The biology of marginal zone lymphoma subtypes: challenge and relevance of classification

Marginal zone lymphomas (MZLs) are a heterogeneous group of low-grade B-cell neoplasms classified into different entities by the current lymphoma classifications. They share some features, but differ significantly in clinical presentation, associated inflammatory conditions, anatomic sites of involvement, and molecular alterations. Etiopathogenesis is strongly linked to chronic antigenic stimulation and specific infections or autoimmune disorders for extranodal disease. Genetic hallmarks include constitutive NF-κB activation and common trisomies 3 and 18, alongside subtype-specific lesions such as translocations in extranodal MZL, recurrent KLF2/NOTCH2 mutations in both nodal and splenic MZL, and deletions involving chromosome 7q, predominantly observed in splenic MZL. Diagnosis can be challenging due to overlapping features with other lymphomas such as follicular and lymphoplasmacytic lymphomas; integrating morphology, immunophenotype, and molecular data is essential. Transformation to aggressive diffuse large B-cell lymphoma occurs in 3% to 15% of cases and is associated with the accumulation of genetic lesions, particularly in cell cycle, NF-κB, and epigenetic regulators, with subtype-specific drivers including TNFAIP3, TP53, and CDKN2A/B alterations. The tumor microenvironment plays a critical but understudied role, influenced by chronic antigen stimulation and involving complex interactions with immune cells that can promote immune suppression and influence therapeutic response. Understanding the heterogeneity of MZLs across their classification, genetic landscapes, and interaction with the microenvironment is crucial for accurate diagnosis, prognosis, and the development of effective targeted therapies.