Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma

Abstract

Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and human epidermal growth factor receptor 2 (HER2) have been considered as potential therapeutic targets in cholangiocarcinoma, but no studies have yet clarified the clinicopathological or prognostic significance of these molecules. Immunohistochemical expression of these molecules was assessed retrospectively in 236 cases of cholangiocarcinoma, as well as associations between the expression of these molecules and clinicopathological factors or clinical outcome. The proportions of positive cases for EGFR, VEGF, and HER2 overexpression were 27.4, 53.8, and 0.9% in intrahepatic cholangiocarcinoma (IHCC), and 19.2, 59.2, and 8.5% in extrahepatic cholangiocarcinoma (EHCC), respectively. Clinicopathologically, EGFR overexpression was associated with macroscopic type (P ¼ 0.0120), lymph node metastasis (P ¼ 0.0006), tumour stage (P ¼ 0.0424), lymphatic vessel invasion (P ¼ 0.0371), and perineural invasion (P ¼ 0.0459) in EHCC, and VEGF overexpression with intrahepatic metastasis (P ¼ 0.0224) in IHCC. Multivariate analysis showed that EGFR expression was a significant prognostic factor (hazard ratio (HR), 2.67; 95% confidence interval (CI), 1.52 -4.69; P ¼ 0.0006) and also a risk factor for tumour recurrence (HR, 1.89; 95% CI, 1.05 -3.39, P ¼ 0.0335) in IHCC. These results suggest that EGFR expression is associated with tumour progression and VEGF expression may be involved in haematogenic metastasis in cholangiocarcinoma.

Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways

“…41 This may also hold true for cholangiocarcinoma, where EGFR was only positive in one case in contrast to that what has been reported in the literature. 42,43 Using the established morphological and immunohistochemical criteria for subtype classification of pancreatic intraductal papillary mucinous neoplasms, 6,31 we were able to classify the majority of intraductal papillary neoplasms of the bile duct (96%) as pancreato-biliary, intestinal, gastric or oncocytic subtype. This indicates that, as expected, intraductal papillary neoplasms of the bile duct share many similarities with pancreatic intraductal papillary mucinous neoplasms from the histological point of view.…”

Loss of EBP50 stimulates EGFR activity to induce EMT phenotypic features in biliary cancer cells

“…Overexpression and sustained activation of EGFR are associated with tumor progression in biliary carcinoma (Yoon et al, 2004;Yoshikawa et al, 2008). In different types of cancer, EGFR activation disturbs cell-cell adhesion by destabilizing the E-cadherin/b-catenin complex, promotes epithelial-to-mesenchymal transition (EMT) and contributes to the acquisition of a motile phenotype (Henson and Gibson, 2006;Sebastian et al, 2006).…”

Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma

“…In addition, VEGF upregulation in tumour cells is considered to be a mechanism of resistance to EGFR inhibitors (Viloria Petit et al, 2001). Earlier, we have also reported that EGFR and VEGF overexpressions are frequent in cholangiocarcinoma (B20 and 50%, respectively), that EGFR overexpression is an independent prognostic factor in IHCC, and that VEGF expression is associated with intrahepatic metastasis in IHCC (Yoshikawa et al, 2008). These observations prompted us to hypothesise that dual inhibition of both EGFR and VEGFR may exert a synergistic anti-tumour effect in cholangiocarcinoma.…”