The genetic landscape of extramedullary plasmacytoma: a comparative analysis with extramedullary disease of multiple myeloma

Abstract

Extramedullary (or extraosseous) plasmacytoma (EMP) is a localized plasma cell neoplasm lacking apparent bone marrow involvement and other features of multiple myeloma (MM). The prognosis is usually favorable and progression to MM is infrequent. The genetic landscape of EMP remains largely unknown. Importantly, EMP must be distinguished from extramedullary disease of MM (EMD), which typically exhibits an aggressive behavior. We performed a comprehensive molecular analysis of EMP (N=24) in comparison to EMD (N=24) using fluorescence in situ hybridization, copy number profiling, and targeted next-generation sequencing. Overall, EMP shared several genetic features with MM, but exhibited markedly lower complexity than EMD. EMP revealed a mean of 4.3 copy number changes versus 19.3 in EMD (P<0.001). IGH breaks were detected in six EMP and ten EMD, and hyperdiploidy in ten and 14 cases, respectively. Gains of 1q21 occurred in nine EMP and 15 EMD (P=0.045). Likewise, EMP harbored fewer mutations (median 2.0 vs. 3.0; P<0.01), yet was enriched for TRAF3 mutations, detected in six cases, which were absent in EMD (P=0.022). In contrast, EMD more frequently harbored mutations associated with advanced MM, including NRAS/KRAS (P<0.01), TP53, TENT5C, ARID1A, and ATM. In conclusion, we demonstrate that EMP shows a significantly less complex and, in part, distinct genetic profile compared to EMD. This may aid in differentiating the two entities in diagnostically challenging cases and could help to identify EMP with an increased risk of progression.