The Role FGFR4 in Pancreatic Endocrine Tumors
S Serra, S Ezzat, R Chetty, SL Asa. UHN, Toronto, Canada
Background: Fibroblast Growth Factor Receptors (FGFRs) are 4 transmembrane kinases. FGFR4, which is the subject of a germline SNP (G388R), interacts with N-Cadherin and NCAM, adhesion molecules implicated in tumor invasion and metastasis. We examined the expression of FGFR4, N-cadherin and NCAM in pancreatic endocrine tumors (PETs) and their relationship to the FGFR4 G388R SNP, clinical and pathological parameters.
Design: Paraffin blocks of 83 PETs classified by WHO criteria were retrieved from Pathology files of University Health Network with ethics consent. FGFR4 SNP was determined by polymerase chain reaction-restriction fragment length polymorphism of somatic DNA. A tissue microarray composed of cores of tumors, corresponding normal pancreas and lymph node metastases was stained for FGFR4, N-Cadherin and NCAM, and evaluated for localization (membrane/cytoplasm), intensity (0-3), and percent positive cells.
Results: Tumors from 83 patients (36 males, 47 females, ages 23-80 mean 52.7 years) ranged from 0.8 cm to 11 cm (mean 3.4 cm). Insulin was localized in 32, glucagon in 14, vasoactive intestinal peptide (VIP) in 8, and 26 tumors were plurihormonal. Local invasion was seen in 22, 36 had lymphovascular invasion, 18 had lymph node spread and 13 had liver metastasis. FGFR4 immunoreactivity was cytoplasmic only and higher in PETs with lymph node spread (p=0.003), liver metastasis (p=0.08), and mitotic count >2/10HPF (p=0.03). It was lowest in insulinomas (p=0.045). FGFR4 expression increased from tumors of benign behavior (TBB) to low-grade carcinoma (LGC) (p=0.005); lower immunoreactivity was found in TBB compared to tumors of uncertain behavior (TUB) and LGC (p=0.022). FGFR4 was overexpressed in LGC compared to TBB and TUB (p=0.002). N-Cadherin immunoreactivity was exclusively cytoplasmic and stronger in PETs with liver metastases (p=0.01) and with mitotic count >2/10HPF (p=0.003). Membranous NCAM (MB-NCAM) was higher in insulinomas (p=0.002) and decreased in glucagonomas (p=0.002). It was also progressively reduced from TBB to TUB to LGC (p=0.007). It was higher in TBB compared to TUB and LGC (p=0.003); it was reduced in LGC compared to TBB and TUB (p=0.025). MB NCAM was overexpressed in patients with homozygous Arg388 compared to homozygous Gly388 (p=0.039). Cytoplasmic NCAM was overexpressed in PETs with liver metastasis (p=0.06).
Conclusions: FGFR4 is implicated in PET progression. Aggressive tumor behavior is associated with FGFR4, N-cadherin and NCAM cytoplasmic overexpression and with loss of MB NCAM, validating the RIP-TAG/NCAM(-/-) mouse model of tumor progression.
Tuesday, March 10, 2009 8:00 AM
Platform Session: Section H1, Tuesday Morning