Clinicopathological and Molecular Genetic Insights into EBV-Positive Inflammatory Follicular Dendritic Cell Sarcoma

Abstract

Epstein-Barr virus (EBV)-positive inflammatory follicular dendritic cell (FDC) sarcoma (EBV+ IFDCS) is a rare entity, and its histopathological characteristics have not been fully described. This study aimed to investigate the clinical characteristics, pathological features, and molecular genetic profiles of EBV+ IFDCS to improve our understanding of these lesions. A total of 12 EBV+ IFDCS specimens were obtained from patients in our pathology diagnostic center. The clinical data, morphology, immunohistochemistry, in situ hybridization, and high-throughput DNA-targeted sequencing data were collected, and follow-up data were analyzed. These data were compared with those of 6 patients with traditional FDCS. The patients with EBV+ IFDCS ranged from 21 to 84 years old, with a mean age of 52.3 years and a male-to-female ratio of 1:5. At the last follow-up, all patients were alive, with 2 experiencing recurrence and metastasis. In these cases, four were classified as the classical subtype, four as the angiomatoid/sclerosing subtype, and four as the lymphoma-like subtype, with two cases also exhibiting epithelioid granulomas. All patients exhibited heterogeneous expression of follicular dendritic cell markers (CD21, CD23, CD35, and CXCL13) alongside the fibroblast marker SMA, with significantly higher expressions of IgG4, EBER, and SMA in EBV+ IFDCS patients compared to FDCS patients (P<0.05). Conversely, SSTR2, EGFR, and STAT3 expression were significantly lower in the EBV+ IFDCS group (P<0.05). The average value of EBER was significantly higher in the classical subtype group (P=0.022). Among the four cases of EBV+ IFDCS analyzed for molecular genetic features, one patient exhibited germline mutations in the CDKN1C, PDGFRA, MSH2, FANCG, MLH1, ALK, and RUNX1 genes; three exhibited simultaneous SNP variations in the MTHFR gene; and two exhibited simultaneous SNP variations in the NQO1 gene. We conducted KEGG pathway analysis on the mutant genes, revealing significant enrichment in the cAMP signaling pathway, which plays a crucial role in tumor development. Survival analysis demonstrated that the median PFS rates were not reached (NR) for EBV+ IFDCS patients, compared to 5 months (HR=7.76) for FDCS patients. The 3-year PFS rates were 66.67% and 16.67%, respectively. Compared with the FDCS group, EBV+ IFDCS patients had a significantly longer median PFS time (p<0.05). In conclusion, EBV+ IFDCS represents a group of tumors with unique clinical, morphological, immunological, prognostic, and molecular cytogenetic characteristics.