Cholangiocarcinoma--controversies and challenges

Abstract

Cholangiocarcinomas are a diverse group of tumors that are presumed to originate from the biliary tract epithelium either within the liver or the biliary tract. These cancers are often difficult to diagnose, their pathogenesis is poorly understood, and their dismal prognosis has resulted in a nihilistic approach to their management. The two major clinical phenotypes are intrahepatic, mass-forming tumors and large ductal tumors. Among the ductal cancers, lesions at the liver hilum are most prevalent. The risk factors, clinical presentation, natural history and management of these two types of cholangiocarcinoma are distinct. Efforts to improve outcomes for patients with these diseases are affected by several challenges to effective management. For example, designations based on anatomical characteristics have been inconsistently applied, which has confounded analysis of epidemiological trends and assessment of risk factors. The evaluation of therapeutic options, particularly systemic therapies, has been limited by a lack of appreciation of the different phenotypes. Controversies exist regarding the appropriate workup and choice of management approach. However, new and emerging tools for improved diagnosis, expanded indications for surgical approaches, an emerging role for locoregional and intrabiliary therapies and improved systemic therapies provide optimism and hope for improved outcomes in the future.

Figure 1. Classification of biliary tract cancers

Biliary tract cancers can be classified into clinically distinct types: gall bladder cancers, ampullary cancers and cholangiocarcinoma. Cholangiocarcinoma are phenotypically classified into intrahepatic or ductal cholangiocarcinoma to emphasize the distinctions between these clinically distinct cancers. Ductal cholangiocarcinoma are further classified as hilar or nonhilar (cystic duct or common bile duct). Hilar cancers that arise from extrahepatic large duct epithelium at the hilum can extend into the liver, and have been misclassified as intrahepatic in some schema and in epidemiological and clinical reports. Further subclassification on the basis of macroscopic or microscopic characteristics can provide additional distinction that might correlate with clinical outcomes. Cancers that arise from the gall bladder or the ampulla of Vater are biliary tract cancers with unique clinical presentations, natural history, etiology and patterns of growth or spread and are considered separately from cholangiocarcinoma.

Figure 2. Approach to management of intrahepatic cholangiocarcinoma

For resectable tumors, consider surgery or ablation. The extent of resection is prognostically important and should form the basis for subsequent management. For R0 resections, with negative surgical margins and lack of regional lymph node involvement, observation for recurrence, with imaging every 6 months for 3 years, or enrollment in a clinical trial of adjuvant therapy should be considered. For resections with either microscopically positive margins (R1) or residual tumor or positive lymph nodes (R2), consider re-resection or ablation. There are no data to guide optimal therapy for patients with unresectable disease and the choice of therapy will be based on the available local expertise and resources. For nonresectable but localized tumors, potential options include locoregional approaches such as chemoembolization, and radioembolization, or systemic chemotherapy. For metastatic or progressive tumors, systemic therapy with gemcitabine and cisplatin, or 5FU could be considered. Abbreviations: 5FU, 5-fluorouracil; OLT, orthotopic liver transplant; SBRT, stereotactic body radiotherapy; TACE, transarterial chemoembolization; TARE, transarterial radioembolization.

Figure 3. Approach to management of ductal cholangiocarcinoma

For resectable tumors, consider surgery. The choice of surgical approach will depend on the location of the tumor. For R0 resections, with negative surgical margins and lack of regional lymph node involvement, observation for recurrence, with imaging every 6 months for 3 years, or enrollment in a clinical trial of adjuvant systemic therapy should be considered. For resections with either positive margins (R1) or residual tumor or positive lymph nodes (R2), consider EBRT or systemic chemotherapy. For nonresectable or metastatic tumors, consider palliative biliary drainage if indicated, followed by intrabiliary PDT or brachytherapy, systemic chemotherapy with gemcitabine, or enrollment in a clinical trial evaluating new treatment modalities. Multimodality management based on liver transplantation might be appropriate for selected individuals with localized tumors and without any extrahepatic spread, but is available only at a few centers. Abbreviations: EBRT, external beam radiation therapy; 5FU, 5-fluorouracil; OLT, orthotopic liver transplant; PDT, photodynamic therapy; SBRT, stereotactic body radiotherapy.