The prognosis of perihilar cholangiocarcinoma after radical treatments

C holangiocarcinoma (CCA) encompasses a heterogeneous group of cancers derived from the malignant proliferation of cholangiocytes, which may arise in any portion of the biliary tree. The second-order bile ducts demarcate CCA into either intrahepatic or extrahepatic (EH-CCA). EH-CCA includes the perihilar (Klatskin) form, which presides in Western countries, accounting for approximately twothirds of all CCA. Perihilar-CCA possesses a peculiar locally invasive growth pattern, characterized by spreading into the liver parenchyma, infiltration of the periductal wall, and spreading into regional lymph nodes via perineural spaces and lymphatic vessels. Less commonly, distant metastases are found (lung or peritoneum) (Fig. 1). Usually, a diagnosis is performed at stages too advanced for radical surgery. This makes perihilar-CCA a devastating cancer, with many challenges including the development of strategies for an earlier diagnosis. For years, the only curative option for perihilarCCA was surgical resection. Today, local excision is reserved for small tumors confined to the bile duct wall (Tis, T1) and the Bismuth I papillary type of perihilar-CCA. For other forms, major liver resection with caudate lobectomy addresses both direct hepatic invasion and intraductal extension of perihilar-CCA, and consequently achieves greater negative radial and longitudinal resection margins. By combining right trisectionectomy and portal vein resection (hilar en bloc resection), a 5-year survival of 58% has been obtained in selected cases. Early attempts of orthotopic liver transplantation (OLT) to treat perihilar-CCA have been disappointing, and thus CCA has been considered as a relative contraindication to OLT in a majority of centers. In 1993, the Mayo Clinic applied a multimodality treatment protocol to a highly selected group of patients with unresectable perihilar-CCA or with CCA arising from primary sclerosing cholangitis (PSC). The Mayo protocol combines neoadjuvant external beam radiotherapy, brachytherapy, chemotherapy, and then a staging laparotomy to rule out metastatic disease. Patients without disease progression underwent OLT, resulting in a 5-year recurrence-free survival rate of approximately 70%. The survival and recurrence rates following resection and OLT shown in Table 1, confirm that OLT preceded by neoadjuvant therapy is a more effective strategy than resection, as it provides a more radical treatment of the tumor. Actually, radiological assessment of the intrahepatic extension of the tumor before surgery is a challenging issue, which often precludes a successful R0 resection. These data indicate that OLT may be regarded as a potential curative treatment for perihilarCCA, but only for selective patients treated in highly specialized centers. In the Mayo experience, tumor size (>3 cm) represents a major criterion excluding OLT; unfortunately, <10% of perihilarCCA at diagnosis has a size below 3 cm. The success of the Mayo protocol most likely depends on the selection of patients with less aggressive perihilar-CCA. Until the organ becomes available for OLT, the time requested to perform neoadjuvant therapy and staging laparotomy may be sufficient to rule out those patients with signs of disease progression. These findings, however, lead to the imperative identification of prognostic factors and predictors of treatment response after surgical resection. In this regard, although extensive investigations have been performed to assess prognostic factors after surgical resection, very few are known for OLT, a topic that has been investigated by Murad in this issue of HEPATOLOGY. Here the investigators report the predictors of dropout before transplantation and of cancer recurrence after transplantation in a population of patients with perihilar-CCA enrolled in the Mayo protocol. By reviewing 198 patients between 1993 and 2010, Abbreviations: CCA, cholangiocarcinoma; EH-CCA, extrahepatic-CCA; OLT, orthotopic liver transplantation; PSC, primary sclerosing cholangitis. Address reprint requests to: Luca Fabris, M.D., Department of Surgical, Oncological and Gastroenterological Sciences, Division of Gastroenterology, University of Padua, Treviso Regional Hospital, Treviso, Italy. E-mail: luca. fabris@unipd.it; fax: 39-049-827-8906. CopyrightVC 2012 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.25808 Potential conflict of interest: Nothing to report.