Immunophenotypic spectrum and mutational landscape of EBV ‐positive inflammatory follicular dendritic cell sarcoma

AIMS: Epstein-Barr virus (EBV)-positive inflammatory follicular dendritic cell sarcoma (EBV+ IFDCS) is a rare, indolent malignant neoplasm. Due to its rarity, a comprehensive assessment of its immunophenotypic spectrum and molecular analysis is still lacking. This study aimed to characterize the immunophenotypic and genetic alterations of EBV+ IFDCS to improve understanding of its cell of origin and molecular pathogenesis and to identify potential therapeutic targets. METHODS AND RESULTS: Immunohistochemical staining for a panel of follicular dendritic cell (FDC) and fibroblastic reticular cell (FRC) lineage markers, along with targeted next-generation sequencing, was performed. Nineteen cases of EBV+ IFDCS were classified into four immunophenotypes: nine FDC, two FRC, three biphasic and five null phenotypes. Morphologically, cases with a null phenotype more frequently exhibited a lymphoma-like growth pattern (4/5, 80%) compared with those with a definite FDC and/or FRC phenotype (1/14, 7.1%, P = 0.006). Moreover, a scattered distribution of neoplastic cells was more commonly observed in null phenotype cases (4/5, 80%) than in FDC and/or FRC phenotype cases (3/14, 21.4%, P = 0.038). Targeted sequencing revealed somatic variants in chromatin modifier-related genes in 60.0% (9/15), homologous recombination repair (HRR)-related genes in 53.3% (8/15) and Hippo pathway-related genes (FAT2 and FAT1) in 26.7% (4/15) of cases. CONCLUSIONS: These findings demonstrate the wide morphological and immunophenotypic spectrum of EBV+ IFDCS. Furthermore, variants in chromatin modifier and HRR-related genes may participate in its pathogenesis, and PARP inhibition may represent a potential therapeutic strategy for patients with unresectable disease.