Potential conflict of interest: Nothing to report.
BRAF V600E mutations in bile duct adenomas
Article first published online: 19 MAY 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 61, Issue 1, pages 403–405, January 2015
How to Cite
Pujals, A., Amaddeo, G., Castain, C., Bioulac-Sage, P., Compagnon, P., Zucman-Rossi, J., Azoulay, D., Leroy, K., Zafrani, E. S. and Calderaro, J. (2015), BRAF V600E mutations in bile duct adenomas. Hepatology, 61: 403–405. doi: 10.1002/hep.27133
- Issue published online: 29 DEC 2014
- Article first published online: 19 MAY 2014
- Accepted manuscript online: 16 MAR 2014 11:58PM EST
- Manuscript Accepted: 13 MAR 2014
- Manuscript Received: 23 FEB 2014
To the Editor:
Bile duct adenomas (BDA) are rare and benign intrahepatic biliary proliferations of uncertain pathogenesis. They are usually small in size (<5 mm) and incidentally discovered during intraabdominal surgery or macroscopic examination of surgical specimens.
Histologically, they consist of numerous and small bile ducts interspersed with fibrous stroma (Fig. 1A,B). These lesions are frequently referred to as “peribiliary gland hamartomas,” and some authors have also proposed that they might represent a focal ductular proliferation developed in response to liver injury. Their reactive versus neoplastic nature, however, is still debated; nevertheless, malignant transformation into intrahepatic cholangiocarcinoma (ICC) has been reported.[3, 4]
We screened a series of 15 BDAs for BRAF mutations to determine if this oncogene, mutated in various benign neoplasms, is involved in their development. These BDAs were observed in 10 patients, among whom four had an associated intrahepatic cholangiocarcinoma (ICC) (Table 1). Genomic DNA was extracted from formalin-fixed paraffin-embedded blocks with Qiagen robot EZ1. Samples were screened for BRAF (codon 600) mutations by means of high-resolution melting analysis and mutant DNA were further analyzed with an allele-specific polymerase chain reaction assay (ENTROGEN).
|Patient No.||Age||Gender||Indication of Liver Surgery||Liver Disease||Number of BDA||Tumor ID||Tumor Histological Diagnosis||BRAF Mutational Status|
|1||56||F||Metastatic colorectal carcinoma||None||2||1a||BDA||V600E|
|4||62||M||Atypical focal nodular hyperlasia||NASH||2||4a||BDA||V600E|
|10||63||F||Pancreatic endocrine tumor||None||1||10a||BDA||wWt|
BRAF V600E mutations were identified in 8/15 (53%) BDAs (Table 1). The existence of a recurrent molecular alteration such as a BRAF mutation strongly supports the hypothesis that BDAs are true neoplasms and that they should no more be designated as reactive processes or hamartomas. Moreover, V600E mutations were also identified in two out of the four ICC associated with BDA (Table 1). As the BRAF mutation rate in ICC is rather low (5-10%), this observation suggests that BRAF mutated ICC might arise from BDA. BRAF mutations also seem to occur early during carcinogenesis, as observed in the serrated pathway of colon cancer.
In conclusion, we have identified a high frequency of BRAF V600E mutations in BDAs, suggesting that they are true neoplasms and that they may be important precursors for the subset of ICC exhibiting BRAF mutations. Our findings support an adenoma to carcinoma sequence associated with BRAF mutations in intrahepatic biliary carcinogenesis.
The authors thank Morgane Fontaine, Simon Auneau, Caroline Taou, Deborah Siroli, Soraya Mehdaoui, Emilie Gelabale for technical assistance; and Tumorotheque/Plateforme Ressources Biologiques of Henri Mondor University Hospital, Tumor Bank of CHU Bordeaux, and Reseau des CRB foie-Inserm for contributing to the tissue collection.
Anaïs Pujals, Ph.D.1-3
Giuliana Amaddeo, M.D., Ph.D.2-4
Claire Castain, M.D.5,6
Paulette Bioulac-Sage, M.D.5,6
Philippe Compagnon, M.D.7
Jessica Zucman-Rossi, M.D., Ph.D.8
Daniel Azoulay, M.D., Ph.D.7
Karen Leroy, M.D., Ph.D.1-3
Elie Serge Zafrani, M.D.1,2
Julien Calderaro, M.D.1,2
1Assistance Publique-Hôpitaux de Paris
Department of Pathology
2Université Paris-Est Créteil
Faculté de Médecine
Institut Mondor de Recherche Biomédicale
4Assistance Publique-Hôpitaux de Paris
Department of Hepatology
5CHU de Bordeaux
Department of Pathology
Université de Bordeaux
7Assistance Publique-Hôpitaux de Paris
Department of Digestive and Hepatobiliary Surgery
Génomique fonctionnelle des tumeurs solides, IUH