Malignant Biliary Neoplasms 741

Cholangiocellular Carcinoma

Cholangiocellular carcinoma (CCC) is a primary malignant tumor arising from the bile duct epithelium and comprises 10-25% of all liver and biliary tract cancers. CCC is usually classified as intra- or extrahepatic based on the location of the involved ducts. Intrahepatic CCC can be further subdivided into peripheral and hilar. A tumor that arises peripheral to the secondary bifurcation of the left or right hepatic duct is considered a peripheral intra-hepatic CCC, whereas a tumor that arises from one of the hepatic ducts or from the bifurcation of the common hepatic duct is considered to be a hilar CCC or "Klatskin tumor", according to Klatskin's description in 1965 (Fig. 24) [31]. Peripheral or lobular intrahepatic CCC arises from the epithelium of the internal wall of the small peripheral in-trahepatic bile ducts and represents about 10% of all tumors. It tends to grow exophytically into the liver parenchyma as a large focal mass and may be polypoid or focally stenotic. Intrahepatic hilar CCC account for approximately 25% of all CCC and are usually scirrhous. Extrahepatic CCC account for approximately 65% of all CCC [31].

The liver cancer study group of Japan has recently proposed a new classification for intrahep-atic CCC as mass-forming, periductal-infiltrating, or intraductal-growing based on their growth characteristics (Fig. 25) [42]. In the mass-forming type, the lesion may be solitary or multiple and possess satellite nodules around the main mass. The periductal infiltrating type of CCC grows

Hepatic Tumors Classification
Fig. 24. Bismuth classification of hilar cholangiocellular carcinoma (Klatskin tumors)

Fig. 25. Intrahepatic cholangiocellular carcinoma: new classification of the liver cancer study group of Japan

Bismuth Ccc

Fig. 25. Intrahepatic cholangiocellular carcinoma: new classification of the liver cancer study group of Japan along the bile duct wall, resulting in concentric thickening of the wall along the bile duct leading to an elongated, spiculated, or branch-like appearance. The bile ducts are narrowed or nearly completely obstructed, and the involved segments vary in length. The intraductal-growing variant is characterized by the presence of intraluminal papillary tumors of the intra- or extrahepatic bile ducts associated with partial obstruction and dilatation of the bile ducts. The tumor fills sometimes and occludes the bile ducts.

Primary sclerosing cholangitis, choledochal cyst, familial polyposis, congenital hepatic fibrosis, infection with the Chinese liver fluke Clonorchis sinensis, and history of exposure to Thorotrast are risk factors for CCC [ 14,38].A mutation in the p53 tumor suppressor gene has been demonstrated in peripheral-type CCC, in contrast to the k-ras mutations observed in lesions that affect the extra-hepatic bile ducts [39,63].

Patients diagnosed with CCC tend to be older than those with HCC; CCC occurs most frequently in patients in their sixth decade, although patients with risk factors may develop the neoplasm at a much younger age. CCC occurs slightly more frequently in men than in women.

The histologic variants of CCC include: adenocarcinoma, mixed CCC-HCC, squamous-, mu-coepidermoid-, cystadeno- and granular cell carci-noma.Adenocarcinoma comprises 95% of the cases, and can range from well-differentiated mucin-producing, to poorly-differentiated [44]. Distinguishing morphological features allow further sub-classification of bile duct adenocarcinomas into papillary, sclerosing, and nodular variants. The sclerosing type is most common, followed by papillary and nodular cholangiocarcinoma [73].

The gross appearance of CCC is a grayish-white, firm/solid, fibrous mass. The cut section usually presents as sclerotic gray-white or pale white, with dense fibrous stranding. Typically, CCC has a large central core of fibrotic tissue that is relatively devoid of neoplastic cells. Cancer cells are mainly located at the periphery of the tumor. Daughter nodules can be found throughout the liver, both close to and distant from the main mass. Generally CCC is not highly vascularized, and hemorrhage and necrosis are uncommon.

CCC arising from the common bile duct appears as a rounded, relatively small intraluminal mass. It is usually located within the mid-extra-hepatic biliary tree either at the distal common hepatic duct or at the common bile duct. The neo-plastic cells have abundant connective tissue stro-ma and produce a variable desmoplastic reaction. The surrounding liver parenchyma is generally non-cirrhotic. Histologically, it is often difficult to distinguish CCC from metastases of adenocarci-noma. In more than 60-70% of cases, hilar or hepatoduodenal ligament lymph nodes are involved.

The clinical signs and symptoms are related to the site of origin of the tumor. In intrahepatic CCC, the symptoms are usually vague until the tumor is at an advanced stage when patients frequently present with anorexia, weight loss, abdominal pain, and a palpable mass in the upper abdomen. Fever may occur but is uncommon. Jaundice is rarely a presenting symptom in intrahepat-ic CCC, although it is common in hilar or ductal CCC [31]. There are no specific tumor markers for CCC, although elevations of serum carcinoembry-onic antigen (CEA) and CA 19-9 are often found

Mri Images The Liver

Fig. 26a, b. Hilar cholangiocellular carcinoma. US (a) reveals an ill-defined heterogeneous mass (asterisk) with dilated bile ducts (white arrows). An ill-defined infiltrative mass (asterisk) from the hilus through the hepatic parenchyma is also seen (b). Some bile ducts around the mass appear dilated (white arrowheads)

Fig. 26a, b. Hilar cholangiocellular carcinoma. US (a) reveals an ill-defined heterogeneous mass (asterisk) with dilated bile ducts (white arrows). An ill-defined infiltrative mass (asterisk) from the hilus through the hepatic parenchyma is also seen (b). Some bile ducts around the mass appear dilated (white arrowheads)

Heterogeneous Nodular Liver
Fig. 27a, b. Peripheral cholangiocellular carcinoma . On US, the neoplasm (asterisk) appears as a well-defined heterogeneous nodule (a) or as an ill-defined mass (b) compared to the surrounding parenchyma

[71]. Elevation of alkaline phosphatase and y-glu-tamyltransferase may be seen and patients may be hypoalbuminemic and mildly anemic.

On US scans, CCC may have mixed echogenicity or may be predominantly hypoechoic or hypere-choic. The sonographic features of Klatskin's tumor include duct dilatation, isolation of the right and left bile duct segments, mass or bile duct wall thickening at the hilus as well as lobar atrophy with crowded, dilated bile ducts. US is accurate for revealing the level of bile duct obstruction, but it shows tumor mass in only 20-70% of patients. When a mass is seen, it is usually poorly defined and echogenic, a reflection of the submucosal, scirrhous nature of this fibrotic neoplasm (Fig. 26) [10,20].

Peripheral CCC may appear as an ill-defined mass with mixed echogenecity (Fig. 27) with or without segmental bile duct dilatation. A hypoe-choic halo is observed in 33% of cases. Sometimes the central portion of the tumor appears hypoechoic due to the presence of necrosis. Hy-perechoic spots with acoustic shadowing indicate the presence of calcifications. The infiltrative pat tern of growth of CCC appears as diffuse architectural changes in the hepatic lobe. Satellite nodules may be seen. Color Doppler US shows scanty color signal because of CCC hypovascularity. This is a useful sign for the differential diagnosis of HCC, which is typically a hypervascular neoplasm. Focally stenotic or papillary CCC often cause segmental bile duct dilatation and may induce lobar atrophy if the location of the tumor is central.

CCC is usually hypodense or isodense relative to the normal liver parenchyma on unenhanced CT scans. After administration of contrast material, most CCC remain hypodense during the portal-venous phase but thereafter show enhancement on delayed phase images. This pattern of enhancement reflects the hypovascular, desmoplas-tic composition of most CCC; therefore, most lesions are better appreciated 15-20 minutes after contrast medium administration. Small necrotic regions are common in larger lesions. Segmental or diffuse bile duct dilatation is a common finding in hilar CCC (Fig. 28) [10].

Peripheral type CCC may simulate other hepatic neoplasms, such as metastases or hypovascular HCC. Its most common pattern consists of a hypo-dense ill-defined lesion on unenhanced CT scans, poor, rim-like enhancement during the arterial and portal-venous phases, and iso- or hyperdensi-ty on delayed phase images (Fig. 29). Other factors such as the grade of the tumor, distribution of fi-brosis, and contrast pooling can affect the delayed enhancement. Peripheral wash-out is another sign that can be seen on contrast-enhanced CT of peripheral CCC.

CCC is either isointense or hypointense relative to the normal liver on T1-weighted MR images, but may range from markedly to mildly hyperintense on T2-weighted images. The signal intensity of the tumor is variable, and depends on the amount of mucinous material, fibrous tissue, hemorrhage and necrosis within the tumor [70]. On dynamic T1-weighted MR images acquired after the intravenous administration of gadolinium, minimal or moderate incomplete enhancement is seen at the tumor periphery on early images, whereas progressive central contrast-enhancement is seen on later images (Fig. 30) [70].

The degree of enhancement varies with the type of tumor. Greater peripheral enhancement is noted in the early phases in large CCC, whereas greater enhancement is noted in the fibrous core of scirrhous CCC on delayed phase images (Fig. 31). Small, incidentally discovered intrahepatic CCC, as well as mixed CCC/HCC tumors can show intense, homogeneous enhancement during the arterial phase with prolonged enhancement on delayed phases due to marked hypervascularity [70,74].

Generally, lesions show peripheral hypointensi-ty and central iso- or hyperintensity on delayed phase images after the administration of contrast agents with liver-specific properties (Fig. 30, 31). However, the central area may also show incomplete enhancement. Satellite nodules are seen in about 10-20% of CCC cases and are chiefly responsible for the poor prognosis of this lesion (Fig. 32). Pooling of contrast within the tumor, and peripheral wash-out on delayed MR images are suggestive findings of CCC in non-cirrhotic patients. This characteristic enhancement pattern reflects the large amounts of fibrous tissue, neovascularity, and neoplastic cells at the periphery of the lesion.

A significant signal drop of the lesion is not detected after SPIO administration, and therefore the neoplasm appears significantly more hyperintense than normal liver parenchyma.

The use of MRC in conjunction with MRI permits the extent of the tumor in bile ducts to be determined. With this technique hilar obstruction and some segment dilatations can be easily diagnosed.

A common finding on all imaging techniques is the presence of lymphoadenopathy. Lymph nodes are typically large and round and hypoechoic, hy-podense, and hypo- or hyperintense on US, CT, and MR studies, respectively, and show uptake of isotope on positron emission tomography (PET) examinations (Fig. 33).

Biliary Cystadenocarcinoma

Biliary cystadenocarcinoma is a rare cystic neoplasm that can arise within liver cysts, bile ducts, and in the context of polycystic liver disease. It also arises as a result of the malignant transformation of biliary cystadenoma. Since malignant degeneration of biliary cystadenoma may require as few as ten years, resection of cystadenoma is recommended.

As in biliary cystadenoma, there exists two forms of biliary cystadenocarcinoma, those with and those without ovarian-like stroma. Microscopically, the neoplasm may contain either mucinous or serous material although mucus is more common. These lesions are sometimes asymptomatic and are therefore discovered incidentally. More frequently patients present with pain, jaundice, nausea, and fever [51].

Unlike cystadenoma, biliary cystadenocarcinoma appears as a multiloculated complex cystic mass with irregular wall thickness, internal septa-tions, and papillary projections on US and CT. MR imaging reveals irregular walls, internal septa-tions, mural nodules and papillary projections within the lesion. The solid portions show enhancement after intravenous administration of gadolinium contrast agent [8].

Biliary Cystadenocarcinoma

Fig. 28a-c. Hilar cholangiocellular carcinoma. On unenhanced CT (a) and early post-contrast dynamic phase CT (b), the neoplasm (white arrows) appears as an ill-defined hypodense mass located near the hilum. Bile duct dilatations (arrowhead are also evident. On delayed phase images after contrast medium administration the lesion is seen as hyperattenuating (c)

Fig. 28a-c. Hilar cholangiocellular carcinoma. On unenhanced CT (a) and early post-contrast dynamic phase CT (b), the neoplasm (white arrows) appears as an ill-defined hypodense mass located near the hilum. Bile duct dilatations (arrowhead are also evident. On delayed phase images after contrast medium administration the lesion is seen as hyperattenuating (c)

Cholangiocarcinoma Cystadenocarcinoma

Fig. 29a-c. Peripheral cholangiocellular carcinoma. On unenhanced CT (a) the lesion (asterisk) appears as a well-defined hypodense mass. Minimal enhancement is seen on images acquired during the portal-venous phase after administration of contrast material (b) while in the equilibrium phase (c) the neoplasm is seen as heterogeneously hyper-dense compared to the liver, which is due to abundant fibrotic desmoplastic reaction

Biliary Cystadenocarcinoma

Fig. 30a-h. Hilar cholangiocellular carcinoma. On the unenhanced T2-weighted TSE image (a) the neoplasm (white arrows) appears slightly heterogeneously hyperintense compared to the normal liver and involvement of the bile duct system can be seen. On the unenhanced Tl-weighted GRE image (b) the lesion appears as a slightly hypointense ill-defined mass. Poor enhancement is seen during the arterial phase after the bolus administration of Gd-BOPTA (c). However, desmoplastic reaction causes a progressive increase of contrast enhancement in subsequent acquisitions during the portal-venous and equilibrium phases (d and e, respectively). After 20 minutes the lesion (arrowhead) appears hyperintense (f). Due to the large amount of fibrotic tissue which causes non-specific contrast agent retention, the lesion retains this hyperintense appearance on images acquired one hour after Gd-BOPTA administration (g). Nevertheless, the presence of a hypointense peripheral rim indicates the malignant nature of the lesion. The involvement of hilar bile ducts (arrow) is clearly demonstrated with MRCP (h)

Fig. 30a-h. Hilar cholangiocellular carcinoma. On the unenhanced T2-weighted TSE image (a) the neoplasm (white arrows) appears slightly heterogeneously hyperintense compared to the normal liver and involvement of the bile duct system can be seen. On the unenhanced Tl-weighted GRE image (b) the lesion appears as a slightly hypointense ill-defined mass. Poor enhancement is seen during the arterial phase after the bolus administration of Gd-BOPTA (c). However, desmoplastic reaction causes a progressive increase of contrast enhancement in subsequent acquisitions during the portal-venous and equilibrium phases (d and e, respectively). After 20 minutes the lesion (arrowhead) appears hyperintense (f). Due to the large amount of fibrotic tissue which causes non-specific contrast agent retention, the lesion retains this hyperintense appearance on images acquired one hour after Gd-BOPTA administration (g). Nevertheless, the presence of a hypointense peripheral rim indicates the malignant nature of the lesion. The involvement of hilar bile ducts (arrow) is clearly demonstrated with MRCP (h)

Bopta Mrcp

Fig. 31a-f. Peripheral cholangiocellular carcinoma. The neoplasm (white arrow/) appears heterogeneously hyperintense on unenhanced T2-weighted images (a) and hypointense on unenhanced T1-weighted images (b). Moderate peripheral enhancement is seen on images acquired during the arterial (c) and portal-venous (d) phases after the administration of Gd-BOPTA. On the equilibrium and delayed phase images (e and f, respectively) the enhancement appears progressive and complete due to desmoplastic reaction. A hypointense rim ( white arrowheads) indicating peripheral wash-out can be seen on the delayed-phase image

Fig. 31a-f. Peripheral cholangiocellular carcinoma. The neoplasm (white arrow/) appears heterogeneously hyperintense on unenhanced T2-weighted images (a) and hypointense on unenhanced T1-weighted images (b). Moderate peripheral enhancement is seen on images acquired during the arterial (c) and portal-venous (d) phases after the administration of Gd-BOPTA. On the equilibrium and delayed phase images (e and f, respectively) the enhancement appears progressive and complete due to desmoplastic reaction. A hypointense rim ( white arrowheads) indicating peripheral wash-out can be seen on the delayed-phase image

Mri Images The Liver

Fig. 32a, b. Cholangiocellular carcinoma. On the unenhanced T2-weighted image (a) a large heterogeneously hyperintense mass (asterisk and numerous satellite nodules (arrowheads) can be seen. On the image acquired during the hepatobiliary phase after injection of Gd-BOPTA (b), the biggest nodule shows central enhancement and peripheral wash-out while the smaller satellite nodules (arrowheads) remain hypointense

Fig. 32a, b. Cholangiocellular carcinoma. On the unenhanced T2-weighted image (a) a large heterogeneously hyperintense mass (asterisk and numerous satellite nodules (arrowheads) can be seen. On the image acquired during the hepatobiliary phase after injection of Gd-BOPTA (b), the biggest nodule shows central enhancement and peripheral wash-out while the smaller satellite nodules (arrowheads) remain hypointense

Hypodense Artifacts
Fig. 33a, b. Cholangiocellular carcinoma. The post-contrast CT scan (a) shows a homogeneous, slightly hypodense, lymphoadenopathy (arrow) adjacent to the portal vein. The lesion is confirmed on the PET examination (b) as a nodule that shows isotope uptake (arrow)
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