Molecular and immunohistochemical analysis of intraductal papillary neoplasms of the biliary tract

Susan C. Abraham, Jae Hyuk Lee, Ralph H. Hruban, Pedram Argani, Emma E. Furth, Tsung Teh Wu

Research output: Contribution to journalArticle

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Abstract

Intraductal papillary neoplasms (IPNs) of the biliary tract are uncommon lesions that may be solitary or may spread extensively along the biliary tree. Some biliary IPNs are histologically and radiologically similar to intraductal papillary mucinous tumors (IPMNs) of the pancreas and present a risk for progression to invasive cholangiocarcinoma. Unlike pancreatic IPMNs, little is known about their molecular pathogenesis. We studied 14 biliary IPNs (including 5 cases with associated invasive cholangiocarcinoma) for genetic alterations in the APC/β-catenin pathway, K-ras oncogene mutations, p53/chromosome 17p alterations, and Dpc4/18q alterations. Immunohistochemistry was performed for β-catenin, p53, and Dpc4, and microdissected tissue was analyzed using direct DNA sequencing for exon 1 of K-ras and exon 3 of β-catenin and allelic loss assays on chromosomes 5q, 17p, and 18q. Activating mutations in codon 12 of the K-ras oncogene were present in 4 of 14 (29%) biliary IPNs. Of these 4 cases, 2 patients had associated invasive cholangiocarcinoma, and identical K-ras mutations were present in both the intraductal and invasive components. Allelic loss on chromosome 18q was present in 4 of 13 informative cases (31%); however, no loss of normal Dpc4 expression was detected by immunohistochemistry. Nuclear accumulation of β-catenin protein was demonstrated in 3 of 12 cases (25%); however, there were no β-catenin gene mutations, and allelic loss on 5q was present in only 1 of 10 informative cases (10%). Both immunohistochemistry for p53 and 17p allelic loss assays were negative. Biliary IPNs therefore demonstrate a K-ras gene mutation frequency that is lower than that previously reported for pancreatic IPMNs, but similar to that reported for hepatic cholangiocarcinomas. The presence of K-ras mutations in 2 purely intraductal neoplasms, and identical K-ras mutations in 2 cases with both intraductal and invasive components, suggests that these mutations arise early in tumorigenesis. Finally, the frequency of allelic loss on 18q suggests that a locus on 18q is involved in the molecular pathogenesis of biliary IPNs, but this locus is not DPC4.

Original languageEnglish (US)
Pages (from-to)902-910
Number of pages9
JournalHuman Pathology
Volume34
Issue number9
DOIs
StatePublished - Sep 1 2003
Externally publishedYes

Fingerprint

Biliary Tract Neoplasms
Catenins
Loss of Heterozygosity
Cholangiocarcinoma
Mutation
Neoplasms
ras Genes
Chromosomes
Immunohistochemistry
Exons
Biliary Tract
Mutation Rate
DNA Sequence Analysis
Gene Frequency
Codon
Pancreas
Carcinogenesis

Keywords

  • Biliary tract
  • Cholangiocarcinoma
  • Intraductal papillary neoplasm
  • Liver

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Abraham, S. C., Lee, J. H., Hruban, R. H., Argani, P., Furth, E. E., & Wu, T. T. (2003). Molecular and immunohistochemical analysis of intraductal papillary neoplasms of the biliary tract. Human Pathology, 34(9), 902-910. https://doi.org/10.1016/S0046-8177(03)00337-X

Molecular and immunohistochemical analysis of intraductal papillary neoplasms of the biliary tract. / Abraham, Susan C.; Lee, Jae Hyuk; Hruban, Ralph H.; Argani, Pedram; Furth, Emma E.; Wu, Tsung Teh.

In: Human Pathology, Vol. 34, No. 9, 01.09.2003, p. 902-910.

Research output: Contribution to journalArticle

Abraham, Susan C. ; Lee, Jae Hyuk ; Hruban, Ralph H. ; Argani, Pedram ; Furth, Emma E. ; Wu, Tsung Teh. / Molecular and immunohistochemical analysis of intraductal papillary neoplasms of the biliary tract. In: Human Pathology. 2003 ; Vol. 34, No. 9. pp. 902-910.
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N2 - Intraductal papillary neoplasms (IPNs) of the biliary tract are uncommon lesions that may be solitary or may spread extensively along the biliary tree. Some biliary IPNs are histologically and radiologically similar to intraductal papillary mucinous tumors (IPMNs) of the pancreas and present a risk for progression to invasive cholangiocarcinoma. Unlike pancreatic IPMNs, little is known about their molecular pathogenesis. We studied 14 biliary IPNs (including 5 cases with associated invasive cholangiocarcinoma) for genetic alterations in the APC/β-catenin pathway, K-ras oncogene mutations, p53/chromosome 17p alterations, and Dpc4/18q alterations. Immunohistochemistry was performed for β-catenin, p53, and Dpc4, and microdissected tissue was analyzed using direct DNA sequencing for exon 1 of K-ras and exon 3 of β-catenin and allelic loss assays on chromosomes 5q, 17p, and 18q. Activating mutations in codon 12 of the K-ras oncogene were present in 4 of 14 (29%) biliary IPNs. Of these 4 cases, 2 patients had associated invasive cholangiocarcinoma, and identical K-ras mutations were present in both the intraductal and invasive components. Allelic loss on chromosome 18q was present in 4 of 13 informative cases (31%); however, no loss of normal Dpc4 expression was detected by immunohistochemistry. Nuclear accumulation of β-catenin protein was demonstrated in 3 of 12 cases (25%); however, there were no β-catenin gene mutations, and allelic loss on 5q was present in only 1 of 10 informative cases (10%). Both immunohistochemistry for p53 and 17p allelic loss assays were negative. Biliary IPNs therefore demonstrate a K-ras gene mutation frequency that is lower than that previously reported for pancreatic IPMNs, but similar to that reported for hepatic cholangiocarcinomas. The presence of K-ras mutations in 2 purely intraductal neoplasms, and identical K-ras mutations in 2 cases with both intraductal and invasive components, suggests that these mutations arise early in tumorigenesis. Finally, the frequency of allelic loss on 18q suggests that a locus on 18q is involved in the molecular pathogenesis of biliary IPNs, but this locus is not DPC4.

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