title: EGFR, COX2, p-AKT expression and PIK3CA mutation in distal extrahepatic bile duct carcinoma.
abstract: Distal extrahepatic bile duct (EBD) carcinoma is a rare but highly aggressive malignant neoplasm. Some in vitro studies have shown that EGFR and PI3K-Akt pathway play an important role in the carcinogenesis of bile duct carcinoma. The aim of the present study is to investigate the expression of EGFR, p-AKT, and COX-2 and the mutation of PIK3CA in distal EBD carcinoma and evaluate the association with clinicopathological factors. Ninety cases of distal extrahepatic bile duct (EBD) carcinoma specimens were studied. Immunohistochemistry (IHC) using antibodies against EGFR, p-AKT, and COX-2 was performed on TMA blocks. The PIK3CA mutation was evaluated using the PNAClamp Detection Kit from DNA samples extracted from formalin fixed, paraffin embedded tissue. EGFR expression of distal EBD carcinomas was 61.9%, 26.2%, 6.0% and 6.0% in the negative, weakly positive, moderately positive, and strongly positive groups, respectively. Positive EGFR expression showed significant relationships with high T stage (p = 0.024). In Kaplan-Meier analysis, EGFR expression was associated with shorter cancer-specific overall survival (p = 0.005). Multivariate analysis also showed that moderate or strong (2+ or 3+) EGFR expression was a significant prognostic factor in distal EBD carcinoma: HR 5.286; p = 0.001. Ninety cases of EBD carcinoma tissue were analysed for hotspot mutations (exon 9 and 20) in the PIK3CA gene. Only one mutation was detected: a missense mutation of H1047 at exon 20. The expression levels of p-AKT and COX-2 showed no association with any clinicopathological parameters, including survival rate. Moderate and strong EGFR expressions demonstrate a direct link to poor prognosis. Although further study is warranted to understand the clinicopathological significance, our finding suggests EGFR is a useful prognostic marker of patients with distal EBD carcinoma. A low prevalence of PIK3CA mutation exists in the distal EBD carcinoma of Korean patients, indicating that mutation screening may not be useful in determining prognosis or in formulating a treatment response to targeted inhibition in Korea.
authors.affiliation: Department of Pathology, Graduate School of Medicine, Kyung Hee University, Seoul, Republic of Korea; Department of Pathology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Gyeonggi-do, Republic of Korea.
authors.forename: Ahrim
authors.initials: A
authors.lastname: Moon
authors.affiliation: Department of Pathology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Gyeonggi-do, Republic of Korea.
authors.forename: Susie
authors.initials: S
authors.lastname: Chin
authors.affiliation: Department of Pathology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Gyeonggi-do, Republic of Korea.
authors.forename: Hee Kyung
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Department of Pathology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Gyeonggi-do, Republic of Korea.
authors.forename: Jeong Ja
authors.initials: JJ
authors.lastname: Kwak
authors.affiliation: Department of Pathology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Gyeonggi-do, Republic of Korea.
authors.forename: Eun Suk
authors.initials: ES
authors.lastname: Koh
authors.affiliation: Department of Pathology, Graduate School of Medicine, Kyung Hee University, Seoul, Republic of Korea. Electronic address: kimyw@khu.ac.kr.
authors.forename: Youn Wha
authors.initials: YW
authors.lastname: Kim
authors.affiliation: Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: ktjang12@gmail.com.
authors.forename: Kee-Taek
authors.initials: KT
authors.lastname: Jang
mesh_terms: D001650:Bile Duct Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D017734:Bile Ducts, Extrahepatic / Q000473:pathology*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt
keywords: COX-2; EGFR; PIK3CA mutation; distal bile duct carcinoma; p-AKT