PURPOSE: The aim of this study was to investigate the biological and clinical 
significance of epidermal growth factor receptor (EGFR) signaling pathway in 
follicular dendritic cell sarcoma (FDC-S).
EXPERIMENTAL DESIGN: Expression of EGFR and cognate ligands as well as 
activation of EGFR signaling components was assessed in clinical samples and in 
a primary FDC-S short-term culture (referred as FDC-AM09). Biological effects of 
the EGFR antagonists cetuximab and panitumumab and the MEK inhibitor UO126 on 
FDC-S cells were determined in vitro on FDC-AM09. Direct sequencing of KRAS, 
BRAF, and PI3KCA was conducted on tumor DNA.
RESULTS: We found a strong EGFR expression on dysplastic and neoplastic FDCs. On 
FDC-AM09, we could show that engagement of surface EGFR by cognate ligands 
drives the survival and proliferation of FDC-S cells, by signaling to the 
nucleus mainly via MAPK and STAT pathways. Among EGFR ligands, heparin-binding 
EGF-like growth factor, TGF-α and Betacellulin (BTC) are produced in the tumor 
microenvironment of FDC-S at RNA level. By extending this finding at protein 
level we found that BTC is abundantly produced by FDC-S cells and surrounding 
stromal cells. Finally, direct sequencing of tumor-derived genomic DNA showed 
that mutations in KRAS, NRAS, BRAF, and PI3KCA, which predicts resistance to 
anti-EGFR MoAb in other cancer models, are not observed in FDC-S.
CONCLUSION: Activation of EGFR by cognate ligands produced in the tumor 
microenvironment sustain viability and proliferation of FDC-S indicating that 
the receptor blockade might be clinically relevant in this neoplasm.