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HeikkiMäkisalo

Cancer of the Liver and the Biliary Tract

Essentials

  • Hepatocellular carcinoma usually develops secondary to a chronic liver disease, nowadays increasingly to non-alcoholic fatty liver disease (NAFLD) Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH).
  • Cancer of the bile ducts, i.e. cholangiocarcinoma, is a disease of older men, but when its development is related to chronicinflammation of the bile ducts (primary sclerosing cholangitis, PSC Primary Sclerosing Cholangitis) it may occur even in under 30-year-olds.
  • The presence of gallstones Cholelithiasis predisposes the patient to gallbladder cancer.
  • Radiological examinations carried out in primary care play a significant role in the early detection of hepatocellular carcinoma and biliary tract cancer.

Epidemiology

  • Two thirds of patients with hepatocellular carcinoma are male and a large share of them have cirrhosis or other chronic liver disease. PThe increasing incidence of NAFLD causes particular concern since it is detected in up to 35% of patients diagnosed with hepatocellular carcinoma.
  • Cholangiocarcinoma also generally affects the older population, but when it is associated with PSC the patients can be quite young. It has been estimated that up to 10% of patients with PSC will develop cholangiocarcinoma during their lifetime. This has led in Finland to regular monitoring of patients with PSC by multi-slice imaging and endoscopic retrograde cholangiopancreaticography (ERCP).
  • There is considerable worldwide variation in the incidence of gallbladder cancer. The majority of patients are older than 64 years. Gallbladder cancer affects women more often than men, and in about four out of five cases it develops in a gallbladder with stones. Gallbladder cancer has been detected in 1-3% of cholecystectomies.

Symptoms

  • Hepatocellular carcinoma is asymptomatic for a long period, and weight loss, tiredness and a palpable mass in the upper abdomen are already late symptoms of the tumour.
  • The tumour may cause decompensation of the underlying cirrhosis (ascites, encephalopathy or jaundice), corresponding to Child stage B or C. The tumour may also cause occlusion of the portal vein as well as intestinal haemorrhages. Hepatocellular carcinoma may also rupture and cause severe bleeding and tumour seeding into the abdominal cavity. The treatment consists of immediate palliative arterial embolization.
  • Peripheral cholangiocarcinoma is associated with weight loss, tiredness and, in some cases, elevation of the body temperature. The first sign of central cholangiocarcinoma located in the porta hepatis is painless jaundice.
  • The presence of gallstones may cause symptoms and lead to the diagnosis of gallbladder cancer; however, symptoms caused by tumour growth, weight loss, pain and jaundice are signs of an advanced disease.

Diagnosis

Hepatocellular carcinoma

  • Weight loss and a palpable mass are signs of a large or multifocal hepatocellular carcinoma. However, extrahepatic metastases develop late.
  • Hepatocellular carcinoma over 2 cm in size in a cirrhotic liver has a typical appearance in a CT scan, and often findings typical for cancer established by two imaging methods are sufficient for making the diagnosis.
  • Alpha-fetoprotein (AFP) is elevated in 80% of cases with large tumours and in 50% of cases with small foci. A significantly increased level or in two consecutive samples increasing level are strongly suggestive of hepatocellular carcinoma. Tumour diagnostics, however, should take place within specialized care. A histological biopsy of the tumour may be necessary in unclear cases and to aid the decision making of oncological treatment options.
  • As patients with liver cirrhosis have a 1-4% yearly risk of developing cancer, it is recommended that those who have stopped alcohol consumption should be followed up by ultrasound every 6 months.

Cancer of the biliary tract and gallbladder

  • Peripheral cholangiocarcinoma, which has its origin in the small biliary ducts, is asymptomatic for a long period and, when detected, often large in size.
  • Central cholangiocarcinoma, which originates from the major bile ducts, causes early obstruction of the bile ducts leading to jaundice.
  • When a tumour is suspected, a CT scan and MRI scan should be perfomed definitely before the invasive investigations. ERCP can be recommended over PTC (percutaneous transhepatic cholangiography) for obtaining cytological samples.
  • Half of all gallbladder cancers are detected in association with surgery performed because of cholelithiasis.
  • Should a preoperative ultrasound examination be suggestive of a gallbladder tumour, the patient needs to undergo preoperative CT scanning.

Treatment

Hepatocellular carcinoma

  • The state of liver function plays a crucial role when considering treatment options. The first-line treatment option is an attempt to remove the tumour with surgical resection. However, this is possible only in 15-30% of cases due to extensive disease or cirrhosis.
  • Even quite large tumours can often be safely removed from a healthy liver, but only smaller ones from a cirrhotic liver. If liver function is impaired, carcinoma foci may be treated - instead of by surgery - by radiofrequency or microwave ablation, in which heat is conducted to the tumour through a needle under ultrasound guidance, or by chemoembolization through an arterial catheter.
  • Liver transplantation may be indicated if the hepatocellular carcinoma is limited and transplantation criteria are fulfilled.
  • Multikinase inhibitor sorafenib and protein kinase inhibitor lenvatinib are available as palliative pharmacotherapy.

Cancer of the biliary tract and the gallbladder

  • Surgery is the treatment of choice in cholangiocarcinoma. About 40% of peripheral cholangiocarcinomas, and 20-25% of central cholangiocarcinomas, are suitable for surgery. The surgical resection needed is often extensive, and simultaneous partial hepatic resection is also always needed, except in distal cholangiocarcinoma.
  • In some rare cases, even a liver transplant operation may be considered as a treatment for hepatic portal cholangiocarcinoma.
  • Palliative treatment of advanced cholangiocarcinoma includes relief of possible jaundice by insertion of stents and an evaluation of need for cytostatic therapy.
  • Gallbladder cancer is treated surgically, but the cancer is operable in one third of the cases only. If the cancer was diagnosed within a gallstone operation, an additional operation is required later. In advanced cholangiocarcinoma and cancer of the gallbladder, relatively good responses have been acquired by cytostatic chemotherapy.

Prognosis

Hepatocellular carcinoma

  • The five-year survival rate is around 50% at the most, after both surgery and radiofrequency ablation. The patient's prognosis is, however, often defined by the stage and progress of cirrhosis. About 75% of patients selected for liver transplantation under strict criteria survive more than 5 years post-transplant.

Cancer of the biliary tract and the gallbladder

  • After surgery, the five-year survival rate among patients with peripheral cholangiocarcinoma is about 50% and among those with central cholangiocarcinoma 20-30%. The life expectancy can be more than two years even after palliative treatment.
  • The prognosis of gallbladder cancer is dependent on the stage of the cancer. Over 75% of the patients are alive 5 years after the surgery in cancer that is localised in the muscle layer of the gallbladder wall, but under 30% of the patients with cancer that invades the full thickness of the wall.

Follow-up after treatment

  • After treatment, it is highly likely that hepatocellular carcinoma recurs or a completely new cancer appears in a cirrhotic liver within a 10-year follow-up period. Therefore the patients are monitored and new tumours treated whenever possible.
  • In cholangiocarcinoma and gallbladder cancer, the most that follow-up will be able to offer is an earlier commencement of cytostatic therapy in recurrent disease.
  • It is not possible to offer indefinite follow-up in specialist health care even for patients with treated hepatocellular carcinoma. Regular ultrasound examinations and AFP measurements should therefore become the responsibility of the primary care about two years after treatment.
    • These investigations should be carried out every six months for at least five years and thereafter annually for up to 10 years.
    • Even a slight increase in the AFP concentration from the baseline is indicative of recurrence. If a tumour is not visible by imaging, the test should be repeated after a few weeks. Constantly increasing concentration indicates the disease recurrence.