1. ¹Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
2. ²Brady Urological Institute, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
3. ³Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

Correspondence: Dr P Argani, MD, Department of Pathology, The Johns Hopkins University School of Medicine, 401 N Broadway, Weinberg 2242, Baltimore, MD 21231-2410, USA. E-mail: pargani@jhmi.edu

^*Current address: Indiana University School of Medicine, Indianapolis, IN, USA.

Received 19 January 2006; Revised 22 February 2006; Accepted 23 February 2006; Published online 24 March 2006.

Abstract

Biliary tract carcinoma, including carcinoma of the gallbladder, intrahepatic bile ducts (cholangiocarcinoma), and extrahepatic bile ducts, affects 7500 people in the United States annually, and has an overall 32% 5-year survival rate for disease limited to the mucosa, and a dismal 10% 5-year survival for more advanced disease. The identification of factors involved in the pathogenesis and progression of biliary tract carcinoma is critical for devising effective methods of screening and treatment. Recent evidence suggests that reduction of the length of telomeres, which normally help maintain chromosomal stability, may promote the development and progression of a variety of carcinomas. Using a novel, recently validated telomere fluorescence in situ hybridization method, we examined telomere length in normal and inflamed gallbladder epithelium, metaplasia and dysplasia of the gallbladder, and biliary tract carcinoma to determine whether telomere shortening is associated with neoplastic progression in the biliary tract. Although normal and inflamed gallbladder epithelium demonstrated uniform normal telomere lengths, over half of all metaplastic lesions demonstrated shortened telomeres, supporting prior evidence that metaplastic lesions of the gallbladder are pre-neoplastic. Dysplastic epithelium and invasive carcinomas demonstrated almost universally abnormally short telomeres, indicating that telomere shortening occurs at an early, preinvasive stage of cancer development. In addition, invasive adenocarcinoma of the biliary tract frequently demonstrated intratumoral heterogeneity of telomere lengths. We conclude that telomere shortening is a consistent and early finding in the development of biliary tract carcinoma.