Histomorphologic spectrum of nodal marginal zone lymphoma as defined by its methylome

Objectives Primary nodal marginal B-cell lymphoma (NMZL) is rare and histologically very variable. Its large-cell presentation is difficult to distinguish from nodal diffuse large B-cell lymphoma (nDLBCL) due to the absence of specific markers for nodal marginal zone lymphomas in general.Methods Using a comprehensive cohort of NMZLs and a control cohort of nDLBCLs, we conducted a methylome analysis on subgroups of both.Results The methylomes were strikingly different between the cohorts but unexpectedly homogeneous within the NMZL cohort. This allowed us to describe the morphologic spectrum of NMZL in all its value ranges. The considerable overlap in growth pattern and cytology of NMZL with nDLBCL was explored morphometrically, leading to an operational tool for separating both by a simple measurement of cell size and nuclear size. This was integrated in a hierarchical approach, including a scoring system for the parameter growth pattern, follicular colonization, follicular dendritic network, IgD expression, and Ki-67 rate, and led to a proposal for a classifier that we present here.Conclusions This methylome-based study extends the morphological spectrum of NMZL towards large cell morphology and offers a conventional way to distinguish it from nDLBCL.