CLINICAL PRACTICE

Diagnosis and Treatment Update: Cholangiocarcinoma

Indra Wijaya, Murdani Abdullah
Department of Internal Medicine. Faculty of Medicine, University of Indonesia-Dr.Cipto Mangunkusumo Hospital. Jl. Diponegoro no. 71 Jakarta Pusat 10430, Indonesia. Correspondence mail to: leon_natan@yahoo.com

ABSTRACT Cholangiocarcinoma is a rare and very aggressive neoplasm that arises from the biliary epithelium, constitutes approximately 2% of all reported cancer, and accounts for about 3% of all gastrointestinal malignancies. Up to date, there are many modalities to diagnosis and treat with a range of sensitivity and specificity, and also the advantage and disadvantage of its modality. As a physician, we should be able to assess and choose promptly which modality is best for our patient, even for paliative care. Treatment modalities are surgery and non-surgery like adjuvant chemotherapy, radiation, chemoradiation, radiotherapy, TACE, 5-FU chemoinfusion, intralesion PEI, photodynamic therapy, liver transplantation, and paliative therapy. The choice of treatment varies individually. Radical surgery remains the optimal therapy and offering a potential for cure. Overall prognosis in these patients is poor and survival is limited to a few months. Key words: cholangiocarcinoma, diagnosis, management.

INTRODUCTION

Cholangiocarcinoma is an uncommon malignancy arising from the epithelial cells of the biliary tract. These tumors may arise anywhere along the intrahepatic or extrahepatic biliary tree. Patients with cholangiocarcinoma typically present at advanced stages, and cure rates are low, even with aggressive therapy. It is estimated that there are 500 new cases annualy in USA and the incidence is increasing with advance imaging technology. Patient with cholangiocarcinoma are predominantly male with age 50-70 years old.1,2 Diagnosis of cholangiocarcinoma should be based on good anamnesis and adequate examination because its variety of clinical manifestations is confounded by a lack of effective therapy modality.3 The exact cause of cholangiocarcinoma is unknown, and most cases occur sporadically, but there are several well-defined risk factors. The most common of these is primary sclerosing cholangitis (PSC) and the clinical features of cholangiocarcinoma depends on the location of the tumor.
DEFINITION

Cholangiocarcinoma is a malignant biliary duct tumor, arising from abnormal growth of biliary duct which can be derived from intrahepatic and extrahepatic. More than 90% cases are adenocarcinoma and the rest are squamous cell tumor.4
CLASSIFICATION

Malignancy in the biliary tract system can be divided into cancer of the gall bladder, extrahepatic duct, and ampulla of Vateri, whereas intrahepatic tumor is classified as primary liver cancer and cholangiocarcinoma is cancer of biliary duct. Perihilar
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Diagnosis and Treatment Update: Cholangiocarcinoma

tumor is the most common form and intrahepatic tumor accounts for the rare one.4 Cholangiocarcinoma can be classified according to its location and morphology. According to its location, it can be divided into 3 regions which are intrahepatic, hilar, and distal extrahepatic. According to its morphology, the non-hilar lesion can be divided into mass-like form, periductal or intraductal, and mixed type of mass-like and periductal, whereas extrahepatic lesion can form sclerotic, nodular, and papillary type. Cancers arising in the perihilar region have been further classified with Bismuth-Corlette classification, which divided into 4 types: Type I: Tumors below the confluence of the left and right hepatic ducts. Type II: Tumors reaching the confluence. Type III: Tumors occluding the common hepatic duct and either the right or left hepatic duct. Type IV: Tumors that are multicentric, or that involve the confluence and both the right or left hepatic duct. This classification is used for treatment decision and epidemiological study.5

For unclear reasons, the incidence of intrahepatic cholangiocarcinoma has been rising over the past two decades in Europe and North America, Asia, Japan, and Australia, while rates of extrahepatic cholangiocarcinoma are declining internationally, with man has five times higher rate than woman.7
ETIOLOGY

A number of risk factors for cholangiocarcinoma have been recognized, although a specific risk factor cannot be identified for many patients, some of them are:8 Age > 65 year old. Primary Sclerosing Cholangitis (PSC), with or without ulcerative colitis. Chronic cholelithiasis intraductal. Adenoma of cystic duct and biliary papillomatosis. Carolis disease. Choledochus cyst. Toxigenic agent. Smoking and alcohol consumption. (related to PSC) In South East Asia: - Chronic infection of Opisthorchis.viverrini and Clonorchis.sinensis. - Chronic typhoid carrier.
DIAGNOSIS

Figure 1. Cholangiocarcinoma classification. (A) By location. (B) By morphology. (C) Bismuth-Corlette classification.5

EPIDEMIOLOGY

Report from National Cancer Institute Surveillance, Epidemiology and End Results (SEER) 2006 in US shows there are 18.510 cases of primary liver cancer with 15% of cases are intrahepatic cholangiocarcinoma.6

Diagnosis should be based on good anamnesis, physical examination, laboratory, and imaging. Cholangiocarcinoma can be asymptomatic in the early stage and symptomatic if theres biliary obstruction, usually with symptoms like pruritus, abdominal pain, weight loss, fever, tea-colored urin, and pale feces.9 Laboratory in patient with biliary obstruction will reveal with increase of direct bilirubin (>10 mg/ dl), alkali phosphatase (2-10x), and GGT can be within normal limit. In advance stage, there can be hypoalbuminemia and elevation of LDH.9 There is no specific tumor marker and no evidence that tumor marker levels are related to progressivity of tumor. Generally, the sensitivity and specificity of the tumor marker is low but is useful if used as combination. CA 19-9, Carcinoembryonic antigen (CEA), and CA-125 was the most used tumor marker. In radiology, USG and CT-scan can be used before performing cholangiography. MRI gives information about hepatobilliary anatomy and local extention from tumor, liver parenchym abnormality, and liver metastases. MRCP shows the extention of billary duct involvement and MRA shows involvement of vascular hilar.9
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Cholangiography is the important modality for diagnostic and evaluation of resection accessability. It can be divided into 3 modality which are MRCP, ERCP, and Percutaneous Transhepatic Cholangiography (PTC).9

TACE, 5-FU chemoinfusion into hepatic artery or billiary duct, and PEI intralesion are still under investigation.13 Photodynamic therapy can eliminate the obstruction but not many facilities can perform this treatment.14 Liver transplantation is still contradictive because of high recurrency and average survival rate is about 3 years.15 Majority of cases, transplantation is done for cholangiocarcinoma with PSC.16 Palliative therapy with stent insertion, PTBD, or bypass can decrease biliary duct obstruction in unresectable case. Paliative therapy can be done by using drug eluting stent, but the effectiveness is still unclear. Endoscopically, plastic or metal stent can be used but metal stent has high patency rate for long term (8-12 month vs 4.8 month).17

Figure 2. Cholangiography in Klatskins tumor9

Other modalities are Endoscopic Ultrasound (EUS) dan Positron Emission Tomography (PET). EUS reveals clear imaging of distal extrahepatic billiary tract, gall bladder, regional lymph nodes, and vascular system. PET with [18F]-2-deoxy-D-glucose will show high glucose metabolism in cholangiocarcinoma cell as hot spots.9
TREATMENT

The goal of treatment is to take out the cancer and relieve the obstruction. Type of treatment depends on its tumor location and must be evaluated individually. Surgery is the mainstay of treatment if no metastases is found. Distal cholangiocarcinoma has high resectability, accounts for 91%, whereas intrahepatic is 60%, and perihilar is 56%.10 Adjuvant chemotherapy or radiation or chemoradiation can be performed following operation to reduce recurrency rate but its effectiveness is still not clear. Cholangiocarcinoma is relatively chemosensitive, mostly with 5-fluorouracil (5-FU). Combination chemotherapy with gemcitabine and cisplatin shows partial response as 3050% of cases and improving quality of life.11 Radiotherapy does not increase survival or quality of life in resectable perihilar cholangiocarcinoma. Local radiation can be implemented as intraoperatively or intraluminal brachytherapy.12
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Figure 3. Management algorithm for cholangiocarcinoma18

PROGNOSTIS

Prognosis depends on the stage, tumor location, and the success of the treatment. Predictor for poor prognostic factors are lymphadenopathy, vascular invasion, and p53 gene mutation. Best results are with distal CBD tumors completely excised (cure

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Diagnosis and Treatment Update: Cholangiocarcinoma

rate 40%), incomplete resection plus radiation gives a median survival of 30 months, stenting plus chemo/ radiation gives a median survival of 17-27 months, with surgery and chemo/radiation is about 24 to 36 months, with chemo/radiation alone is about 12 to 18 months, those stented alone live only a few months. Five years survival rate of cholangiocarcinoma with surgical treatment is 9-18% for proximal lesion and 20-30% for distal lesion.19
CONCLUSION

Cholangiocarcinoma is a biliary duct neoplasm that arises from biliary epithelium, accounts for about 3% of all gastrointestinal malignancies and more than 90% of cases are adenocarcinoma. Diagnosis of cholangiocarcinoma is based on anamnesis, physical examination, laboratory examination, and radiology including USG, CT-scan, EUS, PET, and cholangiography (MRCP, ERCP, PTC). Treatment modality depends on the tumor location, can be surgical and non-surgical like adjuvant chemotherapy, radiation, chemoradiation, radiotherapy, TACE, 5-FU chemoinfusion, intralesion PEI, photodynamic therapy, liver transplantation, and paliative therapy (stent, PTBD, bypass surgery). Prognosis depends on the stage, tumor location, treatment modality, and the success of the treatment.
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