Clinical diagnosis and staging of cholangiocarcinoma

Cholangiocarcinoma is the most frequent biliary malignancy. It is difficult to diagnose owing to its anatomic location, growth patterns and lack of definite diagnostic criteria. Currently, cholangiocarcinoma is classified into the following types according to its anatomic location along the biliary tree: intrahepatic, perihilar or distal extrahepatic cholangiocarcinoma. These cholangiocarcinoma types differ in their biological behavior and management. The appropriate stratification of patients with regard to the anatomic location and stage of cholangiocarcinoma is a key determinate in their management. Staging systems can guide this stratification and provide prognostic information. In addition, staging systems are essential in order to compare and contrast the outcomes of different therapeutic approaches. A number of staging systems exist for cholangiocarcinoma-several early ones have been updated, and new ones are being developed. We discuss the emerging diagnostic criteria as well as the different staging systems for cholangiocarcinoma, and provide a critical appraisal regarding these advances in biliary tract malignancies.     

New insights into the molecular pathogenesis of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma is an aggressive malignancy and is one of the most devastating cancers of the gastrointestinal tract. The molecular mechanisms contributing to the pathogenesis of these cancers are not well understood. The recognition and distinction of these cancers from other tumors such as perihilar or extrahepatic distal cholangiocarcinoma and hepatocellular carcinoma are important in defining the pathogenesis. New insights into molecular mechanisms contributing to disease pathogenesis are emerging from recent epidemiological, genome-wide profiling and laboratory based studies. These have contributed to an improved understanding of risk factors, genetic mutations and pathophysiological mechanisms that are associated with these tumors. The contribution of well-established risk factors such as biliary tract inflammation and key signaling pathways involved in intrahepatic cholangiocarcinoma are being further defined. These new insights have several important implications for both molecular diagnosis and therapy of these cancers.     

Cholangiocarcinoma--controversies and challenges

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.     

Update in biliary endoscopy

Biliary endoscopy has seen the development of several new techniques in the last few years. Its current role includes direct diagnostic imaging, tissue sampling, early diagnosis and palliation of biliary tumors. Relatively new methods for biliary stones management are electrohydraulic lithotripsy combined with choledochoscope guidance and laser lithotripsy. Intraductal ultrasound, confocal laser endomicroscopy and optical coherence tomography are emerging, purely diagnostic endoscopic tools in biliary endoscopy. Cytological examinations such as digital imaging analysis and fluorescence in situ hybridization have the potential of becoming very important in the early diagnosis of biliary tumors. Direct visualization of the biliary mucosa and tissue sampling can be done with the last generation of cholangioscopes. All these tools are promising, especially for the 'undetermined biliary strictures'. Improvements in quality of life, survival and biliary drainage in patients with non-operable cholangiocarcinoma have been reported after the application of both photodynamic therapy and high-dose rate intraluminal brachytherapy. Drug-eluting stents with incorporated anti-tumor agents designed to improve patency and reduce the risk of tumor ingrowth have already been tested, and other stents are under investigation as well.     

Cholangiocarcinoma

Cholangiocarcinomas are rare malignant tumors composed of cells that resemble those of the biliary tract. On the basis of their anatomic location, cholangiocarcinomas can be classified as intrahepatic, extrahepatic and hilar tumors. For reasons that are not clear, the incidence of cholangiocarcinoma is increasing globally. Established risk factors, including conditions associated with chronic biliary tract inflammation, account for a small proportion of cases. Additional risk factors such as cirrhosis, infection with hepatitis B virus and hepatitis C virus are now becoming recognized. The diagnosis of cholangiocarcinoma requires the integration of clinical information, imaging studies of the hepatic parenchyma and biliary tract, tumor markers, and histology. In terms of the treatment options for cholangiocarcinoma, surgery can be curative, although few patients are candidates for surgery. Palliative biliary decompression can provide symptomatic relief. Advances in MRI and positron-emission tomography scanning, identification of new tumor markers, improved utility of biliary cytology, and the use of photodynamic therapy for adjunct treatment are all expected to enhance the diagnosis, evaluation and management of cholangiocarcinoma.     

Biliary papillary tumors share pathological features with intraductal papillary mucinous neoplasm of the pancreas

Recently, attention has been drawn to papillary neoplasm of the pancreatobiliary systems. In the pancreas, the disease entity of intraductal papillary mucinous neoplasm (IPMN-P) is widely recognized. In contrast, the pathological characteristics of biliary papillary tumors, such as biliary papilloma(tosis) and papillary cholangiocarcinoma, have not yet been well documented. In this study, we compared the pathological features and post-operative prognosis among biliary papillary tumors (10 cases of biliary papilloma(tosis) and 22 cases of papillary cholangiocarcinoma), conventional non-papillary cholangiocarcinoma (15 cases), and IPMN-P (31 cases). Macroscopically, all biliary papillary tumors were characterized by the prominent intraductal papillary proliferation, and macroscopic mucin-hypersecretion was seen in 9 of 32 cases (28%). Histologically, biliary papillary tumors consisted of three types of tumor cells (pancreaticobiliary, intestinal and gastric types), whereas only the pancreaticobiliary type was observed in non-papillary cholangiocarcinoma. Immunohistochemically, biliary papillary tumors were characterized by the common expression of MUC2, CDX2 and cytokeratin 20. In addition, biliary papillary tumors could be associated with two types of invasive lesions: tubular adenocarcinoma (9 cases) and mucinous carcinoma (5 cases). Patients with tubular adenocarcinoma had a poor prognosis compared to non-invasive papillary tumor or papillary tumor with mucinous carcinoma. These pathological characteristics and the survival status of biliary papillary tumors were different from those of non-papillary cholangiocarcinoma, and rather closely resembled those of IPMN-P. In conclusion, biliary papillary tumors may be the biliary counterpart (intraductal papillary neoplasm of the bile duct) of IPMN-P.     

Surgical management of cholangiocarcinoma

Biliary tract cancer affects approximately 7500 Americans each year. Tumors arising from the gallbladder are the most common; those of bile duct origin, or cholangiocarcinoma, are less frequently encountered, constituting approximately 2% of all reported cancers. Although cholangiocarcinoma can arise anywhere within the biliary tree, tumors involving the biliary confluence (i.e., hilar cholangiocarcinoma) represent the majority, accounting for 40 to 60% of all cases. Twenty to 30% of cholangiocarcinomas originate in the lower bile duct, and approximately 10% arise within the intrahepatic biliary tree and will present as an intrahepatic mass. Complete resection remains the most effective and only potentially curative therapy for cholangiocarcinoma. For all patients with intrahepatic cholangiocarcinoma and nearly all patients with hilar tumors, complete resection requires a major partial hepatectomy. Distal cholangiocarcinomas, on the other hand, are treated like all periampullary malignancies and typically require pancreaticoduodenectomy. Most patients with cholangiocarcinoma present with advanced disease that is not amenable to surgical treatment, and even with a complete resection, recurrence rates are high. Adjuvant therapy (chemotherapy and radiation therapy) has not been shown clearly to reduce recurrence risk.     

胆管恶性狭窄内镜射频消融术专家共识

内镜引导的胆管射频消融术是近年来新兴的胆管恶性狭窄的治疗手段，联合胆管支架引流和系统化疗等，可有效延缓肿瘤局部进展，改善患者生活质量，延长生存期，主要适用于无法手术的肝外胆管癌和壶腹癌患者。基于现有的临床循证医学依据，中华医学会消化内镜学分会、中国医师协会内镜医师分会消化内镜专业委员会和国家消化系统疾病临床医学研究中心（上海）组织相关专家，对其适应证、禁忌证、技术操作规范及并发症防治等方面进行讨论，并达成共识，旨在为胆管恶性肿瘤的临床规范化治疗提供参考。     

Review of hepatopancreatoduodenectomy for biliary cancer: an extended radical approach of Japanese origin

Cholangiocarcinomas exhibit various modes of local extension, and some tumors can only be completely resected by hepatopancreatoduodenectomy (HPD), which is defined as the resection of the whole extrahepatic biliary system with the adjacent liver and pancreatoduodenum. Since Takasaki et al. introduced HPD for locally advanced gallbladder cancer in 1980, Japanese hepatobiliary surgeons have aggressively challenged this extended procedure for advanced biliary tumors. Early experiences with HPD were frequently associated with liver failure and sequential mortality, leading to an underestimation of the survival benefit of HPD. However, with improvements in surgical techniques and perioperative patient care, including portal vein embolization, over the last two decades, the mortality rate after HPD has gradually decreased. Recent studies have demonstrated a favorable survival in cholangiocarcinoma, provided that R0 resection is achieved. In contrast, HPD for gallbladder cancer remains controversial because of the extremely poor survival, although the study populations have been limited. HPD can be performed with low mortality and offers a better probability of long‐term survival in patients with cholangiocarcinoma. We should consider HPD to be a standard approach for laterally advanced cholangiocarcinomas that are otherwise unresectable.     

Trans-arterial (90)yttrium radioembolization for patients with unresectable tumors originating from the biliary tree

Patients with malignant tumors originating from the biliary tree have a poor prognosis, since only a minority of tumors can be resected and most palliative regimens have shown only limited success. We present two patients with unresectable tumors, who were treated with trans-arterial (90)yttrium radioembolization: a patient with an infiltrating gallbladder carcinoma and a patient with an extensive intrahepatic cholangiocarcinoma. In both cases the treatment was technically feasible, effective in controlling tumor growth, and without significant side effects. In conclusion, the presented cases demonstrate the potential of (90)yttrium radioembolization as a palliative treatment option for malignant tumors of the biliary tree.     

Hilar cholangiocarcinoma: diagnosis and staging

Cancer arising from the proximal biliary tree, or hilar cholangiocarcinoma, remains a difficult clinical problem. Significant experience with these uncommon tumors has been limited to a small number of centers, which has greatly hindered progress. Complete resection of hilar cholangiocarcinoma is the most effective and only potentially curative therapy, and it now clear that concomitant hepatic resection is required in most cases. Simply stated, long-term survival is generally possible only with an en bloc resection of the liver with the extrahepatic biliary apparatus, leaving behind a well perfused liver remnant with adequate biliary-enteric drainage. Preoperative imaging studies should aim to assess this possibility and must evaluate a number of tumor-related factors that influence resectability. Advances in imaging technology have improved patient selection, but a large proportion of patients are found to have unresectable disease only at the time of exploration. Staging laparoscopy and (13)fluoro-deoxyglucose positron emission tomography (FDG-PET) may help to identify some patients with advanced disease; however, local tumor extent, an equally critical determinant of resectability, may be underestimated on preoperative studies. This paper reviews issues pertaining to diagnosis and preoperative evaluation of patients with hilar biliary obstruction. Knowledge of the imaging features of hilar tumors, particularly as they pertain to resectability, is of obvious importance for clinicians managing these patients.     

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.     

Tumors of the gallbladder and bile ducts.

Gallbladder cancer is the fifth most common gastrointestinal cancer in the US (5,000 new cases each year). Primary bile duct cancer (cholangiocarcinoma) is seen most often in patients with risk factors including primary sclerosing cholangitis (PSC), bile duct stones, and fluke infestation. Both cancers have a poor prognosis, in part because they present late. Malignant tumors of the gallbladder and bile ducts are rarely curable by surgery. Benign tumors of the biliary tree are rare, and with the exception of biliary papillomatosis and carcinoids, are not considered premalignant.     

Endoscopy in the management of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver condition characterized by progressive fibrosis and destruction of the intra-and extrahepatic biliary tree. PSC has a clear association with inflammatory bowel disease and is often progressive, leading to cirrhosis and end-stage liver failure. For many patients, liver transplantation offers the only hope of long-term survival. No effective medical treatment exists, and therapy is often aimed at treating complications of the disorder, including dominant biliary strictures, which may cause symptomatic jaundice, cholangitis, and pruritus. Studies on endoscopic therapy (eg, biliary dilation and/or stent insertion) have shown favorable results, although most studies have been small, retrospective, and uncontrolled. Up to 20% of patients with PSC develop cholangiocarcinoma; however, distinguishing between cholangiocarcinoma and benign strictures can be difficult. Ideally, randomized trials are required to determine the safest and most effective endoscopic management for symptomatic dominant strictures.     

Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma

Aberrant expression and signaling of epidermal growth factor receptor （ErbB） family receptor tyrosine kinases, most notably that of ErbB2 and ErbB1, have been implicated in the molecular pathogenesis of intrahepatic cholangiocarcinoma. Constitutive overexpression of ErbB2 and/or ErbB1 in malignant cholangiocytes has raised interest in the possibility that agents which selectively target these receptors could potentially be effective in cholangiocarcinoma therapy. However, current experience with such ErbB- directed therapies have at best produced only modest responses in patients with biliary tract cancers. This review provides a comprehensive and critical analysis of both preclinical and clinical studies aimed at assessing the role of altered ErbB2 and/or ErbB1 expression, genetic modifications, and dysregulated signaling on cholangiocarcinoma development and progression. Specific limitations in experimental approaches that have been used to assess human cholangiocarcinoma specimens for ErbB2 and/or ErbB1 overexpression and gene amplification are discussed. In addition, current rodent models of intrahepatic cholangiocarcinogenesis associated with constitutive ErbB2 overexpression are reviewed. Select interactive relationships between ErbB2 or ErbB1 with other relevant molecular signaling pathways associated with intrahepatic cholangiocarcinoma development and progression are also detailed, including those linking ErbB receptors to bile acid, cyclooxygenase-2,interleukin-6/gp130, transmembrane mucins, hepatocyte growth factor/Met, and vascular endothelial growth factor signaling. Lastly, various factors that can limit therapeutic efficacy of ErbB-targeted agents against cholangiocarcinoma are considered.     

Cholangiocarcinoma and malignant bile duct obstruction: A review of last decades advances in therapeutic endoscopy

In the last decades many advances have been achieved in endoscopy, in the diagnosis and therapy of cholangiocarcinoma, however blood test, magnetic resonance imaging, computed tomography scan may fail to detect neoplastic disease at early stage, thus the diagnosis of cholangiocarcinoma is achieved usually at unresectable stage. In the last decades the role of endoscopy has moved from a diagnostic role to an invaluable therapeutic tool for patients affected by malignant bile duct obstruction. One of the major issues for cholangiocarcinoma is bile ducts occlusion, leading to jaundice, cholangitis and hepatic failure. Currently, endoscopy has a key role in the work up of cholangiocarcinoma, both in patients amenable to surgical intervention as well as in those unfit for surgery or not amenable to immediate surgical curative resection owing to locally advanced or advanced disease, with palliative intention. Endoscopy allows successful biliary drainage and stenting in more than 90% of patients with malignant bile duct obstruction, and allows rapid reduction of jaundice decreasing the risk of biliary sepsis. When biliary drainage and stenting cannot be achieved with endoscopy alone, endoscopic ultrasound-guided biliary drainage represents an effective alternative method affording successful biliary drainage in more than 80% of cases. The purpose of this review is to focus on the currently available endoscopic management options in patients with cholangiocarcinoma.     

Diagnostic approaches for cholangiocarcinoma

Cholangiocarcinomas arise from the epithelial cells of the bile ducts and are associated with poor prognosis. Despite new diagnostic approaches, the definite diagnosis of this malignancy continues to be challenging. Cholangiocarcinomas often grow longitudinally along the bile duct rather than in a radial direction. Thus, large tumor masses are frequently absent and imaging techniques, including ultrasound, CT, and MRI have only limited sensitivity. Tissue collection during endoscopic （ERCP） and/or percutaneous transhepatic （PTC） procedures are usually used to confirm a definitive diagnosis of cholangiocarcinoma. However, forceps biopsy and brush cytology provide positive results for malignancy in about only 50% of patients. Percutaneous and peroral cholangioscopy using fiber-optic techniques were therefore developed for direct visualization of the biliary tree, yielding additional information about endoscopic appearance and tumor extension, as well as a guided biopsy acquistion. Finally, endoscopic ultrasonography （EUS） complements endoscopic and percutaneous approaches and may provide a tissue diagnosis of tumors in the biliary region through fine- needle aspiration. In the future, new techniques allowing for early detection, including molecular markers, should be developed to improve the diagnostic sensitivity in this increasing tumor entity.     

Palliative therapy in cholangio- and gallbladder carcinoma

Non-resectable cholangiocarcinoma and gallbladder carcinoma have a poor prognosis. In addition to the general aspects of "best supportive care", biliary drainage is an important part of the palliative treatment of patients with malignant biliary stenosis. Photodynamic therapy has led to an improved median survival in hilar cholangiocarcinoma in two controlled studies. The survival benefit of external radiation or intraluminal brachytherapy has not yet been convincingly demonstrated. Whether or not systemic chemotherapy should be applied is still under debate. A single study including advanced biliary and pancreatic cancer patients has demonstrated a survival benefit for the combined group. In recent years, new chemotherapy protocols have been applied, some with promising results. Intra-arterial chemotherapy and chemotherapeutically coated stents have not been evaluated well enough to be recommended outside clinical studies. Ablative therapies have been used in a limited number of patients only. Further studies are necessary to clarify whether these treatment modalities are effective.     

TWO CASES OF MUCIN‐PRODUCING CHOLANGIOCARCINOMA DIAGNOSED BY PERORAL CHOLANGIOSCOPY

Mucin‐producing cholangiocarcinoma, which excretes excessive amounts of mucin into the biliary tract and causes obstructive jaundice and cholangitis due to the mucin retention, is rare. In this paper, we report two cases of this disease, which were demonstrated by peroral cholangioscopy (POCS). The radiologic features of these tumors show the diffuse dilatation of the bile ducts demonstrated by computed tomography (CT) and ultrasonography (US), the amorphous filling defects in the dilated bile ducts revealed by cholangiography. Their endoscopic features are mucin flowing out from the papilla of Vater during endoscopic retrograde cholangiography (ERC), and the papillary tumor with contiguous superficial spread in the bile ducts observed by cholangioscopy, although removal of mucin in the biliary tract is sometimes necessary before cholangioscopy in order to examine the lesion sufficiently. According to the previous reports, prognosis after curative resection of these tumors is better than that of ordinary type of cholangiocarcinoma. Therefore, it is important to examine the tumor extension in the bile ducts by cholangioscopy, although a selection of route inserting cholangioscope is controversial.     

Recent advances in the treatment of hilar cholangiocarcinoma: portal vein embolization

The clinical application of portal vein embolization (PVE) has contributed to improving the postoperative outcome of hilar cholangiocarcinoma. The enlarged nonembolized lobe after PVE protects the patient from postoperative hepatic failure, due to the increased functional reserve, and shortens the hospital stay. Although numerous reports have shown beneficial effects of PVE on postoperative outcome after extended hepatectomy, no randomized controlled study has been performed so far. It is urgent to establish a “gold standard” of PVE, because the indications, approach to the portal vein, types of embolic materials, and methods used to evaluate the function of the future liver remnant are variable among institutions. The indications and procedures of PVE for hilar cholangiocarcinoma may be different from those for hepatocellular carcinoma or colorectal metastasis, because, in many patients with hilar cholangiocarcinoma, biliary cancer is associated with biliary obstruction and cholangitis. This review article summarizes the contribution of PVE to the outcome of postoperative management in patients with hilar cholangiocarcinoma needing extended hepatectomy. We also describe our PVE procedure, which has been established from our experience of more than 240 cases of biliary cancer. Furthermore, the drawbacks of PVE, which may reduce the pool of candidates for surgery, are also discussed.