Amplification and Overexpression of Cyclin D1 in Epstein-Barr Virus-Positive Inflammatory Follicular Dendritic Cell Sarcoma: A Targeted Next-Generation Sequencing Study.

Follicular dendritic cell sarcoma (FDCS) is subdivided into conventional type and inflammatory type (IFDCS). IFDCS is consistently associated with Epstein-Barr virus (EBV) infection and generally follows an indolent clinical course. Although EBV is believed to contribute to the pathogenesis of IFDCS, the underlying mechanisms remain incompletely understood. Recent comprehensive next-generation sequencing studies have identified recurrent somatic alterations involving the major histocompatibility complex and epigenetic regulatory pathways as well as signaling pathways related to immune responses. In this study, we performed targeted DNA sequencing of 523 cancer-associated genes (TSO500) in 31 cases of IFDCS. The cohort included 13 men and 18 women, with a mean age of 62.6 years (range, 36-84). Tumors arose in the spleen (n = 20), liver (n = 8), colon (n = 2), and pancreas (n = 1), with a mean tumor size of 5.8 cm (range, 1.4-11.7). Genetic alterations were found in 71% of cases with CCND1 amplifications (3-5 copies) being the most common (45.5%), followed by EZH2 mutations (18.2%), MYC amplifications (3-4 copies, 13.6%), and ATM mutations (9.1%). Pathway analysis identified cell-cycle progression as the main activated signaling in IFDCS. RNA in situ hybridization and double immunohistochemical staining confirmed the overexpression of cyclin D1 and MYC in FDCs. Clinically, overexpression of cyclin D1 was frequently found in both TSO500-positive (88.9%) and TSO500-negative (71.4%) cases and showed no association with tumor behavior. No significant clinicopathologic difference was present between TSO500-positive and TSO500-negative tumors. Notably, splenic origin was associated with female predominance (P = .011) and larger tumor size (P = .048). In addition, tumor cells exhibited a type II EBV latency pattern (latent membrane protein 1 [LMP1]+/Epstein-Barr nuclear antigen-2-) in 84.6% of cases, and LMP1 expression correlated with larger tumor size (P = .021). Taken together, these findings support a role for EBV-driven activation of the cyclin D1 pathway and suggest that EBV-LMP1-CCND1 signaling may contribute to the pathogenesis of IFDCS.