Epidemiology

Hepatobiliary cancer is the sixth most common malignant tumour in the world. The highest incidences are seen in South East Asia. In the United Kingdom, hepatobiliary cancer is relatively uncommon. In 2011, 4348 men and women were registered with liver cancer and sadly 4106 died. The male to female ratio for liver cancers is 1.7:1 and the risk rises with increasing age with 90% diagnosed in people over 55 years of age. In the United Kingdom the 5-year survival for patients with this cancer is just 5% (see Table 9.1).

Pathogenesis

Chronic HBV infection is prevalent in up to 15% of males in certain populations and the lifetime risk of developing HCC is 40% in this group of men. An epidemiological study of 22,707 Taiwanese male government employees followed over 10 years found that the relative risk of liver cancer was 98 for men with HBV. To put this risk into context, the relative risk for lung cancer amongst smokers is around 17. In a study from the National Cancer Centre in Korea, 74.6% of the patients with HCC were HBV positive. The HBV genome encodes four proteins: C (core protein), P (a DNA polymerase), S (surface antigen) and X (whose function is not clear but acts as a weak oncogene) (see Chapter 2). How chronic HBV causes cancer is unclear, but it is thought that the constant proliferation of hepatocytes caused by the need to replace virus-damaged cells and the chronic inflammatory response in the liver are the main culprits. Support for this hypothesis comes from HCV-induced liver cancer. HBV and HCV are very different viruses genetically, but both cause similar chronic infection and inflammation of the liver and both are associated with a high risk of liver cancer.

In terms of the model for chemical carcinogenesis, these viruses appear to act as tumour promoters rather than initiators. This is supported by synergism in risk between chronic HBV infection and mutagens such as aflatoxin B1. Aflatoxin B1 is derived from the fungus Aspergillus fumigatus which commonly infects foods such as peanuts that are stored in damp conditions and which causes mutation of p53. In one study from China, the relative risk of liver cancer in people with chronic HBV was 7, in those exposed to aflatoxin was 3, but in those exposed to both chronic HBV and aflatoxin was 60.

HCC are associated with other causes of chronic liver damage including alcoholism and other hepatitides causing cirrhosis such as primary biliary cirrhosis, haemochromatosis and acute and chronic hepatic porphyrias (acute intermittent porphyria, porphyria cutanea tarda, hereditary coproporphyria and variegate porphyria).

Tumours of the biliary tree are divided into (Figures 9.1 and 9.2):

• intrahepatic bile duct cancers (which are treated in the same way as HCCs).
  
• perihilar cholangiocarcinomas (also known as Klatskin tumours) occurring at bifurcation of hepatic ducts.
  
• extrahepatic cholangiocarcinomas.
  
• gallbladder cancers.

Biliary tree tumours occur at increased frequency in primary sclerosing cholangitis with a lifetime risk of developing cholangiocarcinoma of 10–20%. Congenital conditions that cause dilatation of the biliary tract such as choledochal cysts and Caroli’s disease also transform into cholangiocarcinoma in 25% of patients. Gallstones and cholecystectomy do not influence the risk of biliary tree cancer. In South East Asia, where these tumours are common, they are seen in association with biliary infestation with liver flukes (Clonorchis sinensis and Opisthorchis viverrini) that affect 30 million people worldwide (see Table 2.12).

The aetiology of hepatoblastoma is not known. Hepatic angiosarcoma is associated with exposure to the vinyl chloride monomer (VCM), choloroethene (C₂H₃Cl) that is polymerized to the plastic polyvinyl chloride (PVC), that is used to make everything from vinyl records and PVC trousers to guttering and catheters. The mechanism for this is not clear, and the development of this tumour does not always occur in those men and women who have the heaviest exposure to VCM, as for example, in those workers involved in autoclave cleaning in chemical works. When workers exposed to VCM are examined for their lifetime risk of developing angiosarcoma this is overall clearly four times higher than in the general population. Where there is a coincident HBV infection, the risk increases 25-fold compared with the general population.

Prevention

Presentation

Characteristically, patients with cholangiocarcinoma present with obstructive jaundice and usually require biliary drainage. This can be achieved either by a radiologist placing a percutaneous transhepatic biliary drain (PTBD) or by endoscopic retrograde cholangiopancreatogram (ERCP) and placement of a biliary stent. Histological confirmation of the diagnosis of cholangiocarcinoma is usually made at ERCP with needle aspiration or brush cytology or by radiological guided percutaneous biopsy.

Staging and grading

Treatment

Liver resection is the only treatment that offers a chance for cure for liver cancer. Surgery is limited by the degree of spread of the tumour and the presence or absence of background cirrhosis. The aim of surgery generally is to remove the lobe of the liver containing the tumour. Liver transplantation is potentially curative for patients with solitary HCC <5 cm or up to 3 nodules all <3 cm yielding 5-year survival rates above 70%; however, just 10% of patients with liver cancers have operable tumours. When curative surgery is not possible, hepatic transarterial chemoembolization (TACE), percutaneous tumour ablation including radiofrequency ablation sclerotherapy (see Figure 3.12) and systemic anticancer therapy may be appropriate (Figure 9.3). Sorafenib, an oral receptor tyrosine kinase inhibitor that inhibits angiogenesis, has emerged as a valuable palliative treatment for unresectable HCC that prolongs median overall survival from 5.5 to 9.2 months. Unfortunately, treatment with this agent is not allowed in England as a result of an inappropriate, in the view of most oncologists and their patients, decision by NICE.

Cholangiocarcinomas are chemosensitive but rarely operable. A combination of gemcitabine and cisplatin chemotherapy is currently the gold standard treatment for inoperable cholangiocarcinoma.

Prognosis

Five-year survival for patients with operable liver cancer is in the order of 33% when management involves partial liver resection. The 5-year survival of patients transplanted is 80%. The median survival of patients who are not treated with curative intent is 6–7 months (Table 9.2). The median survival of patients in the Far East is much poorer, and the vast majority die within 2–3 months of diagnosis.

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