Gallbladder and Bile Duct Cancer

2001 News Archive

Molecular and Immunohistochemical Analysis of Intraductal Papillary Neoplasms of the Biliary Tract

Intraductal papillary neoplasms of the biliary tract are rare lesions that may extensively colonize the biliary tree. They are histologically and radiologically similar to the intraductal papillary mucinous neoplasms of the pancreas (IPMNs). Like IPMNs, these biliary intraductal lesions present a risk of progression to invasive carcinoma, in this case invasive cholangiocarcinoma. While IPMNs typically obstruct the pancreatic ducts and lead to chronic pancreatitis and pancreatic failure, intraductal papillary neoplasms of the biliary tract obstruct the bile ducts and therefore lead to hepatic damage. While IPMNs of the pancreas have been analyzed molecularly, little is known about the molecular pathogenesis of intraductal papillary neoplasms of the biliary tract. A group at Johns Hopkins, led by Dr. Susan Abraham, has recently studied fourteen cases of intraductal papillary neoplasms of the biliary tree, including five with associated invasive cholangiocarcinoma. They microdissected tissue from the intraductal and invasive carcinoma and compared it to normal tissue. Specific genes analyzed included the K-ras gene and the b-catenin gene, while allelic loss was analyzed on chromosome 18q (the site of DPC4), 17p (the site of p53), and 5q (the site of the APC gene).

Immunohistochemistry for p53, b-catenin, and Dpc 4 was also performed. The Hopkins group found activating mutations in K-ras in four of fourteen (29%) of intraductal papillary neoplasms of the biliary tree. Of these four

These results show that intraductal papillary neoplasms of the biliary tract are associated with K-ras gene mutations, which appear to arise early in their pathogenesis. The frequency detected in the biliary tree is lower than that seen in pancreatic IPMNs, but similar to that reported in hepatic cholangiocarcinomas. These results further our understanding of this unusual form of biliary tract carcinoma.

PubMed Abstract | Full Text
Abraham SC, Lee JH,Hruban RH, Argani P, Furth EE, Wu TT. The Johns Hopkins University School of Medicine and the University of Pennsylvania Medical Center. Human Pathology. 2003 Sep;34(9):902-10.

~July 2001



Consistent Overexpression of Fatty Acid Synthase (FAS) in Biliary Tract Carcinomas: A Novel Target for Anti-Biliary Tract Cancer Drug Development?

Fatty Acid Synthase (FAS) is the primary enzyme involved in the anabolic conversion of dietary carbohydrates to long chain fatty acids. Specifically, FAS catalyzes the NADPH-dependent reductive synthesis of palmitate from acetyl CoA and malonyl CoA.

FAS is normally expressed in the liver, lactating breast, and adipose tissue (where it functions in anabolic energy storage pathways), but minimally expressed in other adult tissues which preferentially utilize circulating lipids.

FAS has been demonstrated to be overexpressed in several human cancers (breast, endometrial, prostate, colon). In some cancers, high levels of FAS expression have been associated with poor prognosis, suggesting that FAS expression may promote tumor growth and virulence. Recently-synthesized inhibitors of FAS have demonstrated antitumor activity in xenografts without concurrent toxicity to normal proliferative tissues (bone marrow, gastrointestinal mucosa, lymph nodes), and hence hold promise as therapy for tumors that overexpress FAS (Cancer Res 2000; 60: 213-218) (PNAS 2000; 97: 3450-3454).

FAS expression had not been studied in biliary tract carcinomas, which are highly aggressive and often unresponsive to conventional therapy.

We recently examined 107 biliary tract carcinomas for FAS overexpression using an immunohistochemical assay on formalin-fixed, paraffin-embedded tissue. FAS was overexpressed in 93% of carcinomas of the biliary tract. Therefore, FAS inhibitors hold promise as therapy for biliary tract carcinomas.


Differing Rates of Loss of DPC4 Expression and of p53 Overexpression among Carcinomas of the Proximal and Distal Bile Ducts: Evidence for a Biologic Distinction Figure 1: FAS immunolabeling of a bile duct carcinoma. The carcinoma surrounds a benign remnant (outlined in green) of bile duct. While the bile duct carcinoma is strongly positive for FAS(brown staining), the normal bile duct does not label.

P Argani, FP Kuhajda, RE Wilentz, GH Su, TA Sohn, CJ Yeo, JL Cameron, RH Hruban The Johns Hopkins University, Baltimore, MD. Modern Pathology 2001;14: 192A.

~May 2001



Molecular and Immunohistochemical Analysis of Intraductal Papillary Neoplasms of the Biliary Tract

We had previously referred to a study performed at Hopkins (Genes, Chromosomes, and Cancer 1999;26; 185-191) in which our group analyzed the overall genetic composition of distal bile duct cancers using conventional cytogenetics and comparative genomic hybridization. The analysis of distal bile duct cancers revealed frequent loss of genetic material on the long arms of chromosomes 18, 6, and 12 (18q, 6q, and 12q), and the short arms of chromosomes 10, 8, and 17 (10p, 8p, and 17p). Of great interest was the fact that many of these changes are similar to those previously identified in pancreatic cancers, suggesting that these two tumors share a number of genetic changes. Some of the sites identified suggested specific genes that might be involved in bile duct cancers. For example, the p53 gene is located on chromosome 17p and is known to be mutated in the majority of pancreatic cancers.

We have recently completed a follow-up study that appeared in the April 1, 2001 issue of Cancer in which we have identified several specific genes involved in bile duct carcinoma. Using immunohistochemical labeling, we were able to show that the DPC4, a tumor suppressor gene discovered at Hopkins that is known to play a major role in pancreas cancer, is also involved in bile duct carcinomas. Loss of Dpc4 protein was identified in a significant number of bile duct carcinomas. However, not all bile duct carcinomas are equal: we were able to demonstrate that distal common bile duct carcinomas (those located near the pancreas) were far more likely to demonstrate loss of DPC4 than proximal bile duct cancers (Klatskin tumors and cholangiocarcinomas of the liver). In fact, the frequency of DPC4 loss that we demonstrated in distal bile duct carcinomas (55%) is identical to that which was demonstrated in pancreatic cancer. Similarly, we were able to show that the p53 gene product was abnormally expressed far more frequently in distal bile duct cancers than proximal ones. These results show that distal common bile duct cancers have some of the same genetic alterations as pancreatic cancers, while other bile duct cancers are biologically distinct. It is hoped that these results will allow us to develop more rational therapies for these tumors.

Figure 1: Moderately differentiated distal common bile duct adenocarcinoma demonstrating loss of Dpc4 expression and p53 overexpression (160 times magnification). A. Hematoxylin and eosin shows the adenocarcinoma infiltrating between a fibrotic reactive stroma. B. Dpc4 antibody labels the fibrotic stroma surrounding the carcinoma (brown staining is positive), but the carcinoma does not express Dpc4. C. p53 labeling yields the inverse pattern, as the infiltrating carcinoma overexpresses p53 (brown staining in the nucleus), while the stroma does not express p53.


Fig 1a. Hematoxylin and eosin shows the adenocarcinoma infiltrating between a fibrotic reactive stroma


Fig 1b. Dpc4 antibody labels the fibrotic stroma surrounding the carcinoma (brown staining is positive), but the carcinoma does not express Dpc4


Fig 1c. p53 labeling yields the inverse pattern, as the infiltrating carcinoma overexpresses p53 (brown staining in the nucleus), while the stroma does not express p53.


Figure 2: Summary of the results of the study, showing the pattern of Dpc4 and p53 expression in intrahepatic (top), perihilar (middle) and distal (bottom) bile duct carcinomas.


PubMed Abstract | Full Text
Pedram Argani MD1, Aasma Shaukat MD MPH2, Manju Kaushal M.Sc.1, Robb E. Wilentz MD1, Gloria H. Su PhD1, Taylor A. Sohn MD3, Charles J. Yeo MD3,4, John L. Cameron MD3, Scott E. Kern MD1,4, and Ralph H. Hruban MD1,4 From the Departments of Pathology1, Surgery3, and Oncology4, and The Johns Hopkins School of Public Health2, The Johns Hopkins Medical Institutions, Baltimore, Maryland. USA
Cancer 2001;91: 1332-41


~March 2001