Association of B Symptoms With Plasma EBV-DNA Copy Number and Cytokine Profiles in Patients With Nasal Type Extranodal Natural Killer/T-Cell Lymphoma (ENKTL): A Mechanism and Prognostic Study

Abstract

<h3>Purpose/Objective(s)</h3> Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) is characterized with Epstein-Barr virus (EBV) infection and often presence of B symptoms (including fever, night sweat, and weight loss), but the mechanisms of B symptoms remain unclear. We sought to identify the association of B symptoms with plasma EBV-DNA copy number and cytokine profiles in patients with ENKTL to provide some explanation as well as prognostic analyses. <h3>Materials/Methods</h3> We retrospectively analyzed data from 681 newly diagnosed patients with ENKTL at our institution from April 2007 to December 2019. Plasma EBV-DNA copy levels at presentation were divided into 4 groups: group A (EBV-DNA = 0 copies/ml), group B (0 < EBV-DNA < 10³ copies/ml), group C (10³ ≤ EBV-DNA < 10⁶ copies/ml), and group D (EBV-DNA ≥ 10⁶ copies/ml). In the subgroup of 167 patients with detailed data of cytokines (including IFN, IL-10 and IL-6), patients were divided into three tertiles based on individual cytokines. We explored the association between EBV-DNA levels, cytokines tertiles, and B symptoms via Cochran-Armitage trend test and Goodman-Kruskal Gamma test. Univariate and multivariate analysis for PFS and OS were performed. <h3>Results</h3> The median age of all the 681 patients was 44 years (range 9-83 years). There were 467 males, and 321 patients had B symptoms. The majority of patients were those aged ≤60 years (84.9%), presented with early-stage disease (Ann-Arbor I or II) (79.3%), and with tumor originating from the upper aerodigestive tract (UADT, 84.7%). There were 158 (23.2%), 143 (20.1%), 284 (41.7%), and 96 (14.1%) patients in EBV-DNA group A, B, C, and D, respectively. The Cochran-Armitage trend test demonstrated an upward trend in the incidence of B symptoms from 25.9%, 36.4%, 53.2%, to 80.2%, in EBV-DNA groups with increasing copy number (<i>P</i> < 0.0001). Among 321 patients with B symptoms, 82.6% had a fever with significance. Similarly, the incidence of fever also increased over the four EBV-DNA load groups, which were 15.8%, 31.5%, 45.4%, and 68.8%, respectively (<i>P</i><0.0001). Further analysis of 167 patients with cytokines data demonstrated IFN, IL-10, IL-6 were correlated with EBV-DNA load (<i>P</i> < 0.0001 for all). In addition, the tertiles level of IFN, IL-10 and IL-6 were significantly associated with the presence of B symptoms (<i>P</i> < 0.0001, <i>P</i> = 0.0001, <i>P</i> = 0.0001, respectively) and fever (<i>P</i> = 0.0002, <i>P</i> = 0.0003, <i>P</i> = 0.0005, respectively). In univariate analysis, EBV-DNA load and B symptoms were significant predictor of PFS (<i>P</i> < 0.0001 for both) and OS (<i>P</i> < 0.0001 for both). Multivariate Cox regression analysis showed B symptoms (<i>P</i> = 0.026), primary tumor location (<i>P</i> = 0.019), and Ann-Arbor stage (<i>P</i> = 0.032) as predictive factors of OS. <h3>Conclusion</h3> This exploratory study provided more evidence for a potential association and mechanism, that the massive replication of EBV in vivo could trigger cytokinemia, which may lead to B symptoms and poor prognosis in patients with ENKTL.