Liver is one of the most common anatomic sites for metastatic spread of cancers from other organs while primary liver cancer is less frequent. Hepatocellular carcinoma (liver cell cancer) is the most common type of primary liver cancer. It is frequent in Southeast Asia, especially China and sub-Saharan Africa, while it is less common in developed countries, except Japan, Italy, and France. There is a striking difference in the age of patients between world regions. In Asia and Africa, it predominantly affects males between 30 and 50 years of age, and in Europe, North America, and Japan it is more common in men older than 60 years. The liver is also the primary site for intrahepatic cholangiocarcinomas (intrahepatic bile duct cancers) that are relatively rare and account for 10-20% of all primary liver cancers. These tumors occur in older individuals, usually after the age of 60.
Both hepatocellular and cholangiocarcinoma are associated with chronic liver diseases leading to long-term liver damage, inflammation, and cirrhosis. The main risk factors for hepatocellular carcinoma are heavy alcohol consumption, infection with hepatotropic viruses such as hepatitis B and C viruses (HBV, HCV), exposure to aflatoxins, nonalcoholic steatohepatitis, and inborn errors of metabolism such as α-1 antitrypsin deficiency and Wilson disease. Common underlying risk factors for cholangiocarcinoma are a parasitic infestation of the liver (Clonorchis Sinensis), multiple bile duct hamartomas, intrahepatic lithiasis, primary sclerosing cholangitis, and congenital liver diseases (congenital hepatic fibrosis, Caroli disease).
Some of the common symptoms of liver cancer are unintentional itching, yellowing of the skin and eyes (jaundice, weight loss, nausea, enlarged liver or spleen, and fluid build-up in the abdomen. Serum elevation of α-fetoprotein occurs in a large proportion of patients (up to 75%) with hepatocellular carcinoma.
Histologically, hepatocellular carcinomas present a range of appearances. A common feature is the presence of fibrosis and inflammation as hepatocellular carcinoma often develops in the liver of patients with late stages of chronic hepatitis. In well-differentiated tumors, tumor cells resemble normal hepatocytes and may be difficult to determine as malignant. The more poorly differentiated tumors display marked pleomorphism, with giant cells showing little resemblance to normal hepatocytes. Intracellular bile production is sometimes a feature of tumor cells that aids in their classification. A sinusoidal growth pattern and absence of intracellular mucin are characteristic features of hepatocellular carcinoma. Rare histological variants include scirrhous, fibrolamellar, clear cell, and steatohepatic hepatocellular carcinoma. Gland formation is a more typical feature of cholangiocarcinoma and heterogeneity of tumor cells in the same gland is a typical trait. Mucin stains are almost always positive in the tumor cells. Classification of intrahepatic cholangiocarcinoma into large bile duct- and small bile duct types is based on anatomic location and association to bile ducts of different sizes.
Immunohistochemistry is often used to discriminate hepatocellular and cholangiocarcinoma from metastasis. Hepatocellular carcinomas are immunoreactive for α-fetoprotein, various keratins, CD10, Arginase-1 (ARG1), Glypican 3 (GPC3), Heat shock protein family A member 1A (Hsp70), and an antibody called hepatocyte in paraffin 1 (HepPar1) targeting liver mitochondrial proteins. Markers more indicative of cholangiocarcinoma are certain keratins (KRT7, KRT19), maspin (SERPINB5), epithelial membrane antigen, and carcinoembryonic antigen. Molecular investigations of DNAJB1-PRKACA genes fusion or mutations in TSC1 and TSC2 genes, and in promoter region of hTERT gene have role in the diagnosis of hepatocellular carcinoma and its rare variants.
Treatment of patients with hepatocellular and cholangiocarcinoma depends on the tumor size and overall stage of the disease. In localized disease, treatment modalities include surgical resection or tumor ablation, and even liver transplantation. The median overall survival depends on the stage of the disease and available treatment options, and it ranges from 3 months to 6 years for hepatocellular carcinoma and 8 to 25 months for cholangiocarcinoma.