Cholangiocarcinoma: principles and current trends

Review Article

Cholangiocarcinoma: principles and current trends George N Zografos, Athanasios Farfaras, Flora Zagouri, Dimosthenis Chrysikos and Kostas Karaliotas Athens, Greece

BACKGROUND: Cholangiocarcinoma (CCA) is a lethal cancer KEY WORDS: cholangiocarcinoma; of the biliary epithelium, originating from the liver (intrahepatic), treatment; prognostic factors; at the confluence of the right and left hepatic ducts (hilar) or in the extrahepatic bile ducts. It is a rare malignancy associated risk factors; surgery with poor prognosis. DATA SOURCES: We searched the PubMed/MEDLINE database for relevant articles published from 1989 to 2008. The search terms used were related to "cholangiocarcinoma" and its "treatment". Although no language restrictions were imposed initially, for the full-text review and final analysis, our resources only permitted the review of articles published in English. This review deals with the treatment of cholangiocarcinoma, the principles and the current trends. RESULTS: The risks and prognostic factors, symptoms and differential diagnosis are thoroughly discussed. In addition, the tools of preoperative diagnosis such as endoscopic retrograde cholangiopancreatography, digital image analysis, fluorescence in situ hybridization and magnetic resonance cholangiopancreatography are reviewed. Moreover, the treatment of CCA is discussed. CONCLUSIONS: The only curative treatment available is surgical management. Unfortunately, many patients present with unresectable tumors, the majority of whom die within a year of diagnosis. Surgical treatment involves major resections of the liver, pancreas and bile duct, with considerable mortality and morbidity. However, in selected cases and where indicated, appropriate management with aggressive surgery may achieve a good outcome with a prolonged survival expectancy. (Hepatobiliary Pancreat Dis Int 2011; 10: 10-20)

Author Affiliations: Third Department of Surgery, Athens General Hospital, Athens, Greece (Zografos GN, Farfaras A and Chrysikos D); Department of Clinical Therapeutics, Alexandra Hospital, Athens, Greece (Zagouri F); and Department of Surgery, Red Cross Hospital, Athens, Greece (Karaliotas K) Corresponding  Author:  Flora Zagouri, MD, PhD, Vas. Sofias Ave and Lourou str, Ampelokipi, Athens 11528, Greece (Tel: +306946462998; Fax: +302103381511; Email: [email protected]) © 2011, Hepatobiliary Pancreat Dis Int. All rights reserved.

Introduction

U

p to the late 1970s, cases of cholangiocarcinoma (CCA) affecting the confluence of the hepatic ducts were considered rare, difficult to diagnose and unresectable.[1] CCA is relatively uncommon with an annual incidence of 1-2 cases per 100 000 in the Western countries. However, rates have been rising worldwide over the past decades, partly due to advances in diagnostic techniques.[2, 3] In addition, breakthroughs in operative techniques over the last decade have led to a dramatic change in approach; resection is now generally regarded as the best possible treatment. CCA is a lethal cancer of the biliary epithelium and can develop anywhere along the biliary tree. Anatomically, CCAs are classified as intrahepatic when they develop in the liver, as hilar when they arise at the confluence of the right and left hepatic ducts, and as distal extrahepatic bile duct cancers. Based on their appearance, these tumors can be defined as mass-like, periductal, intraductal or mixed bile duct tumors which involve the hepatic duct bifurcation when they are known as Klatskin tumors (by the name of the author who first described this kind of hilar CCA in 1965). Bismuth-Corlette classified perihilar tumors into 4 subtypes (Table 1). The histological types are listed in Table 2. Greater than 90% of bile duct cancers are well-differentiated and mucin-producing adenocarcinomas. Other types include squamous cell carcinoma, small cell carcinoma, and sarcoma. Macroscopically, adenocarcinomas of the bile duct are classified as sclerosing, nodular, or papillary (analogous to the classification scheme for gallbladder adenocarcinomas). Sclerosing (scirrhous)

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Cholangiocarcinoma: principles and current trends

Table 1. The Bismuth-Corlette classification of perihilar tumors Type I II IIIa IIIb IV

Bismuth-Corlette classification Tumor involves the common hepatic duct Tumor involves the bifurcation of the common hepatic duct Tumor involves the right hepatic duct Tumor involves the left hepatic duct Tumor involves both the right and left hepatic ducts

Table 2. Histological types of cholangiocarcinoma (extrahepatic) Histological types of cholangiocarcinoma Carcinoma in situ Adenocarcinoma, NOS Adenocarcinoma, intestinal type Mucinous adenocarcinoma Clear cell adenocarcinoma Signet-ring cell adenocarcinoma Adenosquamous carcinoma Squamous cell carcinoma Small cell (oat cell) carcinoma Undifferentiated carcinoma (spindle and giant cell type; small cell type) Papillomatosis Papillary carcinoma, non-invasive Papillary carcinoma, invasive Carcinoma, NOS Malignant mesenchymal tumors (rare) Embryonal rhabdomyosarcoma Leiomyosarcoma Malignant fibrous histiocytoma

tumors comprising over 80% CCAs are associated with an intense desmoplastic reaction and a low resectability, and tend to be highly invasive. Nodular tumors show the appearance of constricting annular lesions and are also associated with a low resectability. Papillary tumors are rare and present as bulky masses that project into the bile duct lumen. There is no system that stratifies patients into subgroups for potential resectability and simultaneously correlates with survival. For extrahepatic (hilar and distal) CCA there are two systems for staging, the American Joint Committee on Cancer (AJCC) TNM (tumor, node, metastases) Staging System (Table 3) and the modified Bismuth-Corlette classification (Table 1). Intrahepatic CCAs are classified as hepatocarcinomas (Table 4). The peak age for CCA is the seventh decade, with a slightly higher incidence in men. Despite its significant increase, the incidence of the disease remains low, with marked global variations. The highest rates are reported in northeast Asia where the disease affects 96 per 100  000 men. At about 100 times greater than that in the West, this rate presumably reflects differences in local

Table 3. TNM staging for extrahepatic cholangiocarcinomas Stage Tumor Node Metastases 0 Tis N0 M0 IA T1 N0 M0 IB T2 N0 M0 IIA T3 N0 M0 IIB T1-3 N1 M0 III T4 N0-1 M0 IV Any T N0-1 M1 Tis: carcinoma in situ; T1: cancer confined to bile duct wall; T2: cancer invades beyond wall of bile duct; T3: cancer invades liver, pancreas, and/or left or right branches of portal vein or hepatic artery; T4: cancer invades main portal vein or both its left and right branches, common hepatic artery, or other structures, such as colon, stomach, duodenum, or abdominal wall; N0: no regional lymph node metastasis; N1: regional lymph node metastasis present (regional lymph nodes consist of hilar, celiac, periduodenal, peripancreatic, and superior mesenteric groups); M0: no distant metastasis; M1: distant metastasis present.

Table 4. TNM staging for intrahepatic cholangiocarcinomas Stage Tumor Node Metastases I T1 N0 M0 II T2 N0 M0 IIIA T3 N0 M0 IIIB T4 N0 M0 IIIC Any T N1 M0 IV Any T N0-1 M1 T1: solitary tumor without vascular invasion; T2: solitary tumor with vascular invasion or multiple tumors, each 5 cm in diameter; T3: multiple tumors >5 cm in diameter or tumor invasion of a major branch of the portal or hepatic vein(s); T4: direct tumor invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum; N0: no regional lymph node metastasis; N1: regional lymph node metastasis present (hilar, hepatoduodenal ligament, and caval lymph node groups); M0: no distant metastasis; M1: distant metastasis present.

risk factors and genetics. Despite its low incidence, CCA is responsible for about 13% of primary liver cancers and accounts for 1.3% to 2.6% of annual cancer-related deaths worldwide.[4] Surgical resection has been the mainstay of curative treatment for CCA. However, the operative mortality is high and the 5-year survival rate remains disappointing.[5] Most patients who undergo resection die of local tumor recurrence.[6] This is related to the fact that complete surgical resection with tumor-free histological margins is difficult to perform. It is seen only between 10% and 50% of resected specimens.[7] Surgery, frequently incorporating a major hepatic resection, is thus considered as palliative rather than curative. Although surgical principles remain unchanged, significantly increased survival rates over the last decade, improvement in palliative and adjuvant management, and molecular insight into pathophysiology of the

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disease have been conducive to a new approach to CCA. It is important to establish that surgery can be performed with relative safety and to define its optimal place in the overall management strategy.

and inactivation of a number of cell cycle inhibitors as well as the repression of many tumor suppressor genes have been shown to occur in up to 83% of patients with CCA.[22, 23] In addition, inactivation of the tumor suppressor gene Semaphorin3B has been described as methylated in 100% of the studied cases.[24] Furthermore, inherited mutations that affect DNA repair genes have Risk factors [23] Because of its sporadic nature, the etiology of CCA been strongly associated with a high CCA risk. remains enigmatic and evaluation of risk factors poses Inactivation of these genes allows cells to avoid apoptosis a difficult puzzle. The most common predisposing and to undergo unrestricted proliferation and may be factor for CCA is primary sclerosing cholangitis (PSC), vigorously involved in the pathogenesis of CCA. A role is emerging for non-coding RNAs in the which has been reported in up to 40% of patients neoplastic transformation of cells. These microRNAs suffering from a specific malignancy. Although it has been shown that the risk of development of CCA is are gene-specific regulators that act as key regulators in higher within the first 2.5 years following diagnosis of numerous processes including cell proliferation, cell death development PSC, no association has yet been established between and apoptosis and are associated with the [25, 26] Increased of malignancy in various tissues. [4-8] the duration of PSC and the incidence of CCA. activation of microRNAs, such as miR-141, miR-200b In addition, patients with intrahepatic biliary stones have a 10% risk of developing CCA, while up to 70% and miR-21 involved in circadian rhythm and tumor of patients with histologically confirmed CCA have suppression, has been demonstrated in CCA patients, hepatolithiasis.[9-12] Moreover, biliary malformations while a down-regulation of microRNAs processing antisuch as Caroli's disease and congenital fibropolycystic apoptotic functions has also been noted. Alterations in disease carry a 10% to 15% risk of malignancy.[13] Liver microRNA expression may contribute to tumor growth of critical genes fluke infection is another important risk factor for the by modulating the functional expression [27, 28] involved in the development of CCA. development of CCA. Infection by Opisthorchis viverrini The development of novel cell culture models of has been demonstrated as a definite cause of human CCA could provide important research tools with which CCA, whereas infection by Clonorchis sinensis has been we investigate relevant cellular alterations and new [14, 15] linked to a higher incidence of CCA. Chronic pancreatitis, non-specific liver cirrhosis, history of possible risk factors that may be pertinent to human biliary-enteric drainage for benign disease, exposure diseases. In addition, such models can serve as the basis to environmental toxins, primarily including dioxins, for the preclinical testing of new therapeutic strategies. increased body mass index and consumption of alcohol It is also remarkable that few human CCA cell lines now have also been associated with a higher prevalence of exist, and their availability has been limited. CCA.[16, 17] Moreover, many hormones, neuropeptides, and neurotransmitters have been found to regulate malignant and non-malignant cholangiocyte pathways Symptoms: differential diagnosis Symptoms may include jaundice, clay-colored stools, in patients with chronic biliary diseases.[18] Hepatitis B (HBV) and hepatitis C (HCV) are bilirubinuria, pruritus, weight loss, and abdominal pain. established risk factors for hepatocellular carcinoma and Jaundice is the most common manifestation of bile duct their roles have been proposed in the development of cancer. The obstruction and subsequent cholestasis CCA. Various studies have demonstrated a statistically tends to occur early if the tumor is located in the significant increase of antibodies against HBV among common bile duct or common hepatic duct. Jaundice CCA patients, while up to 30% of them have antibodies often occurs later in perihilar or intrahepatic tumors against HCV.[19, 20] and is a marker of advanced disease. Abdominal pain Genetic and epigenetic changes play an integral role is relatively common in advanced disease and is often in the transfer of cholangiocytes to their malignant described as a dull ache in the right upper quadrant. counterparts. Epigenetic gene silencing refers to The differential diagnosis of biliary strictures may non-mutational gene inactivation, mainly based on be difficult to prove the wide spectrum of alternative hypermethylation of promoter sequences. Hyper- diagnoses, including PSC, gallbladder carcinoma, methylation has been shown to play a central role in pancreatic carcinoma, intraductal papillary mucinous the progression of tumor growth in almost all types tumor, or benign biliary strictures from causes such as of cancer, including CCA.[21] The hypermethylation pancreatitis. 12 • Hepatobiliary Pancreat Dis Int，Vol 10，No 1 • February 15，2011 • www.hbpdint.com

Cholangiocarcinoma: principles and current trends

Preoperative evaluation Imaging techniques including ultrasound, CT, and MRI are of limited sensitivity for the detection of CCA. However, technological breakthroughs have made multiple endoscopic modalities available for the evaluation of patients with masses of indeterminate origin and diagnosis of CCA. Endoscopic retrograde cholangiopancreatography (ERCP) is a powerful tool in the diagnosis of CCAs. It has the ability to define the anatomy of the biliary system and to determine the extent of bile duct involvement. Moreover, tissue specimens may be obtained for cytological confirmation. While cytology provides an almost 100% specificity, it carries the disadvantage of low sensitivity. Newer approaches, such as digital image analysis (DIA) and fluorescence in situ hybridization (FISH) promise better results by overcoming the restrictions of specimens with limited cellularity and offering increased sensitivity without compromising its high specificity.[29, 30] In addition, ERCP may be used for stent placement in order to provide palliation and relieve jaundice.[31] Magnetic resonance cholangiopancreatography (MRCP) is a noninvasive technique with the ability to evaluate intrahepatic lesions with a sensitivity of 86% and a specificity of 98%.[32] Unfortunately, this advantage is also its greatest disadvantage, as tissue sampling is not possible. Another available option is CT or percutaneous ultrasound-guided fine needle aspiration. This is a more difficult technique with a long learning curve; tumors are often small and isoechoic to the liver, making them difficult to access.[33, 34] Consequently, despite its good results compared with ERCP, it is less frequently used.

Surgery Surgery is the treatment of choice as it is the only potentially curative therapy for patients suffering from CCA. Tumors arising from cholangiocytes grow slowly and metastasize late during disease progression.[35] Given that in most cases CCAs are well advanced at the time of diagnosis, however, treatment options become limited and surgery ceases to be a feasible proposition. The resectability of CCA depends on the exclusion of peritoneal and distant lymph node metastases and the absence of major vascular invasion.[36] Exclusion criteria for resection include encasement of the contralateral portal vein or hepatic artery, contralateral involvement of secondary biliary radicles and lymph node metastases beyond the hepatoduodenal ligament. Peritoneal metastases that are overlooked on abdominal CT should be excluded laparoscopically.[37]

Segmentectomy or lobectomy is the preferred operation for solitary intrahepatic CCAs.[38] Removal of the caudate lobe during hepatic resection for CCA has been proposed and is widely accepted as offering improved tumor cell-free margins at minimal morbidity cost. Moreover, this procedure eliminates the most frequent site of hepatic recurrence, which is the caudate lobe.[39] Less extensive procedures have proved beneficial for less advanced disease if the resection margins are free of tumor and are the operations of choice in such instances. Major hepatectomy with systematic nodal dissection is associated with prolonged survival in patients with carcinoma involving the hepatic hilus, including those with advanced disease. Extended hemihepatectomy, with or without pancreatoduodenectomy, plus extrahepatic bile duct resection and regional lymphadenectomy, has recently been recognized as the standard curative treatment for hilar bile duct cancer. During left hepatectomy, Spiegel's lobe removal is necessary for Bismuth-Corlette type IIIb tumors, while its efficiency in type I-IIIa hilar CCA remains to be evaluated.[40] Pancreatoduodenectomy is the treatment of choice for middle and distal bile duct cancer. Major hepatectomy with pancreatoduodenectomy has been performed in selected patients with widespread disease with controversial results. In addition, en bloc resection has been linked with a better outcome but may not be technically feasible in the majority of cases, especially when there is involvement of the left hepatic duct.[41] However, in spite of optimum surgery establishing tumor cell-free margins, the absence of lymph node dissemination and despite the improvement achieved over the last decade, the 5-year survival rates still range from 13% to 44%.[5, 42-44] On the other hand, tumors associated with a bilateral lobal extension involving the secondary biliary radicles should be classified as unresectable. Unfortunately, the percentage of patients referred with advanced disease is very high, partly because of the latency and low sensitivity of the symptoms. Other contraindications for curative surgical management include unilobar disease with encasement of the contralateral portal vein or hepatic artery branch, bilateral portal vein or hepatic artery branch encasement, the presence of distant metastases, and significant comorbidities.[3, 45] Perioperative morbidity following resection of CCA has been high, ranging from 31% to 85%. Most of the reported complications are related to the biliary tree, including abscesses, bile and pancreatic leak and cholangitis, whereas others include hemorrhage and miscellaneous infections.[46] The short-term surgical

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procedure outcome has improved over the last decade and postoperative mortality ranges from 5% to 10%.[44-49] In order to increase resectability, portal vein embolization (PVE) has been proposed as adding multiple potential benefits. PVE before hepatectomy is designed to induce atrophy of the embolized lobe scheduled to be resected, while inducing compensatory hypertrophy of the preserved lobe. PVE enables safe and potentially curative extended hepatectomy in a subset of patients who would otherwise be marginal candidates for resection based on a small liver remnant size.[50-52]

Aggressive management Aggressive surgery is indicated in patients with locally advanced CCA, because they are associated with considerable postoperative morbidity and mortality. Recent advances in microvascular techniques in digestive organ surgery are responsible for placing new options on the table. Combined liver and portal vein resection and concomitant reconstruction has been applied, with significantly increased survival rates compared to nonresected patients.[53, 54] Despite the overall improvement, there is a 2-year postoperative survival after portal vein resection of 17% compared with 5% in patients without resection.[55] Several techniques can be used for portal vein reconstruction. End-to-end anastomosis, graft interposition using the iliac vein, hepatic venous segment, saphenous vein or a left renal venous patch are some of the techniques described for portal vein reconstruction without any one of them having been demonstrated as being significantly beneficial over the rest.[56-58] Combined liver and retrohepatic inferior vena cava resection and reconstruction using an artificial graft (ePTFE) has also been used for advanced CCAs. However, the benefits emerging from this technically difficult process are far from proven.[59, 60] In addition, hepatopancreatoduodenectomy has been proposed as a possible alternative technique.[61, 62] An aggressive approach, including portal vein resection combined with major liver resection, should be limited to young patients with locally advanced CCAs that are considered unresectable by standard liver resection. As this surgery has been carried out at experienced centers, the reported postoperative morbidity and mortality rates are within an acceptable range. Moreover, negative margins may be achieved in 80% of cases and this is directly associated with improved survival.[53] Fiveyear actuarial survival with the aggressive approach has been described as high as 32%.[63] Local resection Local resection is widely considered to be safer

than liver resection and can be considered in patients with Bismuth type I hilar CCA.[64] Its mortality is significantly lower; in some studies no mortality has been described after local excision compared with extended procedures. Moreover, the morbidity rates are reduced about 50% after local resection, compared with rates in patients who undergo extended procedures.[5, 65] One of the greatest disadvantages of this procedure lies in the fact that radicality may significantly drop as low as 28%, while the absence of negative margins increases the incidence of recurrence.[66] In earlier reports, the 5-year survival rates were significantly lower after local resection than after extended surgery (7% vs. 17%). In these studies, it is likely that patients undergoing local resection had tumors with or without minimal involvement of the bile duct confluence, which could explain the unsatisfactory results.[5, 45] On the other hand, numerous large studies have shown no evidence of any statistical difference in survival between local resection and extended surgery.[67-69] Furthermore, it has been proposed that local surgery may be beneficial compared to radical resection in strictly selected cases of patients with small, early stage tumors. One such study demonstrated a 5-year survival rate after local resection of up to 27%, a marked improvement on the 5-year survival rate after associated liver resection of just 6%.[70] However, local resection is an inadequate treatment for hilar CCA involving the bile duct confluence; in this instance, liver resection should be recommended. Notwithstanding, it represents an attractive option for selected patients with early stage CCA, who could be benefitted by a notably better short-term outcome and without cost in long-term survival.

Is there a role for liver transplantation? Liver transplantation for CCA remains a controversial subject. However, the prospect of achieving negative margins within the liver and accomplishing a radical resection has rendered transplantation an attractive option. In fact, this technique may only be used for hilar CCAs, as transplantation for intrahepatic or extrahepatic tumors is fraught with high recurrence rates and rapid metastases of the tumor (peritoneal spread, or distant metastases). For this reason, it has been abandoned.[71] Extrahepatic nodal disease or metastases are also contraindications to liver transplantation. In addition, recent multicenter series have reported unsatisfactory results with 3-year survival rates of less than 30% and a 26-month median time to recurrence.[72-74] However, selected patients with early stage CCA can

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be treated with liver transplantation within a research protocol. Preliminary results have shown that liver transplantation combined with external-beam radiation, systemic 5-FU and brachytherapy can be a treatment of choice for highly selected early stage patients. Another therapeutic approach, which combines liver transplantation and preoperative aggressive neoadjuvant therapy, has produced more promising results with 5-year survival rates reaching 71%. This remarkable improvement in survival could possibly be accredited to a better control of locoregional cancer by neoadjuvant therapy, as CCA resection failures are usually thought to be the result of locoregional recurrence rather than distant metastases.[42, 75, 76] As prioritization for deceased donor liver allocation is a highly controversial matter and the prolonged waiting time has been recognized as an adverse prognostic factor, this protocol may only be applied to highly selected patients (younger than 45 years, who develop CCA as a result of PSC with early stage hilar CCA.[76, 77] In summary, the aim to expand the indications for liver transplantation for CCA reflects the efforts of transplant surgeons to provide an effective form of therapy for a previously untreatable disease. In this regard, liver transplantation for CCA should continue in the context of an allocation system that includes the severe organ availability, patient disease factors, and waiting times.

Palliative treatment Palliative surgery in patients with CCA offers an alternative to an aggressive surgical approach, with significantly better short-term outcomes. Patients with intrahepatic CCA have shown no survival benefits from palliative resection over curative resection. Consequently, with the exception of highly selected patients, those with such a malignancy should be excluded from palliative management.[78, 79] Palliative resections have a relevant beneficial impact on the outcome of patients with distal and hilar CCA. Long-term survival has been reported as relatively high and efficiency is noteworthy.[80, 81] Surgical drainage procedures have not been demonstrated to be superior to non-operative palliation with respect to procedure-related mortality and survival. Non-surgical stenting should be regarded as the first choice of palliative biliary drainage for patients with hilar CCA and for those with distal CCA and short life expectancy. For patients with distal CCA and longer projected survival, a surgical bypass should be considered.[82-84] Photodynamic therapy (PDT) has been used in

palliative management with encouraging results. It is a minimally invasive procedure and is based on photosensitizers that are chemical compounds stimulated by light of a specific wavelength. A photosensitizer is administered to the patient and the tissue to be treated is exposed to light suitable for stimulating the photosensitizer. The close proximity of the photosensitizer and an oxygen molecule creates a stimulated singlet state oxygen molecule, which induces tumor cell death through apoptosis or necrosis, occlusion and thrombosis of small vessels supporting the malignant tumor.[85-87] PDT may be used for cholestasis treatment and is reported to improve quality of life with longer survival.[88-93] Side-effects are rare and may include phototoxicity. Despite the use of PDT providing such promising data, its evaluation as an adjuvant treatment remains uncontrolled and therefore should only be regarded as palliative management.[88]

Neo-adjuvant therapy Currently, there are no adjuvant and neoadjuvant treatments available as curative treatment for patients suffering from CCA. In addition, although we know that many neo-adjuvant therapies are effective in eradicating tumors, the frequent lack of residual disease diminishes our capacity to measure the tumor response. The only objective endpoints that can be validated are diseasefree and overall survival. Neo-adjuvant chemoradiotherapy can be an option for selected patients. McMaster et al[94] reported 9 patients with extrahepatic bile duct cancer who underwent preoperative chemoradiation. A pathological complete response was obtained in 3 patients, and negative margins were obtained in all patients (100%). In patients with stage I or II cholangiocarcinoma, Rea et al[95] reported the 1-, 3-, and 5-year survival rates were 82%, 48%, and 21% after neoadjuvant radiotherapy, chemosensitization and resection respectively and the recurrence rate was 25%. This treatment requires further confirmation. As a consequence, the role of neo-adjuvant therapy remains investigational. The role of adjuvant chemotherapy in CCA is yet to be determined, with conflicting data regarding its effect on survival. Some studies[93-96] have proposed that chemotherapy prolongs survival in CCA, especially in patients with unresectable tumors. However, the result has been questioned as in many cases they were statistically underpowered and restricted to short-term follow-up. Most of the studies[96, 97] failed to show any survival benefit gained by chemotherapy. Radiation therapy has also been proposed as an alternative procedure, but the effectiveness of this

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modality remains very low. The CCA cell response to radiation is so poor that radiation therapy has been abandoned in most centers. Moreover, this procedure has been associated with a marked deterioration in patients' quality of life and significant morbidity, including gastrointestinal bleeding, biliary strictures, intestinal obstruction, and hepatic decompensation.[98-100] The combination of chemotherapy and radiation has been demonstrated to provide better results than the individual procedures, however further studies are required to support these findings.[101] In summary, chemotherapy, radiation and PDT cannot be unconditionally recommended for adjuvant therapy of CCA.

Prognostic factors Because of the increasing incidence of CCA worldwide, it is vital to identify the factors associated with a better outcome. Among numerous prognostic factors that have been described, the most important for long-term survival are negative surgical margins, lymph node status, and differentiation grade of the tumor. The most consistent independent determinant for long-term survival after potentially curative resection of a biliary tumor is the surgical margin status of the resected bile duct. Non-free margins are associated with a major decrease in survival rates and an increase in recurrence rates.[102-107] Lymphatic dissemination is also an important prognostic factor. Lymphatic node (LN) involvement is present in up to 55% of patients undergoing operation for CCA. An increased number of infiltrated LNs as well as the presence of para-aortic LNs is associated with a worse outcome. A 5-year survival rate of 14% for patients with regional LN metastases and of 12% for those with positive para-aortic nodes has been reported. LN micrometastasis has no impact on survival in patients with otherwise negative LNs.[107-110] Poorly differentiated adenocarcinomas are linked with lower 5-year survival rates and are commonly associated with LN dissemination. Moreover, microinvasion of small blood vessels is related to high recurrence rates.[45, 111] Portal vein invasion is a strong prognostic factor of CCA and the actual number of 5-year survivors is limited, reaching only 9.9% compared with patients without portal vein resection (36.8%).[54] Furthermore, perineural invasion of malignant cells along the nerve branches present within the biliary tract tissue has been shown to reduce survival rates.[112] Whether the TNM-based staging system is an important predictor remains controversial. Astonishingly, only a

few studies confirm higher classification according to the TNM system with lower survival rates. Controversially, several studies have failed to demonstrate any predictive value for the staging system in use.[105, 113] Low preoperative bilirubin levels are associated with better short-term as well as long-term outcome.[84, 114] Furthermore, patients who undergo combined portal vein resection have been associated with a significantly shorter time of survival compared with those who did not need portal vein resection.[107]

To stent or not to stent? Resectability rates of 20%-55% have been reported when all cases referred to a specialist surgical unit are considered,[115, 116] and for those pending surgery the respectability rates range from 30% to over 90%.[117] For those patients requiring surgery, the practice of placing a stent prior to surgery to achieve biliary decompression remains controversial. It is believed that routine preliminary decompression of the biliary tree is unnecessary. Indeed, controlled trials using preoperative percutaneous transhepatic biliary drainage have shown that as a routine procedure it provides no benefit. Stent associated biliary sepsis poses a considerable problem. In addition, a marked pericholangitic phenomenon has been observed in patients with biliary stents, in the form of surrounding edema and possible periductal fibrosis. It is postulated that this reaction is related to local sepsis and/or the presence of a foreign body. This phenomenon coupled with the presence of the biliary stent that may make it more difficult to assess the proximal extent of the tumor intraoperatively and may increase the risk of infections postoperatively. However, biliary drainage can prove extremely useful in certain circumstances, such as in cases of cholangitis. It certainly reduces liver size and turgidity and renders liver mobilization and subsequent resection technically easier. Incomplete biliary drainage accounts for the high incidence of early cholangitis ranging from 20% to 40% after placement of stents.[118] Moreover, elevated bilirubin levels and liver dysfunction are factors that adversely affect postoperative morbidity, thus advocating stent placement. Unilateral stents are typically adequate and associated with a higher success rate for stent insertion, drainage and lower early complication rate compared to bilateral stenting of both hepatic lobes.[31] Moreover, the introduction of expandable metal stents has resulted in both an improvement of successful palliation rates and a decrease in the frequency of complications. If drainage is indicated, it is important to operate within two weeks, especially if a bypass

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Eur J Gastroenterol Hepatol 2002;14:1025-1027. procedure is contemplated, to ensure an adequate duct 13 Chapman RW. Risk factors for biliary tract carcinogenesis. diameter for anastomotic reconstruction.[119-123]

Conclusion In conclusion, CCA is a rare malignancy associated with poor prognosis. The only curative treatment available is surgical management. Unfortunately, many patients present with unresectable tumors, and the majority of whom die within a year of diagnosis. Surgical treatment involves major resections of the liver, pancreas and bile duct, with considerable mortality and morbidity. However, in selected cases and where indicated, appropriate management with aggressive surgery may achieve a good outcome with a prolonged survival expectancy. Funding: None. Ethical approval: Not needed. Contributors:  ZF wrote the main body of the article under the supervision of ZGN. FA and CD provided advice on medical aspects. KK is the guarantor. Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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