The prognosis of perihilar cholangiocarcinoma after radical treatments
Authors: Luca Fabris, Domenico Alvaro
Journal: Hepatology (2012)

Cholangiocarcinoma (CCA) encompasses a heterogeneous group of cancers derived from the malignant proliferation of cholangiocytes, which may arise in any portion of the biliary tree.1 The second-order bile ducts demarcate CCA into either intrahepatic or extrahepatic (EH-CCA).1, 2 EH-CCA includes the perihilar (Klatskin) form, which presides in Western countries, accounting for approximately two-thirds of all CCA.1, 2 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. Pattern of growth and spreading of perihilar-cholangiocarcinoma (CCA). Tumor spread of perihilar-CCA is underpinned by a unique locally invasive behavior. Structures localized in close vicinity to the common bile duct, including the portal vein, lymphatic vessels, and nerve fibers, offer a preferential route for tumor cells to escape from the primary site of growth. Additionally, the periductal wall may be invaded directly by tumoral infiltrates. Early metastases are therefore more common within the liver and at regional lymph nodes rather than at distant sites (lung), thereby precluding the eligibility of most patients to radical treatments. For years, the only curative option for perihilar-CCA 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.1, 2 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.3 CCA, cholangiocarcinoma; EH-CCA, extrahepatic-CCA; OLT, orthotopic liver transplantation; PSC, primary sclerosing cholangitis. 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.4 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).5 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 resection6 and OLT6, 7 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 perihilar-CCA, 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 perihilar-CCA at diagnosis has a size below 3 cm.8 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.7 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.7 By reviewing 198 patients between 1993 and 2010, predictors were identified by uni- and multivariate Cox regression analysis. About one-third of the cases dropped out before transplant (36 patients had metastasis at staging, 26 progressed). Among transplanted patients 5-year survival was 71%; by intention to treat, it decreased to 53%. Predictors of dropout were CA19-9 ≥500 U/mL, mass ≥3 cm, a malignant brushing or biopsy, and a Model for End-Stage Liver Disease score ≥20. Predictors of recurrence were elevated CA19-9, portal vein encasement, and residual tumor on explants. In contrast, PSC, age, history of cholecystectomy, and waiting time were not found to be independent predictors. Therefore, the risk of dropout is related to both patient and tumor characteristics, whereas recurrence risk is mostly associated with the presence of residual cancer on explants. PSC patients lack an independent survival advantage compared with de novo patients, but have more favorable tumor characteristics. This was not attributable to a better screening approach, which is still far from being established in PSC. Therefore, this study opens a new scenario where prognostic factors and predictors must be investigated toward OLT. Stratification of prognostic classes on the basis of molecular or biologic markers, in addition to clinical and pathologic criteria, is crucial for a better selection of patients for appropriate curative and adjuvant treatments, and this should represent a scientific must for the future, with important advances the management of CCA. Additionally, given the frequent presentation of perihilar-CCA at advanced stages, there is an urgent need for effective surveillance programs based on tumor biomarkers and improved imaging techniques to detect CCA earlier, and therefore offer radical treatments to a higher number of patients. Prognostic factors after curative resection of perihilar-CCA represent the basis for recently proposed staging systems, but not without certain criticisms and controversies. The size and number of the primary tumor, tumor growth type, the depth of tumor invasion, local and distant metastatic disease, vascular encasement, and lobar atrophy have been considered factors affecting overall and disease-free survival, in association with clinical parameters such as cholestasis and its response to stenting, and the patient's performance status.9 Generally, however, R0 resection and lymph node status following R0 resection remain the best chances for long-term survival. In particular, the local spread must be beyond the level of regional lymph nodes (N1) to have a significant impact on prognosis.9 Histologic grade (poorly differentiated cells) has been recently reported to correlate with overall survival after aggressive surgical resection of perihilar-CCA,10 but this finding is at variance with previous larger studies.9 The anatomic extent within the biliary tree, according to the Bismuth-Corlette classification, has been analyzed by several studies; its impact on survival is still uncertain.10 In many carcinomas, tumor-associated vascularization is generally considered a determinant of increased invasiveness, and it consistently also plays a critical role in the tumor progression of perihilar-CCA after curative resection, being strongly associated with both nodal spread and local recurrence.11 Biomarkers of early metastatic behavior would help to assess the eligibility of CCA patients to potential curative treatments, yet very little is known about the molecular mechanisms underpinning the strong invasiveness in CCA. Studies investigating biomarkers of potential prognostic value are limited for perihilar-CCA. Elevated levels of circulating CYFRA21-1, a serum marker that recognizes fragments of the cholangiocyte-specific protein cytokeratin-19, predict a poor outcome and may act as a surrogate marker of circulating tumor cells in CCA following resection.12 In histological specimens, strong expression of CD133, a cancer stem cell marker, was strictly associated with lymph node involvement and positive surgical margins in resected CCA.13 S100A4, a member of the S100 family of small calcium-binding proteins, is expressed by macrophages and epithelial cells in mesenchymal transition. It is known as a biomarker of increased invasiveness in different types of carcinoma, including colon and breast. In CCA, the nuclear expression of S100A4 by neoplastic bile ducts was found to significantly correlate with increased metastasization and reduced survival after resection.14 Once translocated into the nucleus, it could regulate the transcriptional activation of matrix metalloproteinase-9,14 thereby providing cancer cells with enhanced matrix-degrading functions. This latter finding underscores the prognostic relevance of paracrine signals from the stromal compartment, at least in the sclerosing subtypes of CCA where a stromal reaction is particularly abundant. Better understanding of epithelial-mesenchymal interactions in the tumor will lead to improved treatments and decision making also in the novel transplant setting.