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the evidence for the role of opisthorchia-sis in the induction of ICC is compelling {2009, 2008}. Carcinogenesis is probably related to the length and severity of infection, the host's immune response, and other variables such as ingestion of dietary carcinogens, for example nitro-samines. In northeast Thailand, several carcinogenic N-nitroso compounds and their precursors exist at low levels in the daily diet {1230}. In addition, endogenous nitrosamine formation by liver fluke infection has been reported {1673}. Both exogeneous and in situ nitrosamine formation may lead to DNA alkylation and deamination {1346}. It seems that the presence of parasites induces DNA damage and mutations as a consequence of the formation of carcinogens/free radicals and of cellular proliferation of the intrahepatic bile duct epithelium.

Hepatolithiasis

Hepatolithiasis (recurrent pyogenic cholangitis), which is not uncommon in the Far East, is also associated with ICC {1857, 1321}. It is frequently observed in clonorchiasis {746} but not in opisthor-chiasis. Most of these cases are associated with calcium bilirubinate stones; a few cases with cholesterol stones have also been reported. Patients with intrahepatic stones and ICC have a significantly longer duration of symptoms and a higher frequency of previous biliary surgery.

Inflammatory bowel disease and primary sclerosing cholangitis

Patients with primary sclerosing cholan-gitis (PSC) and ulcerative colitis (UC) have a predisposition to develop col-orectal neoplasia and also bile duct carcinoma, including ICC {672, 1993, 194, 2078}.

Epstein-Barr virus (EBV) infection

Rare examples of ICC have a lymphoep-Ithellomatous, undifferentiated pattern. Clonal EBV has been found in such cases {757, 2025}.

Non-biliary cirrhosis

There are several reports of ICC arising in non-biliary cirrhosis, particularly hepatitis virus-related liver cirrhosis {2159, 1940}. HCV is frequent in such cases and ICC is usually of a smaller, mass-forming type. Such ICC and combined hepatocellular-cholangiocarcinomas share apomucin profiles {1669}, suggesting that these two tumours have a similar or common histogenesis, or that ICC associated with cirrhosis might be the result of exclusive proliferation of the cholangiocellular component of the combined type. Genotypes of hepatitis B and C viruses have been shown in cholangiocarcinoma cells {2049, 1787}.

Deposition of Thorotrast

Thorotrast is a radioactive a-particle emitter that was widely used as a radio-opaque intra-arterial contrast medium between 1930 and 1955. ICC has been recorded in many patients with prior exposure to Thorotrast. The data suggest that the chronic alpha-irradiation may be the causative factor, with latent periods ranging from 25 to 48 years.

Biliary malformations and other lesions

ICC may arise rarely in solitary unilocular or multiple liver cysts, congenital segmental or multiple dilatation of the bile ducts (Caroli disease), congenital hepatic fibrosis, and von Meyenburg complexes {736, 2165}.

Clinical features

The site of the tumour, its growth pattern and the presence or absence of stricture

Fig. 8.31 Cholangiocarcinoma, CT images. A The right lobe contains a mass and shows peripheral bile duct dilation. B Arrows indicate a peribiliary spreading type.

Fig. 8.30 Ultrasonography of an intrahepatic cholangiocarcinoma. A hyperechoic mass is present in a dilated bile duct.

Fig. 8.31 Cholangiocarcinoma, CT images. A The right lobe contains a mass and shows peripheral bile duct dilation. B Arrows indicate a peribiliary spreading type.

Fig. 8.30 Ultrasonography of an intrahepatic cholangiocarcinoma. A hyperechoic mass is present in a dilated bile duct.

or obstruction of the biliary tree are responsible for the variable clinical features of ICC.

Symptoms and signs

General malaise, mild abdominal pain and weight loss are frequent clinical symptoms. When the carcinoma infiltrates the hilar region, jaundice and cholangitis become manifest. ICCs, particularly those arising from the small bile ducts, may go unnoticed until they have attained a large size. The liver is enlarged to a lesser extent, ascites is less common, and signs of portal hypertension are absent or minimal. Patients with unrelieved obstruction of the intrahepatic large bile ducts may die from complications, e.g. liver failure or sepsis.

Imaging

Advanced cases of ICC show mixed growth and spreading patterns with intrahepatic metastases. Computerized tomography (CT) images of ICC usually show a lobulated or fused hypodense space-occupying lesion with peripheral enhancement, probably due to central hypocellular dense fibrosis. Secondary dilated ducts around the tumour are detectable by CT and ultrasonography. A focal area of carcinoma involving the bile duct wall is identifiable by spiral CT. Endoscopic retrograde, transhepatic or magnetic resonance cholangiography is a useful adjunct for the identification of the level of biliary obstruction and secondary bile duct dilatation. ICCs at relatively early and surgically resectable stages are classifiable into three representative types of growth patterns {1080}, and these patterns, which are evaluable by imaging studies, can be useful for the preoperative staging of

Fig. 8.32 Macroscopic features of intrahepatic cholangiocarcinoma. A Cut surface shows massive tumour and multiple intrahepatic metastatic nodules. Surrounding liver is non-cirrhotic. B White, scar-like mass in a normal liver (mass forming types) together with dilated peripheral bile ducts. C Intraductal growth type of intrahepatic cholangiocarcinoma.

Fig. 8.32 Macroscopic features of intrahepatic cholangiocarcinoma. A Cut surface shows massive tumour and multiple intrahepatic metastatic nodules. Surrounding liver is non-cirrhotic. B White, scar-like mass in a normal liver (mass forming types) together with dilated peripheral bile ducts. C Intraductal growth type of intrahepatic cholangiocarcinoma.

tumour extent and for designing the surgical procedure. The mass forming type is an expansile nodule and is the most common. The tumour borders between the cancerous and noncancerous portions are relatively clear. The contrast enhanced CT scan shows a low-density tumour with peripheral ring-like increased density. The periductal-infiltrat-ing type, which is usually associated with biliary stricture, is relatively common. The tumour exhibits diffuse infiltration along the portal pedicle. This type resembles hilar or extrahepatic bile duct carcinoma. The contrast enhanced CT demonstrates a small cancerous enlargement of the portal pedicle, or a mass central to the dilated peripheral ducts. The anatomical location of the involved ducts can be evaluated by caliber changes or the rigidity of the bile duct on high-quality cholangiographic images. The intraduc-tal growth type (intraductal papillary cholangiocarcinoma) is less common {351}. These tumours are confined within the dilated part of an intrahepatic large bile duct, with no or mild extension beyond the bile duct walls. Some tumours of this type of ICC might have arisen from biliary papillomatosis after malignant transformation. Marked localized dilatation of the affected duct is detectable by ultrasound or CT. Cholangiography shows filling defects in the biliary tract, due to polypoid tumours and mucin.

Macroscopy

ICC can arise from any portion of the intrahepatic bile duct epithelium {61, 1418}. Lesions are gray to gray-white, firm and solid, although some tumours show intraductal growth, sometimes with polyp formation. Typical tumours consist of variably sized nodules, usually coales-cent. Portal tract infiltration is also seen. Central necrosis or scarring are common, and mucin may be visible on the cut surfaces. ICC cases involving the hepatic hilum are hardly distinguishable from hilar cholangiocarcinoma, and such cases show cholestasis, biliary fibrosis, and cholangitis with abscess formation. ICC is not often noted in a non-cirrhotic liver.

ICC in endemic areas of liver fluke infection is similar to that described in non-endemic regions; liver flukes are rarely seen nowadays due to mass treatment. In hepatolithiasis-associated ICC, the tumour tends to proliferate and spread along the stone-containing ducts. The liver lobe or segments containing stones involved by ICC are atrophic in some cases.

Tumour spread

ICC shows direct spread into the surrounding hepatic parenchyma, portal pedicle and bile duct. Intrahepatic metastases develop in nearly all cases at a relatively advanced stage. Vascular invasion is a frequent histological finding relatively early, suggesting the development of early metastasis. The incidence of metastases in regional lymph nodes is higher than in HCC. Blood-borne spread occurs later, to the lungs in particular; other sites include bone, adrenals, kidneys, spleen, and pancreas.

Fig. 8.33 Intrahepatic cholangiocarcinoma. A Well differentiated tubular adenocarcinoma. B Moderately differentiated tubular adenocarcinoma.

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