Nodal marginal zone lymphoma: genetic analysis and the differential diagnosis from other small B-cell lymphomas.

Nodal marginal zone lymphoma (NMZL) is a rare indolent B-cell lymphoma without a disease-defining phenotype. The distinction from other small B-cell lymphomas is challenging, especially from t(14;18)-negative follicular lymphoma (FL). To find out whether molecular analysis could help in separating NMZL from other small B-cell lymphomas, we analyzed a cohort of 52 cases with the diagnosis or differential diagnosis of NMZL using targeted next generation sequencing and gene expression profiling (GEP). After morphological and mutational analysis, 38 (73%) cases were classified as NMZL, 8 (15%) cases as t(14;18)-negative FL and 6 (12%) cases as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with atypical phenotype. The most frequently mutated gene in NMZL was KLF2 (34%), followed by KMT2D (21%) and TBL1XR1 (16%). Overall, the NF-kB pathway (13%), the NOTCH pathway (16%) and genes involved in chromatin remodeling and transcriptional regulation (55%) were frequently affected. Confirming the classification based on pathological and genetic features, GEP revealed distinct transcriptional profiles for NMZL and t(14;18)-negative FL. While the latter group showed upregulation of genes associated with the germinal center and the IL-4 pathway, NMZL revealed upregulation of genes identified in memory B cells. In summary, despite showing genetic heterogeneity, NMZL is characterized by recurrent genetic alterations resulting in perturbations of specific pathways. These alterations, although not specific per se, render very characteristic genetic profiles, and when used in the context of other findings are a useful adjunct to distinguish NMZL from other small B-cell lymphomas.