Absence of CD38 expression in mantle cell lymphoma correlates with distinct pathological and genetic features

Although CD38 is commonly expressed in mantle cell lymphoma (MCL), a subset of cases lacks CD38 expression, and the biological significance of CD38 negativity remains incompletely understood. In this study, we analyzed 188 MCL patients with available flow cytometry data and stratified cases into CD38-negative and CD38-positive groups based on median fluorescence intensity (MFI). CD38 expression was detected in 90.4% (161/178) of conventional nodal MCLs (cnMCLs), but in only 40% (4/10) of leukemic non-nodal MCLs (lnMCLs). Among the 178 cnMCL patients, CD38 negativity was associated with significantly higher frequencies of TP53 mutation (56% vs 23%, p = 0.0464), del(17p13) (50% vs 12%, p = 0.0077), and concurrent TP53 mutation and del(17p13) (57% vs 11%, p = 0.0101), compared with CD38-positive cases. Notably, cnMCLs harboring concurrent TP53 mutation and del(17p13) demonstrated significantly lower CD38 expression than cases with isolated TP53 mutation or del(17p13) alone. In addition, CD38-negative cnMCLs more frequently exhibited SOX11 negativity (80% vs 11%, p < 0.0001), mutated immunoglobulin heavy-chain variable region (IGHV) genes (55% vs 23%, p = 0.0622), and kappa light-chain restriction (77% vs 49%, p = 0.0407). Targeted mutational profiling further revealed that CD38-negative cnMCLs were enriched for mutations affecting cell-signaling pathways, including NOTCH1, NOTCH2, CD79B, CXCR4, and TRAF2, and were less likely to harbor mutations in ATM and chromatin-modifying or epigenetic regulators, particularly KMT2D and NSD2. Collectively, these findings indicate that CD38 negativity occurs in approximately 10% of cnMCLs and is associated with a distinct pathological and genetic profile that partially overlaps with, but is not identical to, that of lnMCL. Biologically, CD38-negative cnMCLs appear to be more likely driven by CD38-independent, alternative signaling pathways. From a clinical perspective, identification of CD38-negative cnMCLs by flow cytometry may help recognizing patients at increased risk for adverse genetic features, including TP53 inactivation.