Original contributionEpidermal growth factor receptor and HER-2/neu status by immunohistochemistry and fluorescence in situ hybridization in adenocarcinomas of the biliary tree and gallbladder
Introduction
Cholangiocarcinoma is an aggressive tumor with an extremely poor prognosis. The 5-year survival rates are 10% to 40% for resectable tumors and less than 5% for unresectable disease [1], [2]. The worldwide incidence of these tumors is increasing [3]. Adenocarcinomas of the gallbladder also have a poor prognosis, with median overall survival of 10 months and 5-year survival of less than 30% [4]. Surgical resection is the only potentially curative option for these tumors. Systemic chemotherapy using 5-fluorouracil combined with cisplatin, and gemcitabine can improve the quality of life; but the impact on survival is minimal [1], [2], [5], [6]. New modalities of therapy need to be explored for these tumors to improve patient outcome.
Bile acids can activate epidermal growth factor receptor (EGFR), which in turn induces COX-2 expression via MAP-kinase cascade that may play a role in progression of cholangiocarcinoma [7]. Inhibition of EGFR signaling pathway activates apoptosis, inhibits angiogenesis, and induces antimetastatic properties [8]. The efficacy of EGFR antagonists like small-molecule tyrosine kinase inhibitors (EGFR-TKI) and anti-EGFR antibodies has been demonstrated in many tumors [8], [9], [10]. Cetuximab and panitumumab, monoclonal antibodies to EGFR, have been approved by the US Food and Drug Administration for colorectal carcinoma [10], [11]. Cetuximab and gefitinib, a TKI, have been approved for non–small cell lung cancer [10].
EGFR inhibition leads to suppression of tumor growth in cholangiocarcinoma cell lines and chimeric mouse model [12]. Addition of cetuximab to gemcitabine or radiation has yielded improved results in preliminary studies [13], [14], [15]. Therapeutic benefit has been reported with erlotinib in advanced cholangiocarcinomas in a phase II trial [16].
Several studies have demonstrated somatic mutations [17] and immunohistochemical overexpression of EGFR in cholangiocarcinomas and gallbladder adenocarcinomas [16], [18], [19], [20], [21], [22], [23], [24], [25]. EGFR gene amplification is a rare event in these tumors [14], [23]; however, the increase in EGFR copy number without amplification has not been systematically studied in these tumors This study examines the EGFR expression by immunohistochemistry and EGFR gene copy number by fluorescence in situ hybridization (FISH) in cholangiocarcinomas and gallbladder adenocarcinomas. The correlation of EGFR expression and gene copy number with clinical and pathologic parameters is examined. Because there are varying results in the cholangiocarcinoma literature regarding the status of HER-2/neu [23], [24], [26], [27], [28], another receptor in the EGFR family, we also evaluated HER-2/neu expression by immunohistochemistry in these tumors.
Section snippets
Tissue specimens
The study group comprised 51 biliary adenocarcinomas (26 intrahepatic, 19 extrahepatic, 6 gallbladder) retrieved from the surgical pathology files at Veteran Affairs, General Hospital and University of California, San Francisco, medical centers. Data on age, sex, tumor size, lymphovascular invasion, tumor grade, and tumor stage were obtained from review of slides and/or pathology reports. Survival information was obtained from the hospital tumor registries. In each case, a 5-μm section stained
Clinical information
The mean patient age was 63.2 years: 61.7 years for intrahepatic (range, 45-77), 67.4 years for extrahepatic (range, 28-84), and 58.3 years for gallbladder (range, 42-72). There were 23 women and 28 men: 14 and 12 for intrahepatic, 4 and 15 for extrahepatic, and 5 and 1 for gallbladder. All cases of intrahepatic cholangiocarcinoma had normal background liver with no evidence of chronic liver disease. Among the extrahepatic cases, there was no history of primary sclerosing cholangitis. All
Discussion
EGFR is a transmembrane tyrosine kinase whose activation by ligands like epidermal growth factor activates signal transduction pathways like Ras/Ras/MAP kinase and Akt/mTOR that influence cell proliferation, motility, and apoptosis [29], [30]. EGFR overexpression, mutation, or amplification has been reported in a wide variety of tumors [8], [9], [31], [32], [33], [34], [35], [36] and has been associated with tumor progression and poor outcome [9], [37].
EGFR expression in cholangiocarcinoma has
Acknowledgments
The authors would like to thank Elizabeth Pease for her help with FISH.
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2016, Critical Reviews in Oncology/HematologyCitation Excerpt :A recent study performing whole-exome sequencing of 57 gallbladder cancer tumor-normal pairs showed somatic mutations in EGFR (4%), HER2 (10%), ERBB3 (12%), and ERBB4 (4%) (Li et al., 2014). HER2 amplification, a therapeutic target in breast and gastric cancers, has been evaluated in biliary tract cancers as well, with observed rates around 5–15% (Jeffrey et al., 2015; Harder et al., 2009; Shafizadeh et al., 2010; Nakazawa et al., 2005). Highest rates appear to be in gallbladder cancer, with overexpression of HER2 reported in about a third of all cases (Kalekou and Miliaras, 2004).
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Drs. Shafizadeh and Grenert contributed equally to the manuscript.