Histopathologic, immunophenotypic, and mutational landscape of follicular lymphomas with plasmacytic differentiation

Follicular lymphomas with plasmacytic differentiation (FL-PCD) include two major subtypes: one with predominantly interfollicular PCD that usually harbors a BCL2 rearrangement (BCL2-R), and a second that has predominantly intrafollicular PCD and the frequent absence of a BCL2-R. It is proposed that these latter cases share some features with marginal zone lymphomas (MZL). To further explore this hypothesis in an expanded cohort of FL-PCD, a clinicopathologic investigation of 25 such cases was undertaken including an analysis of their mutational landscape. The 10 interfollicular FL-PCDs exhibited typical intrafollicular centrocytes/centroblasts (90%), CD10 expression (90%), full PCD including expression of CD138 by the plasma cells (PC) (100%), and PCs with class-switched immunoglobulin heavy chains (70%). These cases were BCL2-R positive (100%), BCL6-R positive in 30%, lacked extra BCL2 copies, and only 22% had extra copies of BCL6. Similar to classic FLs, 80% of interfollicular FL-PCDs harbored mutations in epigenetic regulators KMT2D (70%), CREBBP (40%), and/or EZH2 (30%). In contrast, only 45% of 11 intrafollicular FL-PCDs demonstrated typical intrafollicular centrocytes/centroblasts, 55% were CD10(-), 80% contained IgM+ PCs, and only 27% harbored BCL2-Rs. BCL6-Rs were identified in 27% of intrafollicular FL-PCD, while 60% showed extra copies of BCL2 and 50% extra copies of BCL6, consistent with complete or partial trisomies of chromosomes 18 and 3, respectively. Only 54% of intrafollicular FL-PCDs showed mutations in epigenetic regulators. Both subtypes showed mutational differences compared to classic FL, but only the interfollicular subtype showed differences from what is reported for nodal MZL. Four additional cases showed mixed intra- and interfollicular PCD. These results suggest that FL-PCD has some distinctive features and supports the existence of two major subtypes. The interfollicular PCD subtype shares many features with classic FL. The intrafollicular FL-PCDs are more heterogeneous, have differences from classic FL, and have a greater morphologic, immunophenotypic, and genetic overlap with MZL.