Cholangiocarcinoma in primary sclerosing cholangitis : K-ras mutations and Tp53 dysfunction are implicated in the neoplastic development

• Published in: Journal of hepatology Vol. 32; no. 3; pp. 374 - 380
• Main Authors: BOBERG, K. M, SCHRUMPF, E, BERGQUIST, A, BROOME, U, PARES, A, REMOTTI, H, SCHJÖLBERG, A, SPURKLAND, A, CLAUSEN, O. P. F
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 2000
• Subjects: Adolescent; Adult; Bile Duct Neoplasms - etiology; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - metabolism; Bile Duct Neoplasms - pathology; Biological and medical sciences; Cholangiocarcinoma - etiology; Cholangiocarcinoma - genetics; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - pathology; Cholangitis, Sclerosing - complications; Digestive system; Disease Progression; Female; Genes, ras - physiology; Humans; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); Ki-67 Antigen - metabolism; Male; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Mutation - physiology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Protein p53 - physiology; Human; Immunopathology; Hepatic disease; Malignant tumor; Biliary tract disease; Carcinogenesis; Pathology; Codon; Histopathology; Malignant cholangioma; Clinical biology; Primary; Digestive diseases; Genetics; Complication; Mutation; Sclerosing cholangitis; Comparative study
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/s0168-8278(00)80386-4

Cholangiocarcinoma is a feared complication of primary sclerosing cholangitis (PSC). Neoplastic bile duct strictures may be difficult to differentiate cholangiographically from the non-neoplastic bile duct irregularities characteristic of this disorder, and the diagnosis of cholangiocarcinoma may be difficult to establish with certainty, even in tissue samples. Thus, new methods which can improve the diagnostic accuracy of cholangiocarcinoma in PSC are needed. We investigated the occurrence of K-ras codon 12 and 13 mutations, p53 protein accumulation, and Ki-67 expression in tumor tissue from PSC patients (n=33) who had developed cholangiocarcinoma, using bile duct specimens exised at liver transplantation of PSC patients without cholangiocarcinoma (n=15) as controls K-ras mutations were present in 11 (33%) of the cholangiocarcinoma samples and significantly more frequent in females. Nine tumors carried a codon 12 mutation, and 2 had a codon 13 mutation. The most frequent substitutions in codon 12 were GGT-->GAT (n=5) and GGT-->TGT (n=3). None of the control bile ducts had K-ras mutations. p53 protein was accumulated in 10 (31%) of the tumors, as opposed to negative findings in all the control samples. Sixteen (48%) tumors revealed either K-ras mutation or p53 accumulation. Ki-67 positivity was significantly higher in cholangiocarcinomas than in the non-neoplastic bile ducts (median 29% vs 12%, respectively; p=0.011). We conclude that K-ras mutations and p53 dysfunction are implicated in tumorigenesis of cholangiocarcinomas arising in PSC patients and that these abnormalities together with increased Ki-67 index may indicate neoplastic progression of bile ducts in these patients.