Francischetti Ivo M B, Alejo Julie C, Sivanandham Ranjit, Davies-Hill Theresa, Fetsch Patricia, Pandrea Ivona, Jaffe Elaine S, Pittaluga Stefania
Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.
Department of Pathology, School of Medicine, University of Pittsburgh, Pennsylvania, USA.
Hemasphere. 2021 Sep 1;5(9):e633. doi: 10.1097/HS9.0000000000000633. eCollection 2021 Sep.
Classic Hodgkin lymphoma (cHL), nodular sclerosis (NS) subtype, is characterized by the presence of Hodgkin/Reed-Sternberg (HRS) cells in an inflammatory background containing neutrophils and/or eosinophils. Both types of granulocytes release extracellular traps (ETs), web-like DNA structures decorated with histones, enzymes, and coagulation factors that promote inflammation, thrombosis, and tumor growth. We investigated whether ETs from neutrophils (NETs) or eosinophils (EETs) are detected in cHL, and evaluated their association with fibrosis. We also studied expression of protease-activated receptor-2 (PAR-2) and phospho-extracellular signal-related kinase (p-ERK), potential targets/effectors of ETs-associated elastase, in HRS cells. Expression of tissue factor (TF) was evaluated, given the procoagulant properties of ETs. We analyzed 32 HL cases, subclassified as 12 NS, 5 mixed-cellularity, 5 lymphocyte-rich, 1 lymphocyte-depleted, 4 nodular lymphocyte-predominant HL (NLPHL), and 5 reactive nodes. Notably, a majority of NS cHL cases exhibited NET formation by immunohistochemistry for citrullinated histones, with 1 case revealing abundant EETs. All other cHL subtypes as well as NLPHL were negative. Immunofluorescence microscopy confirmed NETs with filamentous/delobulated morphology. Moreover, ETs formation correlates with concurrent fibrosis ( = 0.7999; 95% CI, 0.6192-0.9002; ≤ 0.0001). Results also showed that HRS cells in NS cHL expressed PAR-2 with nuclear p-ERK staining, indicating a neoplastic or inflammatory phenotype. Remarkably, TF was consistently detected in the endothelium of NS cHL cases compared with other subtypes, in keeping with a procoagulant status. A picture emerges whereby the release of ETs and resultant immunothrombosis contribute to the inflammatory tumor microenvironment of NS cHL. This is the first description of NETs in cHL.
经典型霍奇金淋巴瘤（cHL），结节硬化（NS）亚型，其特征是在含有中性粒细胞和/或嗜酸性粒细胞的炎症背景中存在霍奇金/里德-斯腾伯格（HRS）细胞。这两种粒细胞都会释放细胞外陷阱（ETs），即由组蛋白、酶和凝血因子修饰的网状DNA结构，可促进炎症、血栓形成和肿瘤生长。我们研究了在cHL中是否能检测到中性粒细胞的ETs（NETs）或嗜酸性粒细胞的ETs（EETs），并评估了它们与纤维化的关系。我们还研究了HRS细胞中蛋白酶激活受体-2（PAR-2）和磷酸化细胞外信号调节激酶（p-ERK）的表达，它们是与ETs相关的弹性蛋白酶的潜在靶点/效应物。鉴于ETs的促凝血特性，我们评估了组织因子（TF）的表达。我们分析了32例HL病例，分为12例NS、5例混合细胞型、5例淋巴细胞丰富型、1例淋巴细胞消减型、4例结节性淋巴细胞为主型HL（NLPHL）和5例反应性淋巴结。值得注意的是，大多数NS cHL病例通过抗瓜氨酸化组蛋白免疫组化显示有NET形成，1例显示有丰富的EETs。所有其他cHL亚型以及NLPHL均为阴性。免疫荧光显微镜证实了具有丝状/分叶状形态的NETs。此外，ETs形成与同时存在的纤维化相关（ = 0.7999；95%可信区间，0.6192 - 0.9002；≤ 0.0001）。结果还显示，NS cHL中的HRS细胞表达PAR-2并伴有核p-ERK染色，表明具有肿瘤或炎症表型。值得注意的是，与其他亚型相比，NS cHL病例的内皮中持续检测到TF，这与促凝血状态一致。由此呈现出一幅画面，即ETs的释放和由此产生的免疫血栓形成促成了NS cHL的炎症性肿瘤微环境。这是cHL中NETs的首次描述。
