see also:

• neoplasia / cancer / tumours
• cirrhosis
• hepatitis

• globally, liver cancer is the 5th most common cancer in men, and the 7th most common in women
• 80-90% have cirrhosis as the main risk factor
• it is rare < 40 years age, and reaches a peak at 70 years age
• hepatocellular carcinoma due to HCV is the fastest rising cause of cancer-related death in the Western world, with incidence in USA tripling over past 20 years while 5yr survival rate remains below 12%.
• surveillance using alpha fetoprotein levels (20ng/ml cutoff gives sensitivity only 25-65%) and US imaging every 6-12 months for those with cirrhosis but no cancer may reduce mortality of hepatocellular carcinoma by up to a third.¹⁾

• chronic inflammation within the liver is a key driver which results in accumulation of DNA mutations as well as epigenetic changes
• hepatitis B virus drives genomic instability
• HCC often develops from dysplastic nodules within a cirrhotic liver, following a progression of molecular alterations and clonal expansion of transformed hepatocytes
• several key molecular pathways are abnormally activated in HCC
  • Wnt/β-Catenin Pathway:
    • promotes cell proliferation, stemness, epithelial-mesenchymal transition (EMT), migration, and invasion. Mutations in genes like CTNNB1 (β-catenin) and loss of inhibitors result in pathway activation.
  • RAS/RAF/MEK/ERK and PI3K/AKT/mTOR:
    • drive cell growth, survival, angiogenesis, and metabolism
    • antioxidant-1 (ATOX1) promotes HCC carcinogenicity through the c-Myb/PI3K/AKT signaling pathway while inhibiting copper accumulation, ROS generation, and apoptosis²⁾
      • the compound DCAC50, by obstructing ATOX1's copper transport function, effectively suppresses the malignant behavior of HCC cells
  • JAK/STAT:
    • influences cell proliferation and the immune microenvironment
  • Hippo and Hedgehog (Hh) Pathways:
    • regulate cell proliferation, apoptosis, stem cell renewal, and are associated with metastasis and therapy resistance.
  • activation of receptor tyrosine kinases (RTKs), TGF-β, and other growth factor pathways also play roles
• immune evasion and immune dysfunction
  • including suppression of cytotoxic T-cell responses, recruitment of immunosuppressive cells (like tumor-associated macrophages), and secretion of immunoregulatory factors
  • chronic viral infections and the tumor microenvironment further impair immune surveillance, allowing malignant transformation and growth
• angiogenesis and tumour microenvironment
  • HCC tumours secrete angiogenic factors (e.g., VEGF) supporting blood vessel growth, which is crucial for tumor expansion and metastasis.
  • tumour microenvironment, including hypoxia and extracellular matrix remodeling (e.g., via MMPs), supports invasion and metastasis

• cirrhosis
  • 5 year cumulative risk of hepatocellular carcinoma in patients with cirrhosis 5-30% depending upon:
    • cause: highest risk with HCV
    • region/ethnicity: Japan 30%, USA 17%
    • stage of cirrhosis: highest risk is among those with decompensated disease
  • globally, chronic HBV infection accounts for 50% of all cases, and virtually all childhood cases
    • although HBV can cause cancer without cirrhosis, 70-80% of cancer patients due to HBV have cirrhosis
    • risk of cancer with chronic HBV increases if either:
      • stage of cirrhosis
      • long duration of HBV infection
      • male
      • elderly
      • FH hepatocellular carcinoma
      • exposure to mycotoxin aflatoxin
      • have used alcohol or tobacco
        • in patients with HBV, each daily consumption of 12 g of alcohol increased the risk of cirrhosis by 6.2% and the risk of HCC by 11.5% ³⁾
      • co-infected with HCV or hepatitis delta virus
      • high levels of HBV hepatocellular replication (ie. high levels of HBV DNA)
      • infected with HBV genotype C
  • HCV infection confers a 15-20x risk of hepatocellular carcinoma (but most of this risk is limited to those with advanced hepatic fibrosis or cirrhosis)
    • HCV epidemics: Japan 1920's; southern Europe 1940's; Nth America 1960's-70's;
    • in patients with hepatocellular carcinoma, HCV markers are found in 80-90% if Japanese, 44-66% if Italian, 30-50% if USA.
    • risk factors of hepatocellular carcinoma with HCV infection include:
      • older age at time of infection
      • males
      • coinfection with HIV or HBV
      • possibly diabetes or obesity
      • chronic heavy alcohol intake
  • prolonged heavy use of alcohol
    • daily ingestion > 40g alcohol increases risk independently by 1.5-2x, and in combination with HCV, and to a lesser extent HBV infection
• non-alcoholic fatty liver disease
  • appears to be a 1.5-2.0x risk factor for hepatocellular carcinoma but requires further study
  • 90% of obese patients have fatty liver disease, while up to 70% of type 2 diabetics have fatty liver disease

• 4 phase (unenhanced, arterial, venous and delayed) CT scan
  • should be adequate to give a diagnosis of focal hepatic mass > 2cm diameter in patients with cirrhosis
  • patients with lesions 1-2cm diameter generally require confirmation with dynamic contrast-enhanced MRI or an alpha-fetoprotein level > 400ng/ml
• atypical features or the absence of cirrhosis may require image guided biopsy for diagnosis
  • if biopsy negatiev, further studies should be done at 3-6 month intervals until it either disappears, grows larger, or displays diagnostic characteristics.