T1

Angiogenesis vi hfl

Fig. 8.27 Malignant progression in a HCC (T1) with new tumour clones (T2, T3). Only T3 shows a mutation in TP53. Macroscopy shows typical 'nodule-in-nodule' pattern. Neo-angiogenesis (arrow) is restricted to one of the nodules.

Growth factors

Transforming growth factor-beta (TGF-ß) was expressed at a high level in 82% of HCCs and was associated with HBV infection {756}. TGF-ß expression could be part of a chain of events by which HBV contributes to the development of HCCs. TGF-ß 1, TGF-ß2, and TGF-ß3 showed marked mRNA overexpression in HCCs {818, 12}. TGF-ß was expressed in both tumour and stroma cells; this suggests that TGF-ß may play a role in hepatocar-cinogenesis through both autocrine and paracrine pathways {12}. The mannose-6-phosphate / insulin-like growth factor-II receptor (M6P/IGF2R) regulates cell proliferation through interactions with TGF-ß and IGF II. A study from the U.S.A. reported LOH at the M6P/IGF2R locus and mutations of the remaining allele were identified in 61% and 55% of HCCs, respectively {2149}, while no M6P/IGF2R mutations were detected in HCCs from Japanese patients {2031}. Angiogenic growth factors. mRNA expression of basic fibroblast growth factor (bFGF) was high in HCCs {1746}. Strong immunoreactivity for bFGF was localised in the progressed HCC component but not in the early-stage component of a nodule-in-nodule HCC {712}. Acquisition by cancer cells of the capacity to produce bFGF could be an important event in the stepwise progression of HCC. Greater mRNA expression of vascular endothelial growth factor (VEGF) was found in 60% of HCCs and was significantly correlated with the intensity of tumour staining in angio-grams. This suggests that VEGF contributes significantly to angiogenesis during hepatocar-cinogenesis {1239, 1869}.

DNA methylation

DNA methyltransferase (DNMT1) mRNA expression was significantly higher in chronic hepatitis and cirrhotic nodules than in normal livers, and was even higher in HCCs {1863}. Indeed, DNA hyper-methylation at D16S32, TAT, and D16S7 loci on chromosome 16 is frequently present even in chronic hepatitis and cir-rhotic nodules {885}. The incidence and degree of aberrant DNA methylation increased in HCCs compared with chronic hepatitis and cirrhotic nodules

{885}. Aberrant DNA methylation may participate even in the early developmental stages of HCCs by predisposing some loci to allelic loss or silencing specific genes {885}.

DNA methylation around the promoter region of the E-cadherin tumour suppressor gene, which is located on 16q22.1, was detected in 46% of chronic hepatitis and cirrhotic nodules and in 67% of HCCs {884}. DNA hypermethylation around the promoter region correlated significantly with reduced E-cadherin expression in HCCs {884}. The HIC-1 (hypermethylated-in-cancer) tumour suppressor gene was identified at the D17S5 locus. DNA hypermethylation at the D17S5 locus was detected in 44% of chronic hepatitis and cirrhotic nodules and in 90% of HCCs {883}. LOH at this locus, which was preceded by DNA hypermethylation, was detected in 54% of HCCs {883}. The HIC-1 mRNA expression level of chronic hepatitis and cirrhot-ic nodules was significantly lower than that of normal livers, and that of HCCs was even lower {883}. Thus, silencing of tumour suppressor genes by aberrant DNA methylation is a significant event during hepatocarcinogenesis.

Prognosis and predictive factors

The prognosis of patients with HCC is generally very poor, particularly in cases with AFP levels greater than 100 ng/ml at the time of diagnosis, partial or complete portal vein thrombosis, and presence of a TP53 mutation {45, 1861}. Spontaneous regression has been reported rarely. Most studies report a five-year survival rate of less than 5% in symptomatic HCC patients. HCCs are largely resistant to radio- and chemotherapy. Long-term survival is likely only in patients with small, asymptomatic HCC that can be treated by surgical resection, including liver transplantation, or non-surgical methods, including percutaneous etha-nol or acetic acid injection and percutaneous radiofrequency thermal ablation.

Intrahepatic cholangiocarcinoma Y Nakanuma ASY Leong

B. Sripa T. Ponchon

V. Vatanasapt K.G. Ishak

Definition

An intrahepatic malignant tumour composed of cells resembling those of bile ducts. Intrahepatic (or peripheral) cholangiocarcinoma (ICC) arises from any portion of the intrahepatic bile duct epithelium, i.e. from intrahepatic large bile ducts (the segmental and area ducts and their finer branches) or intrahepatic small bile ducts. Cholangiocarcinoma arising from the right and left hepatic ducts at or near their junction is called hilar cholangiocar-cinoma and is considered an extrahepat-ic lesion.

Epidemiology

Incidence and geographical distribution

ICC is a relatively rare tumour in most populations but second among primary malignant liver tumours; about 15% of liver cancers are estimated to be ICC {61, 2162, 1467}. The frequency of ICC among all liver cancers ranges from 5% in males and 12% in females in Osaka, Japan, to 90% in males and 94% in females in Khon Kaen, Thailand {1467, 1471} (Fig. 8.29).

The highest incidence of ICC is found in areas of Laos and North and Northeast Thailand suffering from endemic infection with the liver fluke, Opisthorchis viverrini. In 1997, the age standardized incidence of ICC in Khon Kaen (Thailand) was 88 per 100,000 in males and 37/105 in females {1467, 1471}. About 90% of the histologically confirmed cases of liver cancer in Khon Kaen are ICC, and almost all the ICC cases were found to be related to chronic O. viverrini infection {2006, 2007}. In the Clonorchis sinensis endemic area in Korea, there is also a high incidence of liver cancer with truncate incidence rates (35-64 years group) of 75 per 100,000 in males and 16 per 100,000 in females {23}. About 20% of liver cancers in Pusan, Korea, are ICC {871}.

Time trends

In both endemic and non-endemic areas, there have been no significant changes in the incidence of ICC in recent years {61}. It is less than 10 years since O. viverrini drug therapy was initiated; since it probably takes 30 years for ICC to complicate opisthorchiasis, the trends of ICC are probably not likely to change in the next decade {2007, 2009}.

Age and sex distribution

Patients with ICC are elderly, with no clear sex differences. ICC occurs at rather older ages than hepatocellular carcinoma (HCC) in most clinical series {1419}.

Aetiology

Although many aetiological factors have been characterized, the cause of ICC remains speculative in many cases.

Parasites

Clonorchis sinensis parasitizes the bile ducts of millions of individuals in the Far East, particularly China and Korea

Fig. 8.28 Histology of the liver fluke, Opisthorchis viverrini, in a hepatic bile duct.

{1467}. Early reports from Hong Kong have shown that 65% of patients with ICC were infected by C. sinensis {747}. However, the incidence of C. sinensis infection in the general population was also similarly high at that time {308}. ICC from this cause appears to less frequent in recent years.

By contrast, infection of O. viverrini is continuing in Northeast Thailand, and

Fig. 8.29 Age-standardized incidence of liver cancer, per 100,000, in males, 1992 . Rates for cholangiocarcinoma and hepatocellular carcinoma are estimates. From: M. Parkin et al. {1468}

Thailand, Khon Kaen Japan, Osaka Hong Kong Japan, Hiroshima Singapore, Chinese Philippines, Manila Thailand, Chiang Mai Singapore, Malay Italy, Varese France, Bas-Rhin Switzerland, Zurich Spain (6 registries) Finland USA, SEER, Black Denmark Slovakia Scotland Israel, Jews Canada USA, SEER, White New Zealand, non Maori Australia (4 states)

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