Extranodal Marginal Zone Lymphoma: Integrating Etiology, Microenvironment, and Genetics Into Clinical Decision‐Making

ABSTRACT

Extranodal marginal zone lymphoma (EMZL) represents a unique paradigm among indolent B‐cell neoplasms, in which lymphomagenesis is frequently driven by chronic antigenic stimulation within tissue‐specific microenvironments. Persistent infectious or autoimmune triggers promote the development of ectopic lymphoid tissue and sustain B‐cell activation, while recurrent genetic alterations—most prominently those that converge on NF‐κB signaling—enable progressive escape from antigen dependence. This dual biological foundation explains both the indolent clinical course of most cases and the remarkable therapeutic vulnerability of early‐stage, infection‐driven disease. Clinically, EMZL arise across a wide range of anatomical sites, each characterized by distinct etiologic associations and patterns of progression. As a result, management strategies must be tailored to disease site, stage, and biological context, with a consistent preference for the least intensive intervention capable of achieving durable disease control. Pathogen‐directed antibiotic therapy and involved‐site radiotherapy can be curative in localized disease. In contrast, systemic anti‐CD20‐based immunochemotherapy and targeted agents are reserved for disseminated, refractory, or biologically autonomous lymphomas. Recent advances in molecular profiling, functional imaging, and response assessment are refining risk stratification and treatment selection, shifting therapeutic goals toward early depth of response and quality of life rather than maximal cytotoxic intensity. EMZL thus serves as a model for biologically informed, precision‐oriented management of indolent lymphoid malignancies.