drieux, F. et al. Detection of Gene Fusion Transcripts in Peripheral T-Cell Lymphoma Using a Multiplexed Targeted Sequencing Assay. J Mol Diagn S1525-1578, 00124–0 (2021).
Pizzi, M., Margolskee, E. & Inghirami, G. Pathogenesis of Peripheral T Cell Lymphoma. Annu. Rev. Pathol. Mech. Dis. 13, 293–320 (2018).
doi: 10.1146/annurev-pathol-020117-043821
Waldmann, T. A. & Chen, J. Disorders of the JAK/STAT Pathway in T Cell Lymphoma Pathogenesis: Implications for Immunotherapy. Annu. Rev. Immunol. 35, 533–550 (2017).
pubmed: 28182501
pmcid: 7974381
doi: 10.1146/annurev-immunol-110416-120628
Takeuchi, A. & Saito, T. CD4 C. T. L., a Cytotoxic Subset of CD4+ T Cells, Their Differentiation and Function. Front. Immunol. 8, 194 (2017).
pubmed: 28280496
pmcid: 5321676
doi: 10.3389/fimmu.2017.00194
Giacoma De Tullio, Pasquale Iacopino, & Attilio Guarini. The αβ-double negative T cells in lymphoma patients: the predictive role and the functional attitude. J. Immunol. 192, 142.9 (2014).
Voelkl, S. et al. Characterization of MHC class-I restricted TCRalphabeta+ CD4- CD8- double negative T cells recognizing the gp100 antigen from a melanoma patient after gp100 vaccination. Cancer Immunol. Immunother. 58, 709–718 (2009).
pubmed: 18836718
doi: 10.1007/s00262-008-0593-3
Ishida, T. et al. CXC Chemokine Receptor 3 and CC Chemokine Receptor 4 Expression in T-Cell and NK-Cell Lymphomas with Special Reference to Clinicopathological Significance for Peripheral T-Cell Lymphoma, Unspecified. Clin. Cancer Res. 10, 5494–5500 (2004).
pubmed: 15328188
doi: 10.1158/1078-0432.CCR-04-0371
Laginestra, M. A. et al. Correction: Whole exome sequencing reveals mutations in FAT1 tumor suppressor gene clinically impacting on peripheral T-cell lymphoma not otherwise specified. Mod. Pathol. 33, 319–319 (2020).
pubmed: 31558781
doi: 10.1038/s41379-019-0376-8
Ji, M.-M. et al. Histone modifier gene mutations in peripheral T-cell lymphoma not otherwise specified. Haematologica 103, 679–687 (2018).
pubmed: 29305415
pmcid: 5865443
doi: 10.3324/haematol.2017.182444
Watatani, Y. et al. Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling. Leukemia 33, 2867–2883 (2019).
pubmed: 31092896
doi: 10.1038/s41375-019-0473-1
Couronné, L., Bastard, C. & Bernard, O. A. TET2 and DNMT3A mutations in human T-cell lymphoma. N. Engl. J. Med. 366, 95–96 (2012).
pubmed: 22216861
doi: 10.1056/NEJMc1111708
Lemonnier, F. et al. Integrative analysis of a phase 2 trial combining lenalidomide with CHOP in angioimmunoblastic T-cell lymphoma. Blood Adv. 5, 539–548 (2021).
pubmed: 33496747
pmcid: 7839364
doi: 10.1182/bloodadvances.2020003081
Lemonnier, F., Gaulard, P. & de Leval, L. New insights in the pathogenesis of T-cell lymphomas. Curr. Opin. Oncol. 30, 277–284 (2018).
pubmed: 30028743
doi: 10.1097/CCO.0000000000000474
Sakata-Yanagimoto, M. et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat. Genet. 46, 171–175 (2014).
pubmed: 24413737
doi: 10.1038/ng.2872
Pastoret, C. et al. Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells. Blood 137, 3237–3250 (2021).
pubmed: 33512451
pmcid: 8351897
doi: 10.1182/blood.2020006721
Lemonnier, F. et al. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood 120, 1466–1469 (2012).
pubmed: 22760778
doi: 10.1182/blood-2012-02-408542
McKinney, M. et al. The Genetic Basis of Hepatosplenic T-cell Lymphoma. Cancer Disco. 7, 369–379 (2017).
doi: 10.1158/2159-8290.CD-16-0330
Moffitt, A. B. et al. Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2. J. Exp. Med. 214, 1371–1386 (2017).
pubmed: 28424246
pmcid: 5413324
doi: 10.1084/jem.20160894
Palomero, T. et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat. Genet. 46, 166–170 (2014).
pubmed: 24413734
pmcid: 3963408
doi: 10.1038/ng.2873
Pro, B. et al. Romidepsin induces durable responses in patients with relapsed or refractory angioimmunoblastic T-cell lymphoma. Hematological. Oncol. 35, 914–917 (2017).
doi: 10.1002/hon.2320
Falchi, L. et al. Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study. Blood 137, 2161–2170 (2021).
pubmed: 33171487
doi: 10.1182/blood.2020009004
Coiffier, B. et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J. Clin. Oncol. 30, 631–636 (2012).
pubmed: 22271479
doi: 10.1200/JCO.2011.37.4223
Lemonnier, F. et al. Treatment with 5-azacytidine induces a sustained response in patients with angioimmunoblastic T-cell lymphoma. Blood 132, 2305–2309 (2018).
pubmed: 30279227
doi: 10.1182/blood-2018-04-840538
Abate, F. et al. Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas. Proc. Natl. Acad. Sci. USA 114, 764–769 (2017).
pubmed: 28062691
pmcid: 5278460
doi: 10.1073/pnas.1608839114
Rohr, J. et al. Recurrent activating mutations of CD28 in peripheral T-cell lymphomas. Leukemia 30, 1062–1070 (2016).
pubmed: 26719098
doi: 10.1038/leu.2015.357
Vallois, D. et al. RNA fusions involving CD28 are rare in peripheral T-cell lymphomas and concentrate mainly in those derived from follicular helper T cells. Haematologica 103, e360–e363 (2018).
pubmed: 29545337
pmcid: 6068042
doi: 10.3324/haematol.2017.186767
Vallois, D. et al. Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas. Blood 128, 1490–1502 (2016).
pubmed: 27369867
doi: 10.1182/blood-2016-02-698977
Crescenzo, R. et al. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell 27, 516–532 (2015).
pubmed: 25873174
pmcid: 5898430
doi: 10.1016/j.ccell.2015.03.006
Gao, L.-M. et al. Somatic mutations in KMT2D and TET2 associated with worse prognosis in Epstein-Barr virus-associated T or natural killer-cell lymphoproliferative disorders. Cancer Biol. Ther. 20, 1319–1327 (2019).
pubmed: 31311407
pmcid: 6783120
doi: 10.1080/15384047.2019.1638670
Crescenzo, R. et al. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell 27, 516–532 (2015).
pubmed: 25873174
pmcid: 5898430
doi: 10.1016/j.ccell.2015.03.006
Lobello, C. et al. STAT3 and TP53 mutations associate with poor prognosis in anaplastic large cell lymphoma. Leukemia 35, 1500–1505 (2021).
pubmed: 33247178
doi: 10.1038/s41375-020-01093-1
Nicolae, A. et al. Frequent STAT5B mutations in γδ hepatosplenic T-cell lymphomas. Leukemia 28, 2244–2248 (2014).
pubmed: 24947020
pmcid: 7701980
doi: 10.1038/leu.2014.200
Nicolae, A. et al. Mutations in the JAK/STAT and RAS signaling pathways are common in intestinal T-cell lymphomas. Leukemia 30, 2245–2247 (2016).
pubmed: 27389054
pmcid: 5093023
doi: 10.1038/leu.2016.178
Roberti, A. et al. Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations. Nat. Commun. 7, 12602 (2016).
pubmed: 27600764
pmcid: 5023950
doi: 10.1038/ncomms12602
Küçük, C. et al. Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells. Nat. Commun. 6, 6025 (2015).
pubmed: 25586472
doi: 10.1038/ncomms7025
Laurent, C. et al. Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast implant-associated ALCL. Blood 135, 360–370 (2020).
pubmed: 31774495
pmcid: 7059458
Nijland, M. L. et al. Clinicopathological characteristics of T-cell non-Hodgkin lymphoma arising in patients with immunodeficiencies: a single-center case series of 25 patients and a review of the literature. Haematologica 103, 486–496 (2018).
pubmed: 29269521
pmcid: 5830383
doi: 10.3324/haematol.2017.169987
Campidelli, C. et al. Simultaneous occurrence of peripheral T-cell lymphoma unspecified and B-cell small lymphocytic lymphoma. Report of 2 cases. Hum. Pathol. 38, 787–792 (2007).
pubmed: 17270243
doi: 10.1016/j.humpath.2006.10.010
Martinez, A. et al. Clonal T-cell populations and increased risk for cytotoxic T-cell lymphomas in B-CLL patients: clinicopathologic observations and molecular analysis. Am. J. Surg. Pathol. 28, 849–858 (2004).
pubmed: 15223953
doi: 10.1097/00000478-200407000-00002
Gilardin, L. et al. Peripheral T-cell lymphoma in HIV-infected patients: a study of 17 cases in the combination antiretroviral therapy era. Br. J. Haematol. 161, 843–851 (2013).
pubmed: 23593987
doi: 10.1111/bjh.12341
Went, P. et al. Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score. J. Clin. Oncol. 24, 2472–2479 (2006).
pubmed: 16636342
doi: 10.1200/JCO.2005.03.6327
Kato, S., Yamashita, D. & Nakamura, S. Nodal EBV+ cytotoxic T-cell lymphoma: A literature review based on the 2017 WHO classification. J. Clin. Exp. Hematop. 60, 30–36 (2020).
pubmed: 32565530
pmcid: 7337268
doi: 10.3960/jslrt.20001
Dobay, M. P. et al. Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin. Haematologica 102, e148–e151 (2017).
pubmed: 28082343
pmcid: 5395128
doi: 10.3324/haematol.2016.158428
Federico, M. et al. Peripheral T cell lymphoma, not otherwise specified (PTCL-NOS). A new prognostic model developed by the International T cell Project Network. Br. J. Haematol. 181, 760–769 (2018).
pubmed: 29672827
pmcid: 6033106
doi: 10.1111/bjh.15258