Differential Expression of FGFRs Correlates with Outcomes in Pheochromocytomas and Paragangliomas.
Clarissa A Cassol, Sylvia L Asa. University Health Network, Toronto, ON, Canada
Background: FGFRs are receptor tyrosine kinases (RTK) that have been implicated in various malignancies. A recent report from our institution of successful treatment of malignant pheochromocytoma (PCT)/paraganglioma (PGL) with a multitargeted RTK inhibitor (RTKi) provided clinical evidence for involvement of RTKs in the pathogenesis of these tumors. To date, a single study documents overexpression of FGFR1 and 2 in paragangliomas. We analyzed expression of several FGFRs in both tumor types.
Design: We identified 153 PCT/PGL from our institutional files of 2001-2009. Of those, 132 tumors from 115 patients provided enough tissue for Tissue Microarray (TMA) construction. Slides were stained with anti-FGFR2 (SC-122), -3 (SC-123) and -4 (SC-124) antibodies (Santa Cruz), scanned with ScanScope (Aperio) and analyzed using Spectrum Color Deconvolution Algorithm (Aperio). Parameters used for exploratory statistical analysis on SPSS 11.0 were percent total positive (PTP), a weighted score calculated by the program [1*(%Weak) + 2*(%Medium) + 3*(%Strong)], relevant clinical data and 3 outcomes (local recurrence, metastasis, death from disease).
Results: Of 115 patients, 71 were female and 39 were male. Mean age at diagnosis was 46.8 years (±12.3). 18.3 % had bilateral/multiple tumors and 7.8% had a family history of PCT/PGL. 7 PGL patients had metastases, 4 had local recurrences, and 2 died of disease. Of 132 tumors, 43 were PCTs, 82 PGLs and 7 PGL metastases. FGFR2 and 4 were overexpressed (p<0.01) and FGFR3 was underexpressed (p<0.05) in tumors compared to normal medulla. The presence of bilateral/multiple tumors was associated with local recurrence (p=0.021) and the 3 outcomes combined (p=0.055). An inverse correlation between tumor size and FGFR2 score (p=0.002,R=-.276) and PTP (p=0.002,R=-.275) was observed. Increased risk of metastasis was associated with increased tumor FGFR4 score (OR=1.17;95%CI=1.05-1.30;p=0.003) and PTP (OR=1.18;95%CI=1.06-1.31;p=0.003). Conversely, decreased risk of the 3 negative outcomes combined was associated with increased tumor FGFR3 score and PTP (both OR=0.96;95%CI=0.93-0.99;p=0.01).
Conclusions: FGFR2 and 4 are overexpressed in PCT/PGL, while FGFR3 is underexpressed. FGFR2 inversely correlates with tumor size, consistent with a proposed tumor suppressor role for this receptor. FGFR4 overexpression was associated with increased risk of metastases, providing evidence for a role for FGFR4 involvement in the progression of PCT/PGL. Whether a differential expression of these markers could be predictive of RTKi sensitivity in these tumors warrants futher studies.
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 84, Monday Morning