Advances in diagnosis, treatment and palliation of cholangiocarcinoma： 1990-2009

Several advances in diagnosis, treatment and palliation of cholangiocarcinoma （CC） have occurred in the last decades. A multidisciplinary approach to this disease is therefore recommended. CC is a relatively rare tumor and the main risk factors are： chronic inflammation, genetic predisposition and congenital abnormalities of the biliary tree. While the incidence of intra-hepatic CC is increasing, the incidence of extra-hepatic CC is trending down. The only curative treatment for CC is surgical resection with negative margins. Liver transplantation has been proposed only for selected patients with hilar CC that cannot be resected who have no metastatic disease after a period of neoadjuvant chemo-radiation therapy. Magnetic resonance imaging/ magnetic resonance cholangiopancreatography, positron emission tomography scan, endoscopic ultrasound and computed tomography scans are the most frequently used modalities for diagnosis and tumor staging. Adjuvant therapy, palliative chemotherapy and radiotherapy have been relatively ineffective for inoperable CC. For most of these patients biliary stenting provides effective palliation. Photodynamic therapy is an emerging palliative treatment that seems to provide pain relief, improve biliary patency and increase survival. The clinical utility of other emerging therapies such as transarterial chemoembolization, hepatic arterial chemoinfusion and high intensity intraductal ultrasound needs further study.     

Recent advances in multidisciplinary management of hepatocellular carcinoma

The incidence of hepatocellular carcinoma(HCC) is increasing, and it is currently the second leading cause of cancer-related death worldwide. Potentially curative treatment options for HCC include resection, transplantation, and percutaneous ablation, whereas palliative treatments include trans-arterial chemoembolization(TACE), radioembolization, and systemic treatments. Due to the diversity of available treatment options and patients’ presentations, a multidisciplinaryteam should decide clinical management of HCC, according to tumor characteristics and stage of liver disease. Potentially curative treatments are suitable for very-early- and early-stage HCC. However, the vast majority of HCC patients are diagnosed in later stages, where the tumor characteristics or progress of liver disease prevent curative interventions. For patients with intermediate-stage HCC, TACE and radioembolization improve survival and are being evaluated in addition to potentially curative therapies or with systemic targeted therapy. There is currently no effective systemic chemotherapy, immunologic, or hormonal therapy for HCC, and sorafenib is the only approved moleculartargeted treatment for advanced HCC. Other targeted agents are under investigation; trials comparing new agents in combination with sorafenib are ongoing. Combinations of systemic targeted therapies with local treatments are being evaluated for further improvements in HCC patient outcomes. This article provides an updated and comprehensive overview of the current standards and trends in the treatment of HCC.     

Treatment of hepatocellular carcinoma: Steps forward but still a long way to go

Hepatocellular carcinoma(HCC) is the fifth most common malignancy and the third cause of tumor associated deaths worldwide. HCC incidence rates are increasing in many parts of the world including developing and developed countries. Potentially curative treatments for HCC are resection and liver transplantation, but these are only suitable for patients with small tumors, meeting strict pre-defined criteria, or well-compensated liver disease. Early diagnosis of HCCcan be achieved by surveillance of at-risk populations. For patients with non-resectable disease treatments modalities include loco-ablative and systemic therapies. In this review we focus on treatment options in HCC and their allocation. Although significant research is in progress, to this date, the results are unsatisfactory with limited long-term survival. In the fight against this deadly disease, there is still a long way to go.     

Transplant benefit for patients with hepatocellular carcinoma

Although liver transplantation is theoretically the best treatment for hepatocellular carcinoma(HCC),it is limited by the realities of perioperative complications,and the shortage of donor organs.Furthermore,in many cases there are available alternative treatments such as resection or locoregional therapy.Deciding upon the best option for a patient with HCC is complicated,involving numerous ethical principles including:urgency,utility,intention-to-treat survival,transplant benefit,harm to candidates on waiting list,and harm to living donors.The potential contrast between different principles is particularly relevant for patients with HCC for several reasons:(1)HCC candidates to liver transplantation are increasing;(2)the great prognostic heterogeneity within the HCC population;(3)in HCC patients tumor progression before liver transplantation may significantly impair post transplant outcome;and(4)effective alternative therapies are often available for HCC candidates to liver transplantation.In this paper we suggest that allocating organs by transplant benefit could help balance these competing principles,and also introduce equity between patients with HCC and nonmalignant liver disease.We also propose a triangular equipoise model to help decide between deceased donor liver transplantation,living donor liver transplantation,or alternative therapies.     

Choledochal cysts: Similarities and differences between Asian and Western countries

Choledochal cysts(CCs)are rare bile duct dilatations,intra-and/or extrahepatic,and have higher prevalence in the Asian population compared to Western populations.Most of the current literature on CC disease originates from Asia where these entities are most prevalent.They are thought to arise from an anomalous pancreaticobiliary junction,which are congenital anomalies between pancreatic and bile ducts.Some similarities in presentation between Eastern and Western patients exist such as female predominance,however,contemporary studies suggest that Asian patients may be more symptomatic on presentation.Even though CC disease presents with an increased malignant risk reported to be more than 10%after the second decade of life in Asian patients,this risk may be overstated in Western populations.Despite this difference in cancer risk,management guidelines for all patients with CC are based predominantly on observations reported from Asia where it is recommended that all CCs should be excised out of concern for the presence or development of biliary tract cancer.     

Liver transplantation for hepatocellular carcinoma: Where do we stand?

Hepatocellular carcinoma represents an important cause of morbidity and mortality worldwide. It is the sixth most common cancer and the fourth leading cause of cancer death. Liver transplantation is a key tool for the treatment of this disease in human therefore hepatocellular carcinoma is increasing as primary indication for grafting. Although liver transplantation represents an outstanding therapy for hepatocellular carcinoma, due to organ shortage, the careful selection and management of patients who may have a major survival benefit after grafting remains a fundamental question. In fact, only some stages of the disease seem amenable of this therapeutic option, stimulating the debate on the appropriate criteria to select candidates. In this review we focused on current criteria to select patients with hepatocellular carcinoma for liver transplantation as well as on the strategies (bridging) to avoid disease progression and exclusion from grafting during the stay on wait list. The treatments used to bring patients within acceptable criteria (down-staging), when their tumor burden exceeds the standard criteria for transplant, are also reported. Finally, we examined tumor reappearance following liver transplantation. This occurrence is estimated to be approximately 8%-20% in different studies. The possible approaches to prevent this outcome after transplant are reported with the corresponding results.     

Liver transplantation for malignancy:current treatment strategies and future perspectives

In 1967,Starzl et al performed the first successful liver transplantation for a patient diagnosed with hepatoblastoma.In the following,liver transplantation was considered ideal for complete tumor resection and potential cure from primary hepatic malignancies.Several reports of liver transplantation for primary and metastatic liver cancer however showed disappointing results and the strategy was soon dismissed.In1996,Mazzaferro et al introduced the Milan criteria,offering liver transplantation to patients diagnosed with limited hepatocellular carcinoma.Since then,liver transplantation for malignant disease is an ongoing subject of preclinical and clinical research.In this context,several aspects must be considered:(1)Given the shortage of deceased-donor organs,long-term overall and disease free survival should be comparable with results obtained in patients transplanted for nonmalignant disease;(2)In this regard,living-donor liver transplantation may in selected patients help to solve the ethical dilemma of optimal individual patient treatment vs organ allocation justice;and(3)Ongoing research focusing on perioperative therapy and antiproliferative immunosuppressive regimens may further reduce tumor recurrence in patients transplanted for malignant disease and thus improve overall survival.The present review gives an overview of current indications and future perspectives of liver transplantation for malignant disease.     

Biliary complications following liver transplantation

Biliary tract complications are the most common complications after liver transplantation.These complications are encountered more commonly as a result of increased number of liver transplantations and the prolonged survival of transplant patients.Biliary complications remain a major source of morbidity in liver transplant patients,with an incidence of 5%-32%.Post liver transplantation biliary complications include strictures(anastomotic and non-anastomotic),leaks,stones,sphincter of Oddi dysfunction,and recurrence of primary biliary disease such as primary sclerosing cholangitis and primary biliary cirrhosis.The risk of occurrence of a specific biliary complication is related to the type of biliary reconstruction performed at the time of liver transplantation.In this article we seek to review the major biliary complications and their relation to the type of biliary reconstruction performed at the time of liver tranplantation.     

The role of liver transplantation for hilar cholangiocarcinoma

BACKGROUND: Hilar cholangiocarcinoma is a devastating disease. Surgery is the only potentially curative modality. However, the results of surgical resection for hilar cholangiocarcinomas are disappointing. The introduction of liver transplantation for this condition has brought new hope for the management of this disease. The aim of this review is to discuss the role of liver transplantation in this disease. DATA SOURCES: A MEDLINE search was conducted for the articles on liver transplantation for hilar cholangiocarcinoma. Their results have been compiled and compared with the existing literature on resection for this disease. RESULTS: The earlier series on liver transplantation for hilar cholangiocarcinoma were not encouraging because of poor patient selection. The Mayo Clinic protocol of neoadjuvant chemoradiation followed by liver transplantation has shown remarkable success (survival at 1-, 3-, and 5-year post-transplantation being 92%, 82%, and 82%, respectively). With better patient selection and integration of neoadjuvant chemoradiation, the long-term survival is superior to that of the patients who undergo resection, as shown by the published literature on resection. The limitations of organ availability can be overcome by the living donor liver transplantation programme. This review article discusses the rationale, pros and cons of liver transplantation vis-à-vis resection for hilar cholangiocarcinoma.CONCLUSIONS: Liver transplantation, especially living donor liver transplantation, is a new and exciting alternative to resection for hilar cholangiocarcinoma. Integration of neoadjuvant chemoradiation has the potential to further improve the curative potential of liver transplantation. The strategy of combining neoadjuvant chemoradiation and liver transplantation brings new hope for the treatment of this difficult disease.     

胆管癌的分子靶向治疗

胆管癌是起源于胆管上皮细胞的恶性肿瘤,临床较少见.中国胆管癌患者数较多,因而胆管癌研究在我国具有特殊意义.手术切除是所有胆管癌的最佳治疗,但由于早期诊断困难,仅10%患者得到手术治疗.胆管癌患者术后5年生存率约5%,未切除胆管癌患者生存期<1年.胆管癌的临床化疗效果并不尽理想.近期开展的进展期胆管癌分子靶向治疗临床研究是令人期待的探索.本文归纳分析胆管癌靶向治疗药物的分子生物学基础以及临床探索的研究结果.     

Diagnosis and management of cholangiocarcinoma

Cholangiocarcinoma (CC) is a rare yet frequently fatal tumor that causes significant morbidity and mortality due to late presentation. Radiology is the mainstay of CC diagnosis; however, advances in understanding the pathogenesis of CC, including the role of oncogenes, inflammation-mediated genomic instability, and interleukin-6/STAT-3 signaling pathways, may allow development of new diagnostic and prognostic markers and targets for CC therapy. Although surgical resection is the standard of care for resectable CC, liver transplantation has shown excellent results in selected patients. The use of chemotherapy and radiotherapy are currently limited by marginal response rates, toxicity, and biliary complications. Locally ablative therapies in the form of transcatheter arterial chemoembolization and radioembolization are under investigation. Molecular therapies (eg, epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor antagonists) and immunotherapy using diabodies are also under investigation for treatment of unresectable CC.     

Epigenetic DNA hypermethylation in cholangiocarcinoma: potential roles in pathogenesis,diagnosis and identification of treatment targets

Cholangiocarcinomas (CCs) are highly lethal malignant tumours arising from the biliary tract epithelium. The disease is notoriously difficult to diagnose and is usually fatal because of its typically late clinical presentation and the lack of effective non‐surgical therapeutic modalities. The overall survival rate, including resected patients is poor, with less than 5% of patients surviving 5 years, a rate which has not changed significantly over the past 30 years. Although CC is a relatively uncommon tumor, interest in this disease is rising as incidence and mortality rates for intrahepatic cholangiocarcinoma are increasing markedly worldwide. A variety of risk factors, including primary sclerosing cholangitis, liver fluke infestation, and hepatolithiasis have been described. However, for most CCs the cause is unknown, and affected individuals have no history of exposure to, or association with, known risk factors. Recent advances in molecular pathogenesis have highlighted the importance of epigenetic alterations in the form of promoter region hypermethylation and histone deacetylation in addition to genetic changes in the process of cholangiocarcinogenesis. This review provides a comprehensive overview of the genes reported to be methylated in CC to date and their putative roles in cholangiocarcinogenesis. Future directions in the study of methylated genes and their potential roles as diagnostic and prognostic markers are also discussed.     

Liver transplantation in autoimmune liver disease--selection of patients

Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are autoimmune liver diseases, which are good indications for orthotopic liver transplantation (OLT). While there is effective treatment for AIH (steroids with or without azathioprine) and PBC (Ursodesoxycholic acid) no such treatment is currently established for PSC. The need for transplantation can be delayed for AIH and PBC with appropriate therapies, while treatment options for PSC are still controversially discussed. Although the time point for liver transplantation can be roughly estimated for AIH by failure of immunosuppressive therapy and for PBC by prognostic models, the prediction of survival in patients with PSC is more difficult, and further complicated through the risk of developing cholangiocellular carcinoma (CCC). Long-term (5-year) outcome after liver transplantation approaches 80-90% for autoimmune liver diseases unless CC complicates PSC at the time of OLT. The risk of disease recurrence has been recognized for each of these entities although its clinical relevance is controversial. This gets more important as long-term survival can be achieved for most of these patients today. In this review the natural course of autoimmune liver disease will be discussed and prognostic models will be presented, which are helpful for finding the optimal time point for liver transplantation.     

Endoscopic ultrasound‐guided biliary drainage of hilar biliary obstruction

Only 20–30% of patients with hilar cholangiocarcinoma (CC) are candidates for potentially curative resection. However, even after curative (R0) resection, these patients have a disease recurrence rate of up to 76%. The prognosis of hilar cholangiocarcinoma (CC) is limited by tumor spread along the biliary tree leading to obstructive jaundice, cholangitis, and liver failure. Therefore, palliative biliary drainage may be a major goal for patients with hilar CC. Endoscopic retrograde cholangiopancreatography (ERCP) with stent placement is an established method for palliation of patients with malignant biliary obstruction. However, there are patients for whom endoscopic stent placement is not possible because of failed biliary cannulation or tumor infiltration that limits transpapillary access. In this situation, percutaneous transhepatic biliary drainage (PTBD) is an alternative method. However, PTBD has a relatively high rate of complications and is frequently associated with patient discomfort related to external drainage. Endoscopic ultrasound‐guided biliary drainage has therefore been introduced as an alternative to PTBD in cases of biliary obstruction when ERCP is unsuccessful. In this review, the indications, technical tips, outcomes, and the future role of EUS‐guided intrahepatic biliary drainage, such as hepaticogastrostomy or hepaticoduodenostomy, for hilar biliary obstruction will be summarized.     

Management of Hepatocellular Carcinoma: Current Status and Future Directions

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide. This cancer commonly arises against a background of chronic liver disease. As a result, a patient with HCC requires multidisciplinary care. Treatment options vary widely based on tumor burden and metastases. The most widely utilized staging system is the Barcelona Clinic Liver Cancer staging system, which recommends treatments based on tumor size and the underlying liver disease and functional status of the patient. Treatment options range from surgical resection or transplantation to locoregional therapies with modalities such as radiofrequency ablation and transarterial chemoembolization to systemic chemotherapies. Future care involves the development of combination therapies that afford the best tumor response, further clarification of the patients best suited for therapies and the development of new oral chemotherapeutic agents.     

Pathology of peripheral intrahepatic cholangiocarcinoma with reference to tumorigenesis.

Cholangiocarcinomas (CCs) are neoplasms with cholangiocyte differentiation, and may arise from cholangiocytes of the biliary tree and possibly cholangiocyte progenitor cells. Intrahepatic CCs can be divided into the perihilar and peripheral types. Peripheral CCs present grossly as a mass forming tumor, and histologically as an adenocarcinoma of varying shapes and phenotypes. Some peripheral CCs (ductular type) are characterized by: (i) a histological resemblance to reactive bile ductules; (ii) the expression of neural cell adhesion molecule (NCAM) and vimentin. This type shows: (i) grossly, a blurred border; and (ii) histologically, carcinoma cells replacing the adjoining hepatocytes at the border of the tumor. It is frequently associated with neutrophilic infiltration and also with granulocyte and granulocyte macrophage colony-stimulating factors. We propose to call this type "ductular CC." The other peripheral CC (duct type) includes ordinary adenocarcinoma with well to moderately differentiated tubular and micropapillary patterns and is negative for NCAM but positive for mucin. This type can be called "duct CC," and shows a rather compressive growth. Interestingly, CC components of combined hepatocellular CC share the features of ductular CC, suggesting that hepatic progenitor cells may be involved in the tumorigenesis of ductular CC. The biological behavior of ductular CC and duct CC remains obscure, and follow-up and molecular studies on these tumors are required in order for these two CCs to be recognized as disease entities, and so as to evaluate their carcinogenesis.     

Cholangiocarcinoma: Endoscopic therapies

Cholangiocarcinoma (CCA) is a difficult-to-treat biliary malignancy with significant morbidity and mortality because of its typically late symptomatic presentation. Though curative surgical options do exist, most patients with perihilar CCA are deemed unresectable at the time of diagnosis. Furthermore, the efficacy of chemoradiation for tumor control is limited. However, advances in endoscopic technology and techniques have enabled improved symptom palliation via internal biliary decompression, which is associated with improved quality of life. The introduction of radioactive, intraductal brachytherapy for the management of unresectable CCA has resulted in prolonged biliary stent patency and it has the ability to provide local tumor control. Endoscopic retrograde cholangiopancreatography (ERCP)–directed photodynamic therapy (PDT) and radiofrequency ablation (RFA) for the palliative treatment of patients with unresectable CCA have recently been added to the armamentarium of the biliary endoscopist. Patients now have these nonradioactive, minimally invasive endoscopic treatment options at their disposal, which can help to reduce the rate of biliary infections and might also offer survival benefit. Moreover, ERCP–directed PDT has been used in lieu of intraductal brachytherapy for locoregional tumor control in patients with unresectable perihilar CCA who are awaiting liver transplantation. Despite the studies supporting the use of endobiliary PDT and RFA, the optimal timing, treatment locations (in bilateral disease), and frequency for these ablative therapies have yet to be established. Although endobiliary PDT and RFA both have their respective advantages and disadvantages, attention to patient education and providing detailed informed consent remains paramount to their proper use. This is a point of emphasis given the ongoing technological maturation of these endoscopically delivered ablative therapies and the evolving ways in which they are used.     

Photodynamic therapy for cholangiocarcinoma

The prognosis of perihilar cholangiocarcinoma (CC) is limited by tumor spread along the biliary tree leading to refractory obstructive cholestasis, cholangitis, and liver failure. Palliation with biliary endoprostheses yields median survival times between 4 and 6 months for nonresectable CC. Tumor ablation with photodynamic therapy (PDT) combined with biliary stenting reduces cholestasis and significantly improves median survival time to 11.5 to 16.2 months. PDT with porfimer and laser light of 630 nm provides tumoricidal tissue penetration to a depth of only 4 to 4.5 mm that does not eradicate most tumors. Time to progression lasts approximately 6 months; in other words, PDT is required twice annually. PDT costs less and enhances quality of life and survival time as compared with chemotherapy for metastatic colon cancer. These data suggest that PDT should be offered as part of the palliative treatment of CC in hepatobiliary referral centers.