Department of Pathology, Hautepierre, University Hospital Strasbourg, Strasbourg, France.
INSERM, IRFAC / UMR-S1113, ITI InnoVec, FHU ARRIMAGE, FMTS, University of Strasbourg, Strasbourg, France.
Mod Pathol. 2022 Aug;35(8):1126-1136. doi: 10.1038/s41379-022-01022-w. Epub 2022 Mar 17.
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.
非特指结外 T 细胞淋巴瘤，伴有细胞毒性表型（PTCL，NOS）总体较为罕见，大多数报道来自亚洲。鉴于其隐匿的病理生物学特性，我们对 54 例在淋巴结中表达细胞毒性分子的西方 PTCL，NOS 患者进行了临床病理和分子研究。受影响的患者多为男性（M/F-2,6/1），中位年龄为 60 岁。除了淋巴结病外，87%的患者有≥1 个结外受累部位。92%的病例存在高分期疾病（III-IV 期）、国际预后指数>2、B 症状、乳酸脱氢酶水平升高和血细胞减少，分别为 63%、67%、78%和 66%。10 例患者有 B 细胞恶性肿瘤病史，1 例有髓系肿瘤、乳腺癌或前列腺癌病史，另有 4 例有潜在免疫障碍。大多数患者（70%）死亡，主要死于疾病，中位总生存期为 12.7 个月。免疫表型上，肿瘤淋巴细胞为 TCRαβ+（47%）、TCR 沉默（44%）或 TCRγδ+（10%），通常为 CD8+（45%）或 CD4-CD8-（32%）。除 1 例外，所有患者均具有激活的细胞毒性表型，根据 CXCR3、TBX21 和 GATA3 表达模式，95%的患者被归为 PTCL-TBX21 亚型。7 例（13%）患者的肿瘤细胞中发现 EBER+。对 33 例患者进行靶向 DNA 深度测序和对 43 例患者进行多重连接依赖性反转录-聚合酶链反应检测，发现表观遗传修饰物（73%）频繁发生突变，包括 TET2（61%）和 DNMT3A（39%）、影响 TCR（36%）和 JAK/STAT（24%）信号通路的反复改变以及 TP53 突变（18%）。在 6/43 例患者（14%）中鉴定出涉及 VAV1 的融合转录本。结外细胞毒性 PTCL，NOS 患者具有侵袭性行为，并且经常在免疫功能受损的背景下出现，尽管与 Epstein-Barr 病毒的关联较为罕见。参与 DNA 甲基化的基因以及与细胞因子或 TCR 信号相关的基因的反复改变提示，表观遗传调控与细胞信号通路的共同作用在这些淋巴瘤的发病机制中发挥着关键作用。
