Open AccessNeutrophil and Eosinophil Extracellular Traps in Hodgkin Lymphoma
Author(s) -
Francischetti Ivo M. B.,
Alejo Julie C.,
Sivanandham Ranjit,
DaviesHill Theresa,
Fetsch Patricia,
Pandrea Ivona,
Jaffe Elaine S.,
Pittaluga Stefania
Publication year - 2021
Publication title -
hemasphere
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.677
H-Index - 11
ISSN - 2572-9241
DOI - 10.1097/hs9.0000000000000633
Subject(s) - nodular sclerosis , neutrophil extracellular traps , eosinophil , pathology , inflammation , extracellular , lymphocyte , neutrophil elastase , biology , fibrosis , lymphoma , cancer research , immunology , microbiology and biotechnology , medicine , hodgkin lymphoma , asthma
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 ( r = 0.7999; 95% CI, 0.6192‐0.9002; P ≤ 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.