Biology of splenic and nodal marginal zone lymphomas

Abstract: Splenic marginal zone lymphoma (SMZL) and nodal marginal zone lymphoma (NMZL) are recognized as distinct subtypes of marginal zone lymphomas (MZLs) in the World Health Organization (WHO) classification. SMZL and NMZL share several morphological and immunophenotypic features. They are also rare and together, account for just over 3% of all B cell lymphomas. Their rarity and heterogeneity in terms of clinical presentation and biology can make their diagnosis difficult and can also complicate their molecular characterization. Despite these challenges, modern advances in high-throughput sequencing and cancer biology have granted unprecedented insights into the molecular pathogenesis of SMZL and NMZL. These techniques have provided a comprehensive overview of the genes and pathways that are deregulated in these diseases, including the identification of molecular aberrations that are associated with distinct MZL subtypes. SMZL and NMZL are characterized by mutations of genes involved in marginal zone (MZ) B cell differentiation and homeostasis including KLF2 and components of NOTCH, NF-κB, B cell receptor (BCR) and Toll-like receptor (TLR) signaling. Pathways involved in the differentiation of MZ B cells are also deregulated by epigenetic and post-transcriptional modifications. Although the genetic signatures of NMZL and SMZL largely overlap, the exclusive association of PTPRD mutations with NMZL, together with the absence of 7q deletion in this lymphoma, support the designation of NMZL and SMZL as different entities rather than different clinical presentations of the same disease. The aim of this review is to describe the molecular perturbations identified so far in SMZL and NMZL and discuss how these alterations might contribute to disease pathogenesis and inform clinical management.