非特指EBV阳性弥漫大B细胞淋巴瘤的研究进展

Advances in research on EBV positive diffuse large B-cell lymphoma,not otherwise specified

EB病毒(Epstein-Barr virus,EBV)感染人体后,可长期潜伏于静息记忆性或幼稚B淋巴细胞中。随着免疫系统的衰老,EBV感染者发生EBV相关恶性肿瘤的风险明显增加。非特指EBV阳性弥漫大B细胞淋巴瘤(EBV positive diffuse large B-cell lymphoma,not otherwise specified,EBV^(+)DLBCL-NOS)是指发生在无已知免疫缺陷疾病或淋巴瘤病史,且肿瘤细胞核表达EBV编码RNA(EBV encoded RNA,EBER)的大B细胞淋巴瘤。流行病学研究显示,EBV^(+)DLBCL-NOS主要流行于亚洲及拉丁美洲,多数患者年龄超过50岁。临床上,与EBV阴性DLBCL(EBV negative DLBCL,EBV-DLBCL)患者相比,EBV^(+)DLBCL-NOS患者的临床病程更具侵袭性,初诊患者的临床分期多为晚期,且结外受累率可超过80%。老年患者通常较年轻患者的预后更差。尽管包括利妥昔单抗的免疫化疗方案可显著提高EBV-DLBCL患者的预后,EBV^(+)DLBCLNOS的最佳一线治疗方案仍需进一步探索。由于EBV^(+)DLBCL-NOS的发病率相对较低并存在地区分布的差异,也缺乏多中心、高质量的前瞻性临床研究,因此临床医师对该特殊亚型淋巴瘤的认知仍比较有限。随着二代测序等新技术的开展,发现EBV^(+)DLBCL-NOS的肿瘤细胞存在核因子-κB(nuclear factor-κB,NF-κB)和Janus激酶/信号转导和转录激活因子(Janus kinase/signal transducer and activator of transcription,JAK/STAT)等信号转导通路的改变,以及免疫过程如干扰素应答、抗原递呈系统和免疫检查点分子的异常等。这些基础研究成果促进了对相关治疗靶点的识别,有助于新治疗策略的探索。未来,嵌合抗原受体T细胞(chimeric antigen receptor T-cell,CAR-T)疗法、化疗联合免疫治疗及新型靶向治疗药物均有望改善EBV^(+)DLBCL-NOS患者的预后,但仍需要更多研究证实。

Epstein-Barr virus(EBV)can be latent in resting memory or naive B lymphocytes for a long time in affected people.Aging-induced immunosenescence is associated with an increased risk of EBV-related malignancies in EBV-infected patients.EBV positive diffuse large B-cell lymphoma,not otherwise specified(EBV^(+)DLBCL-NOS)is identified as occurring in large B-cell lymphoma with no known history of immunodeficiency disease or lymphoma and whose tumor nuclei expressed EBV encoded RNA(EBER).The prevalence of EBV^(+)DLBCL-NOS is significantly higher in Asia and Latin America than in other regions worldwide,and it mainly affects patients aged 50 years or older.EBV^(+)DLBCL-NOS patients are associated with a more aggressive clinical course,a more advanced disease,and a higher rate of extra-nodal involvement(more than 80%)compared with EBV negative DLBCL(EBV-DLBCL)patients.The elderly patients with EBV^(+)DLBCL-NOS have poorer overall survival and progression-free survival than young adults.Rituximab-containing immunochemotherapy significantly improves the prognosis of patients with EBV-DLBCL,however,the optimal first-line treatment for EBV^(+)DLBCL-NOS still needs to be further explored.The current understanding of EBV^(+)DLBCL-NOS,a rare subtype of DLBCL,is very limited because of the relatively low incidence of EBV^(+)DLBCL-NOS with a regional difference,as well as lacking high-quality clinical study.However,the DLBCL field is changing rapidly with new technologies,such as next-generation sequencing.To date,few studies have reported that multiple cells signaling pathways are aberrantly activated in tumor cells of EBV^(+)DLBCL-NOS,such as nuclear factor-κB(NF-κB)and Janus kinase/signal transducer and activator of transcription(JAK/STAT).In addition,abnormalities in immune processes have been observed in tumor cells of EBV^(+)DLBCL-NOS,such as the response to interferon,the antigen presentation system,and immune checkpoint molecules.The discovery of these basic research findings fosters the identification of relevant therapeutic targets and facilitates the exploration of novel therapeutic strategies.In the future,the benefits of immunotherapy,targeted therapy,and chimeric antigen receptor T-cell(CAR-T)therapy for EBV^(+)DLBCL-NOS patients remain unknown and require extensive research.