Nodal cytotoxic peripheral T-cell lymphoma occurs frequently in the clinical setting of immunodysregulation and is associated with recurrent epigenetic alterations.
[en] 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.
Disciplines :
Hematology
Author, co-author :
Nicolae, Alina; Department of Pathology, Hautepierre, University Hospital Strasbourg, Strasbourg, France ; INSERM, IRFAC / UMR-S1113, ITI InnoVec, FHU ARRIMAGE, FMTS, University of Strasbourg, Strasbourg, France ; INSERM U955, Université Paris-Est, Créteil, France
Bouilly, Justine; Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital (CHUV) and Lausanne University, Lausanne, Switzerland
Lara, Diane; INSERM U955, Université Paris-Est, Créteil, France ; Service d'Hématologie, Centre Hospitalier Robert Boulin, Libourne, France
Fataccioli, Virginie; INSERM U955, Université Paris-Est, Créteil, France ; Département de Pathologie, Groupe Hospitalier Henri Mondor, AP-HP, Créteil, France
Lemonnier, François; INSERM U955, Université Paris-Est, Créteil, France ; Unité Hémopathies lymphoïdes, Groupe Hospitalier Henri Mondor, AP-HP, Créteil, France
Drieux, Fanny; INSERM U1245, Centre Henri Becquerel, Rouen, France ; Service d'Anatomie et Cytologie Pathologiques, Centre Henri Becquerel, Rouen, France
Parrens, Marie; Département de Pathologie, Hôpital Haut -Lévêque, Université de Bordeaux, INSERM, BaRITOn, U1053, F-33000, Bordeaux, France
Robe, Cyrielle; INSERM U955, Université Paris-Est, Créteil, France ; Département de Pathologie, Groupe Hospitalier Henri Mondor, AP-HP, Créteil, France
Poullot, Elsa; INSERM U955, Université Paris-Est, Créteil, France ; Département de Pathologie, Groupe Hospitalier Henri Mondor, AP-HP, Créteil, France
Bisig, Bettina; Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital (CHUV) and Lausanne University, Lausanne, Switzerland
Bossard, Céline; Service d'Anatomie et Cytologie Pathologiques, CHU de Nantes, Nantes, France
Letourneau, Audrey; Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital (CHUV) and Lausanne University, Lausanne, Switzerland
Missiaglia, Edoardo; Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital (CHUV) and Lausanne University, Lausanne, Switzerland ; Swiss Institute of Bioinformatics, Lausanne, Switzerland
Bonnet, Christophe ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'hématologie clinique
Szablewski, Vanessa; Service d'Anatomopathologie, CHU Montpellier, Montpellier, France
Traverse-Glehen, Alexandra; Pathology Department, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France
Delfau-Larue, Marie-Hélène; INSERM U955, Université Paris-Est, Créteil, France ; Département d'Hématologie et Immunologie Biologique, Groupe Hospitalier Henri Mondor, AP-HP, Créteil, France
de Leval, Laurence ; Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital (CHUV) and Lausanne University, Lausanne, Switzerland
Gaulard, Philippe; INSERM U955, Université Paris-Est, Créteil, France. philippe.gaulard@aphp.fr ; Département de Pathologie, Groupe Hospitalier Henri Mondor, AP-HP, Créteil, France. philippe.gaulard@aphp.fr
Nodal cytotoxic peripheral T-cell lymphoma occurs frequently in the clinical setting of immunodysregulation and is associated with recurrent epigenetic alterations.
LLS - Leukemia and Lymphoma Society INSERM - Institut National de la Santé et de la Recherche Médicale CALYM - Institut Carnot CALYM
Funding text :
This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), grants from Leukemia Lymphoma Society (SCOR grant - LLS SCOR 7013-17) and Institut Carnot CALYM.We thank the LYSA-Pathology and the Platform of Biological Resources from Henri Mondor University Hospital. We also thank the participants of TENOMIC consortium (a complete membership list appears in the supplemental Appendix).
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