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)
Pathogenesis
chronic inflammation within the liver is a key driver which results in accumulation of DNA mutations as well as epigenetic changes
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
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:
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
Diagnosis
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.