Molecular biologic and Epstein-Barr virologic advances in extranodal natural killer/T cell lymphoma over the past four decades.

Extranodal natural killer/T-cell lymphoma (ENKTL) is clinically characterized by destructive lesions that first appear in the nasal cavity and progress along the midline of the face. It was historically described as "rhinitis gangrenosa progressiva" or "lethal midline granuloma" due to its destructive clinical nature and had significant diagnostic and therapeutic challenges. This review synthesizes about 40 years of research, beginning with the 1980s and 1990s, when the disease was identified as a T-cell- or NK-cell-derived lymphoma, and the authors' discovery that clearly linked it to Epstein-Barr virus (EBV). ENKTL is highly prevalent in East Asia and characterized by a type II EBV latency pattern, in which the oncoprotein latent membrane protein 1 (LMP1) acts as a central driver of pathogenesis, activating critical signaling pathways including JAK/STAT, NF-κB, PI3K/Akt, and RAS/MAPK. These pathways, often bolstered by mutations in genes, trigger an oncogenic cascade involving epigenetic modifiers-enhancer of zeste homolog 2 (EZH2), histone deacetylase (HDAC). The deletion of chromosome 6q, leading to loss of function of tumor suppressor PR domain zinc finger protein 1 (PRDM1) and forkhead box O3 (FOXO3), as well as transcription of TNF α-induced protein 3 (TNFAIP3) and protein tyrosine phosphatase receptor type kappa (PTPRK), also contributes to pathogenesis. In vitro studies by the author's group demonstrated that autocrine/paracrine positive feedback loops involving several pro-proliferative molecules/cytokine/chemokine-CD27, ICAM1, hepatocyte growth factor (HGF), IL-9, IL-10, IL-15, CCL17, CCL22, CXCL10- further amplify ENKTL proliferation. Diagnostic precision has improved through the use of serum EBV DNA copy numbers and viral microRNAs (miRs), specifically miR-BART2-5p, alongside the emergence of soluble CD27 as a novel biomarker. While early anthracycline-based regimens failed due to multidrug resistance (MDR), modern concurrent chemoradiotherapy composed of MDR-independent drugs has significantly improved 5-year overall survival (OS) rates for localized disease to over 80%. For advanced or relapsed/refractory cases, L-asparaginase-based regimens are standard, though outcomes remain unsatisfactory. The therapeutic paradigm is currently shifting toward chemoradiotherapy combined with either immune checkpoint inhibitors or small-molecule drugs. Future research should focus on novel molecular-targeted therapies, immunotherapies, or combination strategies targeting proliferation-related molecules or LMP1.