Forum on Liver TransplantationSpecial Section Editor and Associate Editor: Pierre-Alain ClavienCholangiocarcinoma: Is transplantation an option? For whom?☆
Introduction
Ductular cholangiocarcinoma is a cancer with features of bile duct epithelial cell differentiation. Given this phenotype it is presumed to originate from bile epithelial cells, although it may also originate from periductular glands. It has a unique propensity to arise within the perihilar region of the liver affecting the right and/or left hepatic bile ducts and their union to form the common hepatic duct. Why this cancer affects these bile ducts and this region of the liver remains biologically enigmatic, but is important clinically. It is a desmoplastic cancer which results in bile duct stricturing and obstruction, a cardinal feature of its clinical presentation. Although bile is generally regarded as a noxious substance, this cancer has a tropism for bile and often extends along the bile ducts and resists growing tangentially or radially away from the bile ducts. This tropism likely results from the ability of bile acids to transactivate the epidermal growth factor receptor in this cell type [1]. Once a mass lesion is apparent, the cancer is quite advanced as it has developed self-sustaining growth characteristics and no longer requires the nutrient biliary stream for survival. An understanding of the composite biological features described above is critical and fundamental to its diagnosis and management. First, because of its perihilar location, this cancer encases (but infrequently invades) the portal vein and hepatic artery. Its extension directly into the liver or into the right and left secondary biliary branches with or without vascular encasement frequently precludes hepatic resection [2]. Second, its growth along rather than radially from the bile ducts due to its tropism for bile often fails to produce a mass lesion on cross-sectional imaging studies despite biliary obstruction. Third, the desmoplastic features of this cancer make it difficult to obtain a diagnosis. Endoscopic obtained brushings are often negative and only have a diagnostic sensitivity of 20–40%. Finally, this cancer predominantly recurs regionally which implies persistent micrometastatic nodal disease or disease at the margins of resection despite extended surgical resection. This regional recurrence is frequent and devastating and survival after apparent curative resection is only 20–40% at 5 years [3]. Adjuvant approaches to better control regional disease combined with operation should result in enhanced clinical outcomes.
The majority of cholangiocarcinomas arise in the absence of risk factors [4]. However, chronic bile duct inflammation is a well-recognized risk factor for this neoplasm. In particular, primary sclerosing cholangitis (PSC), an inflammatory disease of large bile ducts, clearly and unquestionably predisposes to the development of this cancer. Up to 10% of patients with cholangiocarcinoma in the United States have PSC [5], [6]. The presence of underlying PSC confounds the diagnosis and management of superimposed cholangiocarcinoma. The differentiation between a benign and malignant stricture in patients with PSC is problematic. Moreover, cholangiocarcinoma with PSC is frequently multicentric. Finally, like hepatocellular carcinoma occurring in cirrhosis, the presence of cholangiocarcinoma in PSC is frequently complicated by chronic parenchymal liver disease, cirrhosis and portal hypertension. It is not surprising therefore, that resection of cholangiocarcinoma in PSC can be considered futile [7].
These observations raise several key questions: (i) how can cholangiocarcinoma be best diagnosed definitively? (ii) If surgical resection is neither technically feasible nor rationale in patients with PSC, what is the role of liver transplantation in this setting? Our goal is to address these two issues in this mini-review.
Section snippets
Diagnosis of limited stage cholangiocarcinoma
If survival following liver transplantation is expected as a viable therapeutic modality, an early diagnosis of cholangiocarcinoma is not only desirable, but is essential for cure. Therefore, early diagnostic criteria for cholangiocarcinoma need to be established and validated. In the absence of PSC, a de novo bile duct stricture involving the main right and left hepatic ducts and/or common hepatic duct is highly suspicious for cholangiocarcinoma. However, in all surgical series, 10–15% of such
Liver transplantation alone for limited stage cholangiocarcinoma
Liver transplantation for hepatocellular carcinoma has evolved over the last several decades. Patients undergoing liver transplantation for multicentric cancer, tumors >5 cm and those cancers manifesting vascular invasion frequently develop rapidly progressive, lethal, recurrent disease. In contrast, patients with unicentric cancers <5 cm or three lesions all less than <3 cm, without vascular invasion, are frequently cured by liver transplantation [14]. Although the role of neoadjuvant therapy for
When should liver transplantation be performed for cholangiocarcinoma?
First and foremost, the authors want to affirm an exceedingly conservative approach to an aggressive protocol. Like a legal document, text and phraseology is often open to interpretation. We emphasize that in all instances we have taken a conservative interpretation to our protocol declining participation for patients with criteria in the ‘gray area’. Consequently, it may be difficult to generalize this protocol to all transplant centers. Considerable resources, experience and effort have been
Acknowledgement
The authors thank Erin Bungum for the excellent secretarial assistance.
References (24)
- et al.
Differential diagnosis of proximal biliary obstruction
Surgery
(2006) - et al.
Advanced cytologic techniques for the detection of malignant pancreatobiliary strictures
Gastroenterology
(2006) - et al.
Diagnostic benefit of biliary brush cytology in cholangiocarcinoma in primary sclerosing cholangitis
J Hepatol
(2006) - et al.
Diagnosis of cholangiocarcinoma in patients with PSC: a sight on cytology
J Hepatol
(2006) - et al.
Transarterial chemoembolization as a bridge to liver transplantation for hepatocellular carcinoma: an evidence-based analysis
Am J Transplant
(2006) - et al.
Liver transplantation for primary sclerosing cholangitis; predictors and consequences of hepatobiliary malignancy
J Hepatol
(2004) - et al.
Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma
Am J Transplant
(2002) - et al.
Liver transplantation for perihilar cholangiocarcinoma after aggressive neoadjuvant therapy: a new paradigm for liver and biliary malignancies?
Surgery
(2006) - et al.
Bile acids activate EGF receptor via a TGF-alpha-dependent mechanism in human cholangiocyte cell lines
Am J Physiol Gastrointest Liver Physiol
(2003) Cholangiocarcinoma of the extrahepatic bile ducts
Semin Surg Oncol
(2000)
Major hepatic resection for hilar cholangiocarcinoma
Arch Surg
Review article: the modern diagnosis and therapy of cholangiocarcinoma
Aliment Pharmacol Ther
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The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.