Epidemiology and management of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a major world health problem because of the high incidence and case fatality rate. In most patients, the diagnosis of HCC is made at an advanced stage, which limits the application of curative treatments. Most HCCs develop in patients with underlying chronic liver disease. Chronic viral hepatitis B and C are the major causes of liver cirrhosis and HCC. Recent improvements in treatment of viral hepatitis and in methods for surveillance and therapy for HCC have contributed to better survival of patients with HCC. This article reviews the epidemiology, cause, prevention, clinical manifestations, surveillance, diagnosis, and treatment approach for HCC.

Fig. 1

Risk factors of primary liver cancer and estimated attributable fractions in different parts of the world. (From Bosch FX, Ribes J, Diaz M, et al. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004;127:S5; with permission.)

Fig. 2

Two major signaling pathways activated by HBV and HCV in hepatocarcinogenesis. Cytosolic β-catenin is normally phosphorylated by a complex of adenomatous polyposis coli (APC), Axin, and glycogen synthase kinase 3β(GSK3β) and then degraded by the proteasome (dotted lines). Increased Wnt expression by HCV core protein activates Wnt/β-catenin pathway. GSK3β, APC, Axin complex is dissociated by Dishevelled and this results in the accumulation of cytosolic and nuclear β-catenin, which interacts with T-cell factor (TCF) and lymphoid enhancer binding protein (Lef), leading to the expression of target genes that stimulate liver cell proliferation. (A) HBx protein inactivates GSK3β via Src. This inactivation eventually results in the accumulation of nuclear β-catenin and increases the expression of genes involved in liver cell proliferation. (B) HCV NS5a protein interacts with p85. This interaction leads to the activation of Akt. Activated Akt phosphorylates Bad and decreases apoptosis of liver cells. At the same time, Akt phosphorylates GSK3β, thereby preventing proteasomal degradation of β-catenin. (C) HBx protein increases the cytosolic calcium level, leading to activation of the Ras-Raf-ERK and Ras-MEKK-JNK cascades. AP-1, activator protein-1; ERK, extracellular signal-regulated kinase; IRS-1, insulin receptor substrate-1; JNK, jun, N-terminal kinase; PI3K, phosphatidylinositol-3 kinase. (Modified from Branda M, Wands JR. Signal transduction cascades and Hepatitis B and C related hepatocellular carcinoma. Hepatology 2006;43(5):891; with permission.)

Fig. 3

Algorithm for HCC diagnosis suggested by the American Association for the Study of Liver Disease. (Modified from Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208; with permission.)

Fig. 4

Treatment recommendation according to the modified BCLC staging classification. PEI, percutaneous ethanol injection; RFA, radiofrequency ablation; TACE, transarterial chemoembolization; TARE, transarterial radioembolization.

Fig. 5

Treatment effect of radioembolization (TheraSphere treatment). (A) Contrast-enhanced CT of the abdomen with biphasic imaging of the liver found a 2.6×1.9-cm mass (white arrow) located near the portal vein bifurcation. This mass was treated with radioembolization because of the patient’s older age, tumor location, and increased bilirubin. (B) One month after the treatment, the mass immediately adjacent to the right portal vein has decreased to 1.4 cm (white arrow). (C) Three months after the treatment, the previously noted hepatic mass adjacent to the right portal vein has decreased further in size (white arrow) and is difficult to differentiate from the background heterogeneous enhancement. Patient has survived for more than 3 years since the treatment without any evidence of recurrence.

Fig. 6

Mechanism of the antitumor effect of sorafenib. Sorafenib has dual antitumor effects. (1) Inhibition of vascular endothelial growth factor/platelet-derived growth factor signaling; (2) inhibition of Raf kinase-1 activities.